Faculty Bibliography

BACKGROUND:Metabolic syndrome is a pressing public health issue and risk factor for the development of type 2 diabetes (T2D) and cardiovascular disease (CVD), yet clinical practice is lacking in biomarkers that represent pre-clinical perturbations of the heterogenous subtypes of risk. This study aimed to characterize the baseline metabolome in relation to known clinical characteristics of risk in a sample of obese adults. METHODS:Untargeted metabolome data from N = 126 plasma samples with baseline data from a previously completed study including obese adults with metabolic syndrome. Metabolites were acquired using validated liquid chromatography mass spectrometry methods with 15-25 internal standards quantified by peak heights. Pearson's correlations were used to determine relationships between baseline metabolites, sample characteristics (e.g., age, body mass index (BMI)), and atherosclerotic clinical characteristics (e.g., high-density lipoprotein cholesterol (HDL), low-density lipoprotein cholesterol (LDL), triglycerides), adjusting for multiple comparisons using the Benjamini-Hochberg False Discovery Rate (FDR) method. Differences in metabolite levels between clinical classifications of dysglycemia (e.g., normal, prediabetes, diabetes) at baseline were assessed using ANOVA and adjusted for multiple comparisons and adjusted for covariates. RESULTS:The sample consisted primarily of female (74%) participants, predominantly white (70%), with an average age of 56 years. After FDR adjustment, two baseline metabolites were significantly associated with age (xylose, threitol), two with BMI (shikimic acid, propane-1,3-diol), one with LDL (tocopherol-alpha), and 42 with HDL cholesterol. Three metabolites were significantly associated with fasting blood glucose (FBG) levels at baseline (glucose, gluconic acid lactone, pelargonic acid). CONCLUSIONS:This study identified novel metabolite associations with known markers of T2D and CVD risk. Specific metabolites, such as alpha-tocopherol, branched-chain amino acids (BCAAs), and sugar-derived metabolites like mannose and xylose, were significantly associated with age, BMI, lipid profiles, and glucose measures. Although most sample participants had normal HDL cholesterol at baseline, 42 metabolites including branched chain amino acids were significantly associated with HDL, suggesting pre-clinical perturbations in biological pathways associated with both diabetes and cardiovascular comorbidities. Metabolomic signatures specific to prediabetes and metabolic syndrome can enhance risk stratification and enable targeted prevention strategies for T2D. Longitudinal studies are needed to understand how these associations change over time in at-risk individuals compared with controls.

INTRODUCTION/UNASSIGNED:The furosemide stress test (FST) is used to assess urine flow rate (UFR) after a furosemide bolus. FST predicts severe acute kidney injury (AKI) and renal replacement therapy (RRT) receipt in adults, with limited data in pediatric intensive care unit (PICU) patients. We implemented AKI risk stratification using the renal angina index (RAI) with urine neutrophil gelatinase-associated lipocalin (uNGAL) to guide FST in high-risk children but have not evaluated outcomes. METHODS/UNASSIGNED:We combined 2 prospective, observational studies of high AKI risk PICU patients (RAI+: ≥ 8, uNGAL+: ≥ 150 ng/ml). We compared patients who underwent FST (≥ 0.75 mg/kg i.v. furosemide) in the first week versus those who did not, and FST responders (≥ 3 ml/kg/h UFR over 4 hours) versus nonresponders. We examined UFR's predictive performance for new or persistent severe AKI or RRT receipt 2 days later. RESULTS/UNASSIGNED:< 0.001]) with optimal cutoff < 1 ml/kg/h (PPV: 68%, NPV: 86%). UFR predicted RRT receipt in patients with stage 3 AKI with similar test characteristics. CONCLUSION/UNASSIGNED:FST is used inconsistently in high AKI risk children but has prognostic utility for new or persistent severe AKI, including RRT receipt, independent of AKI stage.

Outreach medical programs refer to medical or surgical care initiatives provided by volunteer teams typically from higher income countries and last from a few days to 8 weeks. To appreciate the development and empowerment of the onsite team, the use of "Sustainable Health Programs" (SHP) has become the preferred terminology at Global Smile Foundation. This study aims to review the challenges faced with implementing SHPs and propose a framework with the goal of implementing successful and sustainable programs. The cornerstone of such success is forging long-term, bidirectional partnerships with local healthcare teams, empowering them not only with clinical skills but also with the ability to mobilize resources independently. A SHP's success is gauged by how well it strengthens the local system to carry the mission forward long after the international team departs.

PURPOSE/UNASSIGNED:Polypoidal choroidal vasculopathy (PCV) demonstrates significant prognostic variability, and the impact of age-related scattered hypofluorescent spots observed in late-phase indocyanine green angiography (ASHS-LIA) on the prognosis of PCV remains under-researched. This study aims to investigate the association between ASHS-LIA in PCV and prognosis using the AdaBoost machine learning model. DESIGN/UNASSIGNED:A cross-sectional study. PARTICIPANTS/UNASSIGNED:The study included patients diagnosed with PCV and treated with anti-VEGF therapy at 2 medical institutions between 2012 and 2021. METHODS/UNASSIGNED:We conducted a retrospective analysis of the clinical characteristics, anti-VEGF treatment history, and outcomes of the participants, classifying them based on the presence or absence of ASHS-LIA. An AdaBoost meta-estimator was applied to predict prognosis, including disease stability, injection frequency, and time to first remission, utilizing features selected through principal component analysis. MAIN OUTCOME MEASURES/UNASSIGNED:The prognostic significance of ASHS-LIA was assessed by feature importance, with the mean decrease in impurity serving as the evaluation metric. RESULTS/UNASSIGNED:< 0.001). AdaBoost models confirmed the importance of ASHS-LIA for predicting disease stability, injection demand, and time to first remission, ranking it as the third, seventh, and eighth top contributory factor, respectively. CONCLUSIONS/UNASSIGNED:Machine learning analysis identified ASHS-LIA as a negative prognostic factor in PCV, correlating with reduced disease stability, higher recurrence rates, and increased treatment requirements. These findings suggest that ASHS-LIA could serve as a valuable marker for assessing prognosis and guiding treatment strategies in PCV management. FINANCIAL DISCLOSURES/UNASSIGNED:The author(s) have no proprietary or commercial interest in any materials discussed in this article.

The treatment patterns and clinical outcomes for patients experiencing progression of disease (POD) following CD19-directed chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory (R/R) mantle cell lymphoma (MCL) are undefined. We identified all patients who received CD19-directed CAR T-cell therapy for R/R MCL therapy across 15 international centers, and studied those experiencing POD post-CAR T-cell therapy in detail. We extracted clinical/treatment/pathologic variables, and associated these features with survival outcomes. In total, 384 patients received CAR T-cell therapy, and 135 (35%) experienced POD. POD occurred at a median of 6 months following CAR T-cell therapy infusion, and most (64%) patients with POD had complete response as best response to CAR T-cell therapy. Tumor features at POD included blastoid/pleomorphic morphology in 29 of 78 (37%) patients, and TP53 mutation in 21 of 41 (51%) patients. Following POD, 17 patients received no further therapy, 13 underwent local therapy, and 105 received systemic therapy. The most common first-line systemic therapies were chemo(immuno)therapy (22 patients; overall response rate [ORR], 40%), pirtobrutinib (17 patients; ORR, 36%), and bispecific antibodies (13 patients; ORR, 67%). Among patients experiencing POD, the median progression-free survival and overall survival (OS) were 2.5 months and 5.4 months, respectively, from POD. Lack of response to CAR T-cell therapy and short time from CAR T-cell therapy infusion to POD (<3 vs 3-6 vs >6 months), among other factors, were associated with inferior OS after POD. In conclusion, we confirm the challenging prognosis for patients experiencing POD following CD19 CAR T-cell therapy for R/R MCL, and establish a benchmark for future investigations in this patient population.