Citations

Abstract Introduction: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive disease with limited treatment options and poor survival. This study explores how a medically supervised ketogenic diet (MSKD) impacts the gut microbiome and treatment response in patients with newly diagnosed metastatic PDAC receiving gemcitabine, nab-paclitaxel, and cisplatin chemotherapy. Methods: As part of a randomized Phase II trial, 32 evaluable patients (median age 65.9 years; 53% male), 16 were randomized to either MSKD or standard diet (SD) combined with chemotherapy. Stool samples were collected from 4 patients in the MSKD group (13 samples) and 8 patients in the SD group (23 samples). Deep shotgun metagenomic sequencing was conducted using NovaSeq (Illumina). Taxonomical and functional microbiome characterization was performed using MetaPhlAn 4.0 and HUMAnN 3.6 (The Huttenhower Lab, Harvard). Comprehensive bioinformatics analyses, using QIIME2, were performed to analyze microbiome composition and function over time. Results: Patients in the MSKD group showed better treatment responses overall. Microbiome profiles between the two groups remained distinct throughout therapy. Though not statistically significant due to sample size, MSKD patients showed lower alpha diversity (Shannon diversity; p-value=0.1339), likely reflecting reduced intake of fermentable fiber. Differential abundance analysis using the ANCOM-BC method revealed a significant enrichment of beneficial taxa in the MSKD group compared to the SD group (p<0.05, log-fold change [lfc]≥2), including Akkermansia muciniphila (linked to improved response to immune checkpoint inhibitors; p=0.017931, q=1), Intestinimonas butyriciproducens (a short-chain fatty acid [SCFA] and butyrate producer; p=3.09E-05, q=0.017), and Streptococcus thermophilus (a supporter of gut mucosal health; p=1.15E-05, q=0.006). During the course of the study, only MSKD patients showed sustained increases in Roseburia hominis (SFCA/butyrate producer; p=3.94E-05, q=0.021) and Lacticaseibacillus rhamnosus (with anti-inflammatory and immune-modulating properties; p=7.28E-19, q=3.98E-16), along with a marked reduction in potentially pro-inflammatory Actinomyces spp.(p≤4.47E-05, q≤0.024). Functional profiling showed increased abundance of cancer-relevant microbial pathways in MSKD patients, including phosphatidate metabolism (PWY-7039; involved in lipid signaling and immune regulation; p=4.36E-04, q=0.20) and allantoin degradation (PWY-5705; linked to redox balance; p=9.16E-06, q=0.004). Conversely, L-ascorbate biosynthesis V (PWY-6415) was reduced (p=3.80E-04, q=0.17), likely due to decreased D-galacturonate substrate availability from fiber restriction. Conclusion: These findings suggest that an MSKD may beneficially modulate the gut microbiome in ways that support and enhance therapeutic response in patients with PDAC. Further validation in a larger cohort is warranted to confirm these results and improve analytical resolution. Citation Format: Keehoon Lee, Derek Cridebring, Gayle S. Jameson, Denis J. Roe, Erkut Borazanci, Diana L. Hanna, Caroline G.P. Roberts, Meredith S. Pelster, Richard C. Frank, Angela T. Alistar, Alan M. Miller, J. Erin Wiedmeier-Nutor, Sandra D. Algaze, Alison R. Zoller, Sarah J. Hallberg, Betsy C. Wertheim, Joshua D. Rabinowitz, Stephen Gately, Jennifer Keppler, Sunil Sharma, Drew W. Rasco, Daniel D. Von Hoff. Ketogenic Diet Modulates Gut Microbiome Composition and Enhances Treatment Response in Patients with Advanced Pancreatic Cancer: A Phase II Study [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B094.

BACKGROUND. We developed a prospective, multicenter “registry” to evaluate the effect of extracorporeal photopheresis for lung transplant recipients who develop chronic lung allograft dysfunction (CLAD) with the bronchiolitis obliterans syndrome (BOS) phenotype (CLAD/BOS) and who are refractory to conventional standard-of-care therapy. METHODS. Data from 258 lung transplant recipients enrolled in the Registry between April 2015 and April 2022 were included in this analysis. All recorded parameters (eg, demographics), including forced expiratory volume in 1 s (FEV1) measurements and indices (FEV1% baseline, FEV1 rate of decline) at several time periods, were included in multivariate linear/logistic and Kaplan-Meier analyses to evaluate potential associations with survival. RESULTS. Mortality at 6 and 12 mo after CLAD/BOS diagnosis was 5% and 14%, whereas mortality at 6 and 12 mo after enrollment was 15% and 26%, respectively. The primary cause of death in the cohort was respiratory failure or graft failure (74%). Rate of FEV1 decline (log) at enrollment was independently associated with survival (log days) from CLAD/BOS diagnosis and enrollment (r = 0.55 and r = 0.3, respectively). The rates of FEV1 decline among survivors were lower (–77 ± 89 mL/mo) compared with nonsurvivors (–148 ± 155 mL/mo) at 6 mo after enrollment (P = 0.0001). CONCLUSIONS. The rate of FEV1 decline quantified using at least 5 FEV1 measurements is a robust surrogate outcome. We plan to use these findings to revise our randomized controlled trial to facilitate risk adjustment using FEV1 rate of decline strata at enrollment and as a scientifically valid surrogate for outcome.

ImportanceStudies suggest that everolimus may reduce the risk of rejection, cardiac allograft vasculopathy (CAV), chronic kidney disease (CKD), and cytomegalovirus (CMV) after heart transplant. Everolimus use is controversial because of data demonstrating higher infection deaths when everolimus is introduced de novo after transplant. It is unclear whether everolimus is safe and effective when initiated at 6 months posttransplant in children, a population in which median graft survival is limited to 15 years and randomized clinical trials are lacking.ObjectiveTo evaluate the safety and efficacy of everolimus combined with low-dose tacrolimus to prevent major adverse transplant events (MATEs) in children after heart transplant.Design, Setting, and ParticipantsMulticenter, randomized, open-label, clinical trial enrolling 211 patients who were alive 6 months after pediatric heart transplant at 25 US sites from February 2018 to August 2020. The last date of follow-up was April 17, 2023.InterventionsParticipants were randomized to receive everolimus and low-dose tacrolimus (n = 107) or standard-dose tacrolimus and mycophenolate mofetil (n = 104) for 30 months.Main Outcomes and MeasuresThe primary efficacy end point was the MATE-3 score at 30 months, a validated composite ordinal end point including acute cellular rejection, CAV, and CKD. The primary safety end point was the MATE-6 score, encompassing the MATE-3 score plus antibody-mediated rejection, infection, and posttransplant lymphoproliferative disorder.ResultsAmong 211 children randomized, the mean age was 8.2 (SD, 6.3) years, 97 (46%) underwent transplant for congenital heart disease, and 49 (23%) were treated for rejection before 6 months. At 30 months, the mean MATE-3 score did not differ between the 2 treatment groups (mean difference, −0.32; 95% CI, −0.90 to 0.20; P = .16). The mean MATE-6 score was no higher in the everolimus group than in the mycophenolate group (baseline-adjusted mean difference, −0.40; 95% CI, −1.81 to 0.93), meeting the success criterion for safety (noninferiority margin <3). There were no differences in graft survival, MATE-free survival, or freedom from any individual MATE. Everolimus was associated with greater improvement in estimated glomerular filtration rate at 12 months (mean difference, 10.5 mL/min/1.73 m2; 95% CI, 1.09-19.91 mL/min/1.73 m2) and a lower incidence of CMV infection (hazard ratio, 0.50; 95% CI, 0.26-0.93).Conclusions and RelevanceAmong 6-month pediatric heart transplant survivors, everolimus and low-dose tacrolimus did not differ from tacrolimus and mycophenolate in preventing the composite of cellular rejection, CAV, and CKD at 30 months. However, everolimus and low-dose tacrolimus appear to be safe based on the total burden of 6 MATEs and may be associated with improved kidney function and less CMV infection.Trial RegistrationClinicalTrials.gov Identifier: NCT03386539

Abstract Error analysis is a critical step in evaluating and improving clinical concept extraction models, the most common clinical natural language processing (NLP) task. Unlike corpus annotation, which follows standardized protocols for creating gold-standard datasets, error analysis requires nuanced judgment grounded in both clinical expertise and NLP knowledge. This is especially important given the heterogeneity of clinical text, where variations in documentation style, note structure, and terminology can substantially influence model behavior. Despite its importance, there is currently no standardized, user-level framework to support systematic error analysis in clinical concept extraction task. In this study, we developed and validated MedError, a machine-assisted, human-in-the-loop framework designed to standardize and enhance error analysis for clinical concept extraction tasks. We collected and manually curated a corpus of 1,187 unique errors from a total of 4,237 notes across three different distinct hospitals. The error categories were defined using our previously validated error taxonomy and included 480 false negatives and 707 false positives across 25 error types and 48 clinical concept categories. We evaluated the performance of three proprietary and three open-source large language models (LLMs) in automatically classifying these errors into 26 and 15 predefined categories. We further developed a machine-assisted framework, MedError, which integrates best practices in error analysis, LLM-assisted classification and reasoning, and a user-friendly interface to enable more efficient, reproducible, and context-aware error analysis. The framework supports both single-site and federated multisite error analysis, facilitating the effective translation of clinical NLP systems into real-world settings.

Abstract Meniscus allograft transplant (MAT) can provide meaningful improvement in patient outcomes in those who are otherwise meniscus deficient. A common finding in the setting of a failed MAT is meniscus extrusion. Meniscus centralization is a technique performed to reduce the meniscus to its intra‐articular location and has been shown to improve postoperative pain and function in patients with an extruded meniscus. Prior techniques have been described for meniscus centralization in the setting of a meniscus root tear or with the use of single tension devices that are tensioned after meniscocapsular fixation. We present a minimally invasive technique for meniscus centralization that can be performed in conjunction with MAT using a centralization stabilization suture and re‐tensionable root‐fixation subchondral anchors that can be secured prior to meniscocapsular fixation. Technique Video video See video under supplementary data.

Background and importance Emergency airway management in the emergency department (ED) is a high-risk procedure associated with patient outcomes. First-attempt success is a widely recognized quality metric, as multiple attempts are associated with an increased risk of peri-intubation complications. In Brazil, where emergency medicine is a recently established specialty, many ED are staffed by physicians without formal emergency medicine training. The association between emergency medicine training and intubation outcomes in this setting has not been well characterized. Objective To assess the association of physician specialty with first-attempt success and immediate peri-intubation complications in Brazilian EDs. Design Secondary analysis of a multicenter, prospective cohort study from the Brazilian Airway Registry Cooperation. Setting and participants This study included adult patients who underwent tracheal intubation in EDs between March 2022 and April 2024. Patients were excluded if the intubation occurred outside the ED, during cardiopulmonary resuscitation, or for elective procedures. Intubations performed by medical students were also excluded. Physicians were categorized by specialty as emergency medicine or nonemergency medicine. Outcome measures and analysis The primary outcome was first-attempt success; secondary outcomes included peri-intubation complications (severe hypoxemia, hemodynamic instability, and cardiac arrest). Multivariable logistic regression was used to assess the association between physician specialty and outcomes. Main results Among 2582 patients, 1087 (42.1%) were intubated by emergency physicians and 1495 (57.9%) by other physicians (mainly internal medicine and surgery). Intubations by emergency physicians were associated with a higher rate of first-attempt success [80.4 vs. 70.9%, adjusted odds ratio [aOR]: 1.63, 95% confidence interval (CI): 1.34–1.97]. There was also a higher odds of intubations without major complications (aOR: 1.20, 95% CI: 1.01–1.42). Conclusion In this study, there was a higher rate of first-attempt success in intubations performed by board-certified emergency physicians compared with other physicians working in Brazilian EDs.

Intravenous dexmedetomidine infusion (selective α 2 -adrenergic receptor agonist) 1) reduced the firing probability and strength of baroreflex control over medium-sized sympathetic action potentials in muscle sympathetic nerve activity (MSNA) and 2) attenuated the transduction of MSNA bursts to changes in blood pressure (BP) by reducing the magnitude of BP responses and increasing the time to peak BP. These data suggest that neural and vascular α 2 -adrenergic mechanisms contribute to sympathetic baroreflex regulation of human BP.