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Background The association between lifestyle factors and Alzheimer's disease (AD) pathophysiology remains incompletely understood. Objective The aim of this study was to assess the association of alcohol consumption, smoking behavior, sleep quality and physical, cognitive, and social activity with cerebral amyloid pathology. Methods For this cross-sectional study, we selected participants from the Amyloid Biomarker Study data pooling initiative. We used generalized estimating equations to assess associations of dichotomized lifestyle measures with amyloid pathology. Results We included 9171 participants with normal cognition (NC) and 2555 participants with mild cognitive impairment (MCI) from the Amyloid Biomarker Study. Of participants with NC, 58% were women, 34% were APOE ε4 carrier, and 27% had amyloid pathology. Of participants with MCI, 48% were women, 47% were APOE ε4 carrier, and 57% had amyloid pathology. In NC, cognitively active participants were less likely to have amyloid pathology (OR = 0.77, 95%CI 0.66–0.89, p < 0.001). In MCI, participants who had ever smoked or had sleep problems were less likely to have amyloid pathology (OR = 0.85, 95%CI 0.73–0.99, p = 0.029; OR = 0.62, 95%CI 0.45–0.86, p = 0.004). Conclusions In NC, cognitive activity was associated with a lower frequency of amyloid pathology. In MCI, favorable lifestyle behaviors were not associated with a lower frequency of amyloid pathology. The results of the current study contribute to the broader evidence base on lifestyle and AD by further characterizing the role of lifestyle behaviors in AD pathology across different clinical stages.

ABSTRACT Background and hypothesis End-stage renal disease patients require peritoneal dialysis (PD) as a life-saving therapy; however, they continue to experience systemic inflammation and increased cardiovascular pathology. These complications can be exacerbated by exposure to PD solutions (PDS) containing glucose. This highlights the clinical unmet need for novel osmotic agents to replace glucose. Here, we tested troxerutin, a Food and Drug Administration–approved drug, as a potential osmotic agent. Methods To evaluate troxerutin osmotic and non-toxic effects, in vitro and in vivo experiments were carried out using artificial membranes, mice and cultured human mesothelial cells (MCs). The local and systemic consequences of chronic peritoneal exposure to PDS associated to renal insufficiency were investigated in a preclinical model. 5/6 nephrectomized C57BL/6J mice were daily exposed to glucose- or troxerutin-PDS for 60 days, then evaluating tissue damage, proinflammatory markers and cardiac damage. Results In vitro and in vivo studies revealed that troxerutin exhibits similar osmotic and ultrafiltration capacities to glucose, but with colloidal properties. Moreover, only glucose, but not troxerutin, reduced MC viability, induced mesothelial-to-mesenchymal transition, and increased damage markers (such as interleukin-6 and vascular endothelial growth factor A). In the preclinical model, long-term treatment with glucose-PDS, but not troxerutin-PDS, significantly increased peritoneal membrane thickening, tissue proinflammatory markers (evaluated in peritoneum, kidney, heart and aorta) and cardiovascular damage (cardiac hypertrophy and fibrosis) in mice. These preclinical data clearly demonstrate the wide deleterious effects of chronic peritoneal exposure to glucose-containing PDS in mice with kidney insufficiency and that the replacement of glucose with troxerutin notably reduces these effects. Conclusion Troxerutin emerges as a more biocompatible alternative to glucose as an osmotic agent for PD therapy, exhibiting no adverse local or systemic side effects in preclinical studies. This research presents a novel approach to reduce cardiovascular complications of PD in end-stage kidney disease.

Background: Anterior vertebral body tethering (AVBT) is a promising fusionless alternative for treating idiopathic scoliosis; however, limited data exist on the learning curve for this procedure. Previous studies are limited by single-center and short-term complication data. This multicenter study assesses the learning curve by evaluating improvements in operative characteristics over time and radiographic measurements up to 2 years postoperatively. Methods: As recorded from a multicenter registry, surgeons with ≥10 index AVBT procedures for patients with idiopathic scoliosis aged 16 years and below were included. Relationships between case number and multiple surgical variables were determined using Pearson correlation and linear regression testing. For identification of an inflection point, consecutive cases were plotted against operative time per level and fitted with a locally weighted scatterplot smoothing curve. Independent samples t test and χ 2 test were used to compare outcomes between cases before and after the inflection point. Outcomes of interest included demographic, surgical, and radiographic information at the baseline, immediate postoperative, and 2-year timepointswhere available. Results: Eight surgeons and 325 index AVBT patients met the inclusion criteria. Inverse relationships were identified between case number and estimated blood loss, operative time, anesthesia time, and fluoroscopic time per level ( P < 0.005). The inflection point was identified at 15 cases. Operative time, anesthesia time, and fluoroscopy time per level were greater in the first 15 cases compared with those after ( P < 0.05). There were no significant differences in demographic variables, intraoperative complications, or length of stay between the early and late cases. Greater correction in the major coronal curve, minor coronal curve, and coronal balance occurred in the cases performed after the inflection point ( P < 0.05). Conclusions: AVBT is a safe alternative to posterior spinal fusion and demonstrates a predictable improvement in surgical performance over time. Large improvements can be expected during the first 15 AVBT cases performed with minimal differences in complications. Level of Evidence: Level III.

Abstract Context Benign thyroid nodules (BTNs) are highly prevalent, and current treatment options are primarily invasive. There is a need for effective, noninvasive alternatives. Objective To systematically evaluate the efficacy of repurposed pharmacologic agents in reducing the size of BTNs. Data Sources MEDLINE, EMBASE, Cochrane databases, and Scopus were searched from inception to December 18, 2024. Study Selection We included preclinical and clinical studies evaluating repurposed drugs for BTNs in adults. Of 1499 records screened, 20 studies met inclusion criteria: 6 randomized controlled trials (RCTs), 6 prospective cohorts, 3 retrospective observational studies, 3 case reports, 1 cross-sectional study, and 1 preclinical study. Data Extraction Data were extracted independently in duplicate using a standardized form. Data Synthesis Narrative synthesis was conducted due to heterogeneity. Metformin was the most frequently evaluated agent (7 studies), with 5 studies (including 2 RCTs) reporting statistically significant reductions in dominant nodule volume. One prospective study demonstrated a reduction in the maximum nodule diameter, which was not statistically significant, and 1 RCT showed no changes in nodule size after intervention. Statins (4 studies) and somatostatin analogues (4 studies) showed mixed results. Myo-inositol with selenium, herbal formulations, and immune checkpoint inhibitors showed promise in single studies or case reports. Conclusion Metformin shows the most consistent potential for noninvasive reduction of BTN size, particularly in patients with metabolic comorbidities. However, current evidence is limited and heterogeneous. Further large-scale studies are needed to confirm efficacy and guide clinical use.

Abstract Glioblastoma is an aggressive brain cancer with poor prognosis. Recent evidence implicates metabolic reprogramming, including the hexosamine biosynthetic pathway (HBP) and pentose phosphate pathway (PPP), as critical for tumor survival, therapy resistance, and progression. HBP inhibition with a proprietary small molecule (G2Bz) reduced stemness and migration and increased apoptosis of GBM in vitro. HBP inhibition was concomitant with an accumulation of metabolites in the Pentose Phosphate Pathway (PPP). Therefore, we further inhibited HBP with G2Bz and/or PPP with 6-aminonicotinamide (6-AN) in primary patient-derived GBM lines and evaluated additive or synergistic effects. Ultrastructural and functional changes were examined by electron microscopy (EM), high content imaging of endoplasmic reticulum (ER) and lipid droplets (LD), extracellular-flux analysis, and lipid profiling. Synergism was validated in an orthotopic model receiving lipoparticle-encapsulated G2Bz via intranasal delivery and/or intraperitoneal 6-AN; tumor burden was monitored via bioluminescence. Dual inhibition of HBP/PPP revealed additive or synergistic anti-proliferative effect. EM displayed severe ultrastructural cell damage with mitochondrial disorganization, ER dilation, and cytoskeletal remodeling. These changes coincided with increased ROS generation and reduced spare respiratory capacity suggesting higher sensitivity and lower ability to fight stress. Reduced ER–mitochondria contacts accompanied by increased expression of BiP and ER expansion suggest an unfolded protein response. Loss of LDs were associated with downregulation of lipid biosynthesis regulator SREBF1 and an increase in free fatty acids with a rise in lipid peroxidation. Reduced mitochondria–LD contacts correlate with lower endogenous fatty acid oxidation and a shift to exogenous fatty acid utilization. Dual inhibition in-vivo, suppressed tumor growth compared to control. These findings support that dual inhibition of HBP/PPP synergistically disrupts tumor metabolism, promoting organelle disorganization and lipid remodeling and highlight metabolic co-targeting as a strategy to impair GBM metabolism.

Abstract Berubicin is a unique anthracycline engineered to have the ability to cross the blood-brain barrier (BBB). Herein we present the primary results from a large global trial of Berubicin vs. Lomustine randomizing patients with progressive disease after only one prior therapy, all being IDH WT and stratified for MGMT methylation. The primary endpoint was overall survival (OS), secondary endpoints included progression-free survival (PFS), overall response rates (ORR) of complete (CR) and partial (PR) responses. Eligibility was determined radiologically by central reads based on progression of disease, and in 2.5 years 252 patients were enrolled with 168 randomized to Berubicin and 84 to Lomustine. Safety assessment showed that Berubicin was well tolerated and myelosuppressive side effects were manageable with growth factors. Importantly, although anthracyclines are known to cause cardiotoxicity, evaluation with frequent troponin measurements, ECG and ECHO testing revealed no evidence of impact on cardiac function. The primary endpoint, OS, showed Berubicin and Lomustine had similar outcomes. Median overall survival for Berubicin was 8.7 months (6.7, 9.9) and for Lomustine was 9.3 months (6.7, 10.7) with a Hazard Ratio of 1.13 (p = 0.5351). PFS of Berubicin and Lomustine were also similar (1.5 vs, 1.6 months). There were no responses in the Lomustine arm and stable disease in 35.2% of patients while Berubicin had a response rate of 5.8% (PR) and stable disease of 33.6% with a combined disease control rate (DCR) of 39.4%. Additional data will be presented and discussed. Anthracyclines are characteristically used in combination for systemic therapy (e.g. leukemia, lymphoma, certain breast cancers), so there is promise that combination therapy will be the next pertinent approach to treatment of GBM. Evaluation of activity against a range of pediatric brain tumors is being pursued and preliminary results will be presented at the time of the conference.

Importance Treatment for cognitive dysfunction due to postacute sequelae of long COVID (ie, symptoms of fatigue, malaise, weakness, confusion that persist beyond 12 weeks after an initial COVID infection) remains a significant unmet need. Objective To test evidence-based rehabilitation strategies for improving cognitive symptoms in persons with long COVID. Design, Setting, and Participants This was a 5-arm, multicenter, randomized clinical trial of 3 remotely delivered interventions conducted between August 17, 2023, and June 10, 2024. The study took place at 22 trial sites and included the screening of individuals with cognitive long COVID. Interventions Participants were randomized to 1 of 5 arms: adaptive computerized cognitive training (BrainHQ [Posit Science]), cognitive-behavioral rehabilitation involving both group and individual counseling sessions (PASC-Cognitive Recovery [PASC-CoRE]) paired with BrainHQ, and transcranial direct current stimulation (tDCS) paired with BrainHQ. Two comparator arms were included as follows: unstructured computer puzzles and games (active comparator) and sham tDCS paired with BrainHQ. The interventions occurred 5 times per week over 10 weeks. Main Outcomes and Measures Cognitive and behavioral in-person assessments were performed at baseline, midintervention, at the end of intervention, and 3 months after the end of the intervention. The primary outcome measure was the modified Everyday Cognition Scale 2 (ECog2) completed at the end of the intervention compared to the baseline visit based on participant self-report looking back over the prior 7 days. Results A total of 378 individuals were screened, from which there were 328 participants (median [IQR] age, 48.0 [37.0-58.0] years; 241 female [73.5%]; race: 15 Asian [4.6%], 47 Black [14.3%], and 235 White [71.6%]; ethnicity: 52 Hispanic [15.9%]). None of the 3 active interventions demonstrated benefits on the modified ECog2 in the intention-to-treat population by the end of the intervention period. The adjusted differences in mean change were 0.0 (95% CI, −0.2 to 0.2) for BrainHQ vs active comparator, 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs active comparator, 0.0 (95% CI, −0.2 to 0.2) for tDCS-active + BrainHQ vs tDCS-sham + BrainHQ, and 0.1 (95% CI, −0.1 to 0.3) for PASC-CoRE + BrainHQ vs BrainHQ alone. Secondary participant-reported outcomes and neuropsychological tests showed no differential benefits for any treatment arm. All 5 arms demonstrated some improvements over time on the modified ECog2 and on secondary outcomes. There were no serious adverse events attributable to the interventions. Conclusions and Relevance This phase 2 randomized clinical trial failed to demonstrate differential benefits for online cognitive training, a structured cognitive rehabilitation program, and tDCS for cognitive long COVID. Trial Registration ClinicalTrials.gov Identifier: NCT05965739 .

Abstract Aims We evaluated clinical outcomes with GLP-1 RA use post-TAVI in patients with T2D. GLP-1 receptor agonists (GLP1-RAs) lower cardiovascular risk in type 2 diabetes (T2D), but their impact in patients with valvular heart disease, including those undergoing transcatheter aortic-valve implantation (TAVI), remained unexplored. Methods and results We conducted a retrospective cohort study using the TriNetX network, including 25 184 adults (≥18 years) with T2D who underwent TAVI (2015–2023). Patients were stratified based on GLP1-RA initiation within 14 days post-TAVI. Baseline characteristics, comorbidities, medications, and laboratory data were balanced using 1:1 propensity score matching (PSM). Cox models estimated hazard ratios (HRs) and 95% confidence intervals (CIs) for events from one-month post-TAVI until the most recent follow-up. PSM yielded 1101 patients per group, with a mean age of 73 years and 39% female. Mean follow-up duration was 2.2 ± 1.1 and 2.6 ± 1.8 years for GLP1-RA users and non-users, respectively. GLP1-RA use was also associated higher survival probability (HR: 0.708 [95% CI: 0.583–0.859]), and lower rates of all-cause hospitalization (HR: 0.790 [95% CI, 0.706–0.885]), major cardiovascular events (HR: 0.849 [95% CI: 0.749–0.963]), and acute heart failure exacerbation (HR: 0.785 [95% CI: 0.677–0.909]), acute kidney injury (HR: 0.843 [95% CI: 0.719–0.988]), and major kidney events (HR: 0.665 [95% CI: 0.510–0.866]). No differences were observed in acute myocardial infarction, cerebral infarction, or cardiac arrest. Conclusion In patients with T2D undergoing TAVI, GLP1-RA use is associated with significant survival benefits and improved cardiorenal outcomes. However, these findings are limited by the observational design, high comorbidity burden, lack of data on medication compliance, and specific cause of death. Prospective trials are warranted to confirm these benefits.

Abstract Background Global longitudinal strain (GLS) by 2D speckle tracking echocardiography (2D-STE) has been widely utilized to detect early underlying systolic myocardial dysfunction in patients with normal ejection fraction (EF). Reduced GLS is observed in patients with hypertrophic and amyloid cardiomyopathies. However, the impact of chronic kidney disease (CKD) on GLS remains underexplored. CKD patients present with multiple cardiovascular comorbidities, increased left ventricular mass index (LVMI), and altered cardiac remodeling which is a dynamic and adaptive physiological response. Left ventricular (LV) remodeling is classified based on relative wall thickness (RWT ≤ or &gt; 0.42) and LVMI (≤ or &gt; 88 g/m² for women and ≤ or &gt; 102 g/m² for men) into four distinct categories: normal geometry (NG), concentric remodeling (CR), concentric hypertrophy (CH), and eccentric hypertrophy (EH). Purpose To assess and describe the LV-GLS values (SD) in male and female patients with CKD across different remodeling patterns and compare them to controls without comorbidities Methods A retrospective echocardiographic analysis was conducted on patients evaluated from 01/01/2008 to 12/31/2018. A total of 546 CKD patients and 1041 controls were identified and matched in a ≈2:1 ratio by age, gender, and cardiac geometry. ANOVA and Tukey-Kramer analysis compared GLS across groups, with data distributions visualized via box plots. P-values &lt;0.05 were considered significant. Results The mean age of CKD patients and controls was 63.3 (SD 12.7) and 63.1 (SD 12.6) years, respectively. Overall, GLS values in CKD patients were comparable to controls, with significant differences in select subgroups. In females with eccentric hypertrophy, GLS was lower in CKD stage V vs. controls (-16.2 ± 2.5 vs. -20.7 ± 2.3, p &lt; 0.05), CKD stage III (-16.2 ± 2.5 vs. -19.5 ± 2.4, p &lt; 0.05), and CKD stage IV (-16.2 ± 2.5 vs. -20.2 ± 2.4, p &lt; 0.05) (Table 1). Across CKD stages, GLS trended toward the lower limit of normality, particularly in advanced CKD. In males with normal geometry, GLS values for controls and CKD stages I, II, III, IV and V were -20.3 ± 1.9, -19.1 ± 2.3, -19.4 ± 2.7, -19.5 ± 2.8, -19.8 ± 3.6, and -17.7 ± 2.7 (Figure 1a). In females, corresponding values were -21.0 ± 2.2, -19.9 ± 2.7, -20.2 ± 2.0, -20.8 ± 2.5, -20.2 ± 3.4, and -18.8 ± 3.4, respectively (Figure 1b). Conclusion GLS values in CKD patients were largely comparable to controls for both genders. However, those with CKD V exhibited GLS values near the lower limit of normality, particularly in eccentric hypertrophy. These findings suggest that in this group of patients there is subclinical myocardial dysfunction, warranting further investigation. The values reported may serve as reference points for GLS assessment in CKD patients.