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Abstract Topic Benign Disease: Gastro-Esophageal Reflux and Hiatal Hernia Background Ambulatory reflux monitoring (wireless pH or catheter-based pH-impedance) performed off acid suppression is the gold standard for diagnosing gastroesophageal reflux disease (GERD). Barium esophagram (BE), commonly used to evaluate esophageal symptoms, routinely assesses reflux, yet its diagnostic accuracy relative to ambulatory monitoring remains unclear. Existing studies are limited, relied on outdated reflux criteria, and demonstrated poor concordance with BE-based GERD diagnoses. We aimed to determine whether BE reliably identifies GERD compared with ambulatory reflux monitoring interpreted using updated Lyon 2.0 consensus criteria. Methods Retrospective analysis of adult patients that underwent BE and ambulatory reflux monitoring (wireless pH or pH-impedance) off PPI within an 8-month interval. Patients with a history of fundoplication were excluded. Esophagram was performed with standard technique and reported by radiology, considered positive for GERD if there was reflux above the thoracic inlet with or without provocative maneuvers. Reflux monitoring studies were considered positive or negative for GERD based on Lyon consensus 2.0 recommendations. Inter-rater reliability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and received operating characteristic (ROC) curve analysis were calculated for esophagram, with reflux monitoring diagnosis as the gold standard. Results 64 patients were included, 31 % male, mean age = 60 years, mean Body Mass Index = 26. GERD was diagnosed by esophagram in 20 patients (31%), and by reflux monitoring in 19 (30%). Compared to reflux monitoring, BE had sensitivity: 47%, specificity: 76%, PPV: 45%, NPV: 77%, and area under the ROC curve: 0.61 (Figure 1). Inter-rater reliability between BE and ambulatory reflux monitoring was poor (Cohen's Kappa = 0.226). Conclusion There was poor concordance between BE and ambulatory reflux monitoring for diagnosing GERD. BE overall had suboptimal diagnostic performance, with low sensitivity, and moderate specificity. Furthermore, the area under the ROC curve indicates limited ability to distinguish correctly between patients with and without GERD. These findings indicate that barium esophagram should not be relied upon as a diagnostic tool for GERD.

Abstract Topic Benign Disease: Gastro-Esophageal Reflux and Hiatal Hernia Background Ambulatory reflux monitoring off acid suppression is the gold standard for diagnosing gastroesophageal reflux disease (GERD). Barium esophagram (BE) routinely evaluates reflux, but its diagnostic accuracy remains uncertain. We assessed whether BE reliably identifies GERD compared with ambulatory reflux monitoring interpreted using updated Lyon 2.0 consensus criteria. Methods Retrospective analysis of adult patients that underwent BE and ambulatory reflux monitoring (wireless pH or pH-impedance) off PPI within an 8-month interval. Patients with a history of fundoplication were excluded. Esophagram was performed with standard technique and reported by radiology, considered positive for GERD if there was reflux above the thoracic inlet with or without provocative maneuvers. Reflux monitoring studies were considered positive or negative for GERD based on Lyon consensus 2.0 recommendations. Inter-rater reliability, sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and received operating characteristic (ROC) curve analysis were calculated for esophagram, with reflux monitoring diagnosis as the gold standard. Results 64 patients were included, 31 % male, mean age = 60 years, mean Body Mass Index = 26. GERD was diagnosed by esophagram in 20 patients (31%), and by reflux monitoring in 19 (30%). Compared to reflux monitoring, BE had sensitivity: 47%, specificity: 76%, PPV: 45%, NPV: 77%, and area under the ROC curve: 0.61 (Figure 1). Inter-rater reliability between BE and ambulatory reflux monitoring was poor (Cohen's Kappa = 0.226). Conclusion There was poor concordance between BE and ambulatory reflux monitoring for diagnosing GERD. BE overall had suboptimal diagnostic performance, with low sensitivity, and moderate specificity. Furthermore, the area under the ROC curve indicates limited ability to distinguish correctly between patients with and without GERD. These findings indicate that barium esophagram should not be relied upon as a diagnostic tool for GERD.

Abstract Distal radius fracture (DRF) open reduction and internal fixation (ORIF) is a common procedure performed across inpatient and outpatient settings. This study compared postoperative complications and healthcare utilization between these settings using a large national claims database. Patients aged 18 years and older who underwent DRF ORIF were identified in the PearlDiver Mariner database using International Classification of Diseases and Current Procedural Terminology codes. Service location determined surgical setting. Patients with pathological fractures, malignancy, or polytrauma were excluded. Cohorts were propensity matched 1:1 based on age, sex, Charlson and Elixhauser comorbidity indices, and relevant comorbidities. The matched cohort included 9,697 inpatient and 9,697 outpatient DRF ORIF cases. Serious postoperative complications occurred in 16.8% of inpatient procedures versus 5.0% of outpatient procedures. Inpatient surgery was associated with higher odds of surgical site infection (OR 2.23, 95% CI: 1.78–2.79), wound dehiscence (OR 2.57, 95% CI: 1.07–6.17), and deep vein thrombosis (OR 7.75, 95% CI: 3.53–17.04). Inpatients also had greater odds of emergency department visits (OR 1.17, 95% CI: 1.05–1.31), readmissions (OR 3.64, 95% CI: 2.91–4.54), reoperations (OR 2.15, 95% CI: 1.70–2.73), and higher 90-day reimbursements. Inpatient DRF ORIF was associated with significantly higher complication rates and increased postoperative healthcare utilization compared with outpatient procedures, with the largest absolute differences seen in readmissions, reoperations, and 90-day reimbursements. These associations are unlikely to be causal, as inpatient admission typically reflects greater medical necessity and clinical complexity not fully captured by administrative data. Nonetheless, because admission status is readily available at the point of care, it may serve as a practical flag to identify patients who warrant closer post-discharge surveillance and individualized follow-up planning. III.

ABSTRACT Studies in humans and murine models have pointed towards a possible link between metabolic syndrome, which shows insulin resistance and metabolic dysregulation, and Alzheimer’s disease (AD) pathology marked by amyloid-beta (Aβ) accumulation at the BBB and hypometabolism in the brain. Yet, the underlying biological mechanisms by which metabolic syndrome affects these pathological changes in AD brain remain unknown. We hypothesized that insulin resistance is responsible for alterations in blood-brain barrier (BBB) transport of Aβ peptides and glucose. This hypothesis was tested by employing radiolabeled tracers ( 125 I-Aβ40, 125 I-Aβ42, and 18 F-FDG) in high-fat diet (HFD)-fed mouse models that manifest metabolic syndrome. Further, we assessed alterations in the expression of various molecular mediators within the brain microcapillaries harvested from both low-fat diet (LFD)-fed and HFD-fed mice. As expected, our studies show that HFD- fed mice developed peripheral insulin resistance and obesity. In addition, HFD-fed mice demonstrated an increase in the influx rate of Aβ peptides and a reduction in 18 F-FDG (a glucose surrogate) influx rate at the BBB compared to LFD-fed mice. These transport changes are associated with increase in the BBB endothelial expression of RAGE (receptor to traffic Aβ from plasma-to-brain) and a reduction of GLUT1 (glucose transporter) expression in HFD-fed mice compared to LFD-fed mice. Moreover, disruption in insulin signaling, as indicated by reduced pAKT and pERK expression, was observed in HFD-fed mice. Inhibiting AKT or ERK phosphorylation with specific inhibitors resulted in similar changes in Aβ and glucose uptake in polarized BBB endothelial cell monolayers in vitro. These results indicate that HFD induced metabolic syndrome may lead to BBB dysfunction, characterized by increased plasma-to-brain Aβ trafficking and diminished glucose transport at the BBB, thereby aggravating the expression of AD pathological hallmarks.

Introduction Antibody–drug conjugates (ADCs) are now widely used in breast cancer across multiple disease subtypes. With increasing clinical use, treatment-related toxicities have become an important factor in therapeutic decision-making. However, comparative safety data among ADCs are limited because direct head-to-head trials are lacking. Methods We conducted a systematic review and Bayesian network meta-analysis of randomized controlled trials evaluating ADCs in breast cancer, with the literature search updated through March 31, 2025. Treatment-related adverse events (TRAEs) and serious adverse events (SAEs) were classified according to the Common Terminology Criteria for Adverse Events. A Bayesian random-effects network meta-analysis was used to compare toxicity risks across regimens. Odds ratios (ORs) with 95% credible intervals (CrIs) were estimated, and surface under the cumulative ranking curve (SUCRA) values were used as descriptive ranking summaries interpreted alongside the corresponding comparative estimates. The protocol was registered in PROSPERO (CRD42024606194). Results Seventeen randomized trials including 8,946 patients and five ADCs—trastuzumab emtansine (T-DM1), sacituzumab govitecan (SG), trastuzumab deruxtecan (T-DXd), datopotamab deruxtecan (Dato-DXd), and ARX788—were analyzed. SG and T-DXd showed the least favorable hematologic safety profiles, with SUCRA values for anemia/neutropenia of 22.6%/17.4% and 12.0%/27.0%, respectively. T-DM1-based regimens had the highest risk of thrombocytopenia. For gastrointestinal toxicities, SG ranked worst for diarrhea (SUCRA 6.0%), whereas T-DXd was associated with higher risks of nausea (2.2%), vomiting (7.9%), and decreased appetite (8.6%). In analyses of SAEs, SG had the highest rates of anemia (11.7%) and neutropenia (8.5%), while gastrointestinal SAEs occurred more frequently with T-DXd. Conclusions This network meta-analysis highlights clinically meaningful differences in ADC safety profiles and may help guide individualized toxicity management in breast cancer.

Abstract Objective Resective surgery achieves seizure freedom in approximately 60%–80% of patients with drug‐resistant temporal lobe epilepsy (TLE), yet the extent to which seizure cessation permits recovery of disrupted functional brain networks remains unclear. Increasing evidence suggests that recurrent seizures alter subcortical–cortical communication involved in arousal and cognition, contributing to chronic interictal deficits, such as in executive function. Prior work demonstrates that the nucleus basalis of Meynert (NBM), the primary source of cortical cholinergic input to the cortex, exhibits aberrant functional connectivity in patients with TLE. We examined NBM connectivity in patients with TLE before and after surgery using patient‐specific NBM segmentations. We sought to investigate whether seizure freedom is associated with recovery of NBM functional connectivity, consistent with previous observations of interictal network dysfunction reversal in other subcortical arousal structures. Methods Resting‐state functional magnetic resonance imaging was analyzed in 75 patients with TLE, including 34 patients postoperatively, and 106 controls. Patient‐specific NBM segmentations were used to compute functional connectivity between the NBM and frontoparietal association cortex (FPAC) and across the whole brain. Subcortical arousal network community structure was assessed using community detection. Postoperative network changes were evaluated relative to seizure outcome. Results Prior to surgery, patients exhibited reduced bilateral NBM connectivity to the FPAC and whole brain compared to controls, indicating widespread cholinergic network disruption beyond the ipsilateral hemisphere. Following surgery, NBM connectivity increased and no longer differed from controls. Seizure‐free patients demonstrated greater postoperative increases in ipsilateral NBM‐FPAC connectivity than non‐seizure‐free patients, which was not explained by time to postoperative scan or volumetric change. Subcortical arousal community structure remained altered postoperatively. Significance Successful TLE surgery is associated with partial restoration of cholinergic arousal network connectivity, supporting the idea that seizure cessation enables recovery of brain networks disrupted by recurrent seizures. These findings position the NBM as a potential biomarker of network recovery following epilepsy surgery.

Left atrial (LA) myopathy plays a critical role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). This study aimed to evaluate LA function in a murine model of hypertension-induced HFpEF, with and without obesity, by analyzing left ventricular (LV) pressure signals to quantify the contribution of LA systole to total LV volume. HFpEF was induced in C57BL/6J mice using the SAUNA model, which involves uninephrectomy, chronic aldosterone infusion, and high-salt drinking water for four weeks. To model obesity-associated HFpEF, a high-fat diet (HFD) was added to the SAUNA protocol. Invasive hemodynamic measurements were obtained, and a novel method was developed to assess atrial systole using the second-order derivative of the LV pressure signal during diastolic filling. SAUNA HFpEF mice exhibited preserved LVEF, moderate hypertension, pulmonary congestion, and diastolic dysfunction as evidenced by a prolonged time constant of relaxation (Tau). In sham control mice, atrial systole accounted for 23.0 ± 2.4% of LV volume, whereas this contribution was significantly reduced to 13.9 ± 2.3% in SAUNA HFpEF mice ( P < 0.01). In obese sham controls, atrial systole contributed 53.1 ± 2.2%, which was markedly decreased to 36.8 ± 3.6% in obese-SAUNA HFpEF mice ( P < 0.003). This novel method enables precise quantification of LA systolic contribution to LV filling in mice and highlights the pathophysiological effects of hypertension and obesity on LA function in HFpEF.

Background Glioblastoma (GBM) remains the most aggressive primary adult brain cancer attributed to its immunosuppressive nature. Radiation therapy (RT) and concurrent temozolomide chemotherapy are the standard treatments for GBM. Emerging evidence indicates that metformin has potential as an anti-tumor agent that can reshape the immune landscape across various malignancies. We thus postulate that metformin may enhance the anti-tumor effect of RT by modulating the immunosuppressive milieu in GBM. Methods We first explore multiple in vitro conditions, with or without pre-induction, and mimicked a tumor microenvironment to demonstrate a highly context-dependent effect of metformin on the polarization of bone marrow-derived macrophages (BMDMs). We then investigated the antitumor activity and immune-modulatory effects of metformin in combination with RT in GBM-bearing mice. Results The in vitro experiment showed that metformin inhibited the immunosuppressive effects of IL-4/IL-13 but also the immunostimulatory effects of Lipopolysaccharide (LPS) on BMDMs, demonstrating bidirectional immunomodulatory properties that depend on the baseline inflammatory stimulus. In tumor cell co-culture environment, metformin exhibited context-dependent immunoregulatory effects, predominantly promoting M1-associated activation. Notably, concurrent metformin treatment counteracted M2 polarization typically induced by the tumor microenvironment. In a high m-MCSF inducted M2-dominated condition, metformin preferentially shifted the highly polarized M2 phenotype toward an M1-like state in a time and dose-dependent manner but with limited promotion of M1 subtype maturation. RNAseq results on BMDM treated with metformin showed increased homeostasis. Metformin showed dose-dependent immunomodulatory effects when combined with RT in vitro . In syngeneic GBM mouse models, concurrent metformin + RT significantly prolonged survival and reduced tumor burden by reprogramming tumor-associated macrophages (TAMs), elevating intratumoral CD8+ T-cell infiltration and the CD8+/Treg ratio, increasing circulating CD8+ T cells, reversing RT-induced expansion of monocytic myeloid-derived suppressor cells (mMDSCs), and expanding CD4+ and CD8+ effector memory populations in peripheral blood. Conclusion Metformin demonstrates inhibitory effects on M2 phenotype of macrophages. However, it is not a simple M2 inhibitor; instead, it functions primarily as a neutralizer of highly polarized macrophage states by promoting transcriptomic homeostasis. This context-dependent activity enables metformin to relieve the profoundly immunosuppressive TME of GBM to potentiate the anti-tumor effects of RT and by enhancing systemic immune memory.

PURPOSE Age ≥40 years is regarded as a high-risk feature and an indication for adjuvant chemoradiotherapy for patients with lower-grade glioma in clinical practice guidelines. It is unclear whether age remains a relevant prognostic factor for contemporary definitions of lower-grade gliomas in the molecular era. METHODS The Prospective Gliomas Research (PROGRES) database contains individual patient-level data from 11 prospective clinical trials or observational registries of histologically defined lower-grade 2-3 oligodendroglioma or astrocytoma. We determined the association of age (18-39 years v ≥40 years) with progression-free survival (PFS) stratified by isocitrate dehydrogenase 1 or 2 ( IDH1/2 ) status, using log-rank tests and Cox regression models. We validated our findings in a separate multi-institutional retrospective cohort (Retrospective Glioma Research [REGRES] database). RESULTS We identified 1,619 and 1,292 eligible patients in the PROGRES and REGRES cohorts, respectively. IDH -wildtype tumors were more common in patients 40 years and older (38% v 5%, odds ratio: 11.3 [95% CI, 6.5 to 19.7]). Age was associated with PFS in IDH -wildtype (5-year PFS for ≥40 v 18-39 years: 6% v 24%, hazard ratio [HR], 1.74 [95% CI, 1.21 to 2.50]) but not in IDH -mutant glioma (60% v 59%, HR, 0.89 [95% CI, 0.76 to 1.05], P interaction < .001). In IDH -wildtype tumors, older age predicted aggressive molecular features, including TERT promoter mutation (65% v 28%), EGFR amplification (41% v 15%), and chromosome +7/–10 alteration (57% v 25%). In a pooled analysis of four clinical trials, age was not predictive of a benefit from chemoradiotherapy versus radiotherapy alone for IDH -mutant glioma. CONCLUSION In the absence of additional clinical or molecular risk factors, age alone should not be considered an indication for administration or deferral of adjuvant treatment. Practice guidelines should be revised to reflect contemporary prognostic factors in the molecular era.