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Abstract Rationale Chronic thromboembolic disease (CTED), which is the result of persistent pulmonary vascular obstruction despite 3 months of anticoagulation, can present with significant functional limitations and exercise intolerance despite normal resting hemodynamics. These patients may experience functional impairment due to exercise-induced pulmonary hypertension, impaired stroke volume augmentation with exercise, ventilatory inefficiency, and/or preload insufficiency. Such exercise-induced pathophysiological abnormalities can significantly impair quality of life and contribute to poor long-term outcomes. Although balloon pulmonary angioplasty (BPA) has shown benefit in patients with chronic thromboembolic pulmonary hypertension (CTEPH), its role in CTED patients with normal resting hemodynamics remains uncertain. This systematic review and meta-analysis evaluated the efficacy of BPA in this population. Methods A systematic search of PubMed, Cochrane, Embase, and Scopus was performed from inception through March 1, 2025. A total of 763 studies were screened, of which 42 full-text articles were assessed: six met the inclusion criteria (four retrospective, two prospective), comprising 98 patients. Results Across the included studies, baseline mean values were 20.81 +/- 3.62 mmHg for mean pulmonary arterial pressure (mPAP), 3.49 +/- 1.42 Wood units for pulmonary vascular resistance (PVR), and 405.72 +/- 108.40 m for the 6-minute walk distance (6MWD). Balloon Pulmonary Angioplasty (BPA) was consistently associated with significant improvements in hemodynamic and functional outcomes; BPA reduced mPAP by 3.40 mmHg and PVR by 0.90 WU, while increasing 6MWD by 31.90 m. These changes were also statistically robust across studies, with pooled standardized mean changes (SMC) of -0.88 for mPAP (95% CI, -1.10 to -0.67; P < .05), -0.68 for PVR (95% CI, -0.87 to -0.49; P < .05), and 0.29 for 6MWD (95% CI, 0.13 to 0.45; P < .05). Study-level effect sizes for 6MWD ranged from 0.19 to 0.54 (Figure 1A). Functional improvements were further demonstrated by shifts in NYHA class distribution (Figure 1B). Conclusion BPA was associated with meaningful reductions in mPAP and PVR and significant improvements in functional capacity among patients with CTED. These results indicate that BPA could be an effective treatment for certain patients with CTED, though more research is necessary. This abstract is funded by: None

Abstract Rationale Chronic thromboembolic disease (CTED) is characterized by persistent pulmonary vascular obstruction due to unresolved thromboemboli despite at least three months of anticoagulation. Although resting hemodynamics often remain normal, affected patients frequently develop functional limitation due to exercise-induced pulmonary hypertension, ventilatory inefficiency, limited stroke volume augmentation, or preload insufficiency. Such exercise-induced pathophysiological dysregulation can significantly impair quality of life and contribute to poor long-term outcomes. Pulmonary endarterectomy (PEA) is an established treatment for Chronic Thromboembolic Pulmonary Hypertension (CTEPH), offering significant improvements in hemodynamics and survival. Its role in CTED, however, remains unclear. While CTED has traditionally been managed with anticoagulation and supportive therapy, emerging evidence suggests PEA may provide symptomatic and functional benefit in selected CTED patients. Given the ongoing uncertainty regarding the role of PEA in CTED, we performed a systematic review and meta-analysis to define its safety profile and clinical efficacy in this patient subset. Methods A systematic search of PubMed, Cochrane, Embase, Scopus, Web of Science, ClinicalTrials.gov, and Google Scholar was conducted from database inception to March 1, 2025. Of 2,244 records screened, 34 full-text articles were assessed, and seven met the inclusion criteria. Results Across the included studies, the pooled baseline mean values were 20.48 ± 3.03 mm Hg for mean pulmonary arterial pressure (mPAP), 2.83 ± 1.11 Wood units for pulmonary vascular resistance (PVR), and 397 ± 100.08 m for the 6-minute walk distance (6MWD). Pulmonary Endarterectomy (PEA) was consistently associated with significant improvements in hemodynamic and functional outcomes; PEA reduced mPAP by 3.58 mmHg (pooled Standardized Mean Change (SMC)=-1.03; 95% CI, -1.23 to -0.83; P < .05), PVR by 0.86 Woods units (pooled SMC=-0.86; 95% CI, -1.05 to -0.67; P < .05), while, conversely, increased 6MWD by 37.49 m (pooled SMC, 0.49; 95% CI, 0.32 to 0.67; P < .05). Study-level effect sizes for 6MWD ranged from 0.21 to 1.47 (Figure 1A). This clinical improvement is further reflected in the enhancement of the NYHA functional class, as illustrated in Figure 1B. Conclusion PEA was associated with significant reductions in mPAP and PVR, as well as a considerable improvement in functional capacity in patients with CTED, with robust results across multiple tests for bias, influence, and sensitivity analyses. These findings support PEA as a viable therapeutic option for selected patients with CTED, although further research is warranted. This abstract is funded by: None

Alzheimer’s disease (AD) is characterized by profound metabolic dysfunction and disturbances in gut–brain axis signaling. Ketogenic diet (KD) has demonstrated metabolic and cognitive benefits in both preclinical and clinical studies. However, factors that determine individual responsiveness or non-responsiveness to KD interventions remain poorly understood. Emerging evidence suggests that gut microbiome composition plays a critical role in modulating these factors. This study examined how KD responsiveness, determined by fecal microbiota transplantation (FMT) derived from human KD responders (RES) or non-responders (nRES)- influences cognition, gut barrier function, neuroinflammation, and microbial structure in 3xTg-AD mice. We further evaluated whether supplementing KD with a novel Synbiotic Yogurt (SY) formulated by our team could augment or restore responsiveness. We hypothesized that RES microbiota would confer superior KD-driven benefits and that KD-SY would synergistically improve metabolic and neurobiological outcomes, particularly among nRES recipients. Adult 3xTg-AD mice were antibiotic-cleansed and randomized to receive Control-, RES-, or nRES – FMT, while maintained on KD for four weeks. A second cohort received KD supplemented with SY or non-fat milk along with RES- or nRES-FMT. Behavioral tests, gut permeability assay, serum inflammatory markers, brain amyloid beta (Aβ), intestinal morphology, gene expression, and 16S rRNA microbial profiling were measured. RES-FMT recipients showed early improvements in spatial memory (Y-maze and novel object recognition) and consistently lower Aβ accumulation in cortex and hippocampus. They also showed higher synaptophysin and IL-10 expression. In contrast, nRES-FMT mice exhibited distinct microbiome clustering, lower microbial diversity, enrichment of Proteobacteria, and impaired gut barrier function relative to RES-FMT recipients. Functionally, specific taxa like Enterococcus, Enterobacter, and Paenibacillus were associated with greater vulnerability to AD-related pathology, while Akkermansia, Bifidobacterium, and Muribaculum were linked with lower vulnerability. SY supplementation improved metabolic and gut barrier indices across groups characterized by increased circulating ketone levels, lowered fasting glucose and glucose-ketone index, and decreased gut permeability. nRES-SY mice showed the strongest gains in recognition memory and reductions in brain Aβ1–42 burden. SY increased expression of barrier- and inflammation-modulating genes, including occludin, APLP2, and IL-10. Microbiome analysis demonstrated higher microbial diversity and enrichment of beneficial genera such as Paralactobacillus, Eubacterium, and Muribaculum. These findings show that KD responsiveness is strongly determined by gut microbiota composition and that SY supplementation can enhance or rescue metabolic, cognitive, and microbial outcomes, particularly in nonresponders. This supports a precision-microbiome strategy combining metabolic and Synbiotic interventions to improve gut–brain axis function in AD. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Abstract Background and aims Dementia represents a growing global health burden, with vascular dementia and Alzheimer's disease accounting for most cases through cumulative cerebrovascular damage. While periodontal disease (PD) is associated with cognitive decline, dental caries represents a distinct oral infection pathway characterized by bacterial invasion and infection, potentially contributing to vascular brain injury through microbial translocation, endothelial dysfunction, systemic inflammation, and cerebral microvascular damage. The relationship between dental caries and incident dementia within a vascular framework remains understudied. Methods We analyzed 6,542 participants from the Atherosclerosis Risk in Communities (ARIC) Study who received dental examinations at Visit 4 (1996–1998) and followed for incident dementia through 2023 using standardized surveillance (Figure-1). Cox proportional hazards models with competing risk accounted for death. Multivariable models adjusted for demographic factors, cardiovascular risk factors, BMI, physical activity, education, income, insurance status, APOE4 genotype, PD, and regular dental care. Results Mean age was 62.4 years; 54% female, 82% White, and 18% Black. Dental caries was present in 20%. Over median 25-year follow-up, individuals with dental caries demonstrated significantly higher cumulative dementia incidence (Gray’s test p<0.0001). After full adjustment, dental caries remained independently associated with increased dementia risk (adjusted HR 1.20, 95% CI 1.02–1.42), independent of PD and APOE4 status (Figure-2). Conclusions Dental caries was independently associated with increased incident dementia risk. These findings support a potential role for caries-related oral infection in vascular brain injury pathways relevant to vascular dementia and stroke-related cognitive impairment. Oral infection prevention may represent a modifiable target within cerebrovascular disease prevention strategies. Conflict of interest Alana E. Barton, Souvik Sen, Kevin Moss, James Selph, Ryan Demmer, Pamela L. Lutsey, Priya Palta, Kamakshi Lakshminarayan, Karly Pikel, Wayne Rosamond: nothing to disclose Figure 1 - belongs to Conclusions Figure 2 - belongs to Conclusions

Importance Allogeneic hematopoietic cell transplant (HCT) is curative for hematologic cancers, yet access remains inequitable for racially and ethnically underrepresented and socioeconomically disadvantaged populations, making the goal of having a suitable donor for every patient who needs a transplant challenging. The ACCESS trial broadened access by enrolling patients without matched donors, who instead received an HCT from a mismatched unrelated donor. Objective To compare baseline characteristics of ACCESS trial participants with participants enrolled in a similar clinical trial and a patient-reported outcome (PRO) protocol cohort. Design, Setting, and Participants This cross-sectional study included adult participants (aged ≥18 years) from 3 cohorts—the ACCESS trial (2021-2024), BMT CTN 1703 trial (2019-2021), and Center for International Blood and Marrow Transplant Research (CIBMTR) PRO Protocol observational study (2020-2025)—who completed a baseline PRO survey. The ACCESS and PRO Protocol cohorts were stratified by conditioning intensity (myeloablative [MAC] vs reduced-intensity and nonmyeloablative [RIC/NMA]); all BMT CTN 1703 participants received RIC/NMA. Exposure Hematopoietic cell transplant. Main Outcomes and Measures Racial and ethnic diversity, insurance type, education, and income were compared among cohorts using counts and percentages, and socioeconomic and structural disadvantage were measured using the Social Vulnerability Index and Comprehensive Score for Financial Toxicity–Functional Assessment of Chronic Illness Therapy. Results Baseline surveys were completed by 208 participants in the ACCESS trial (median [range] age at transplant, 62.3 [20.4-78.9] years; 108 male [51.9%]), 122 participants in the PRO Protocol study (median [range] age at transplant, 63.9 [21.1-78.0] years; 67 male [54.9%]), and 342 participants in the BMT CTN 1703 trial (median [range] age at transplant, 66.9 [20.7-78.6] years; 218 male [63.7%]). Participants in ACCESS were more racially and ethnically diverse, with 15 (7.2%), 25 (12.1%), 46 (22.2%), 110 (53.1%), and 11 (5.3%) of Asian, Black or African American, Hispanic or Latino, White, and other race and ethnicity, respectively, compared with 4 (3.3%), 2 (1.6%), 8 (6.6%) 104 (85.2%), and 4 (3.3%), respectively, in the PRO Protocol and 10 (3.0%), 0, 16 (4.8%), 302 (91.0%), and 4 (1.2%), respectively, in the BMT CTN 1703 trial. Participants in ACCESS were more likely to have Medicaid (36 [18.1%]) vs PRO Protocol (8 [6.7%]) and BMT CTN 1703 (16 [5.1%]) participants and reported lower education (some college or an associate’s degree: 103 [49.5%] vs 73 [59.8%] in the PRO Protocol; postcollege education: 34 [17.3%] vs 35 [29.2%] in the PRO Protocol) and household income (<$40 000 annually: 25 [24.0%] vs 8 [11.6%] in the PRO Protocol and 7 [38.9%] in the BMT CTN 1703 trial). Median Social Vulnerability Index scores were highest among participants in the ACCESS MAC group (median [range], 0.72 [0.01-0.97] vs 0.61 [0.16-0.78] in the PRO Protocol MAC group), and 16 participants [27.6%] in the ACCESS MAC group reported moderate to severe financial toxicity. The ACCESS participants lived closer to transplant centers, especially in the RIC/NMA group (median [IQR], 28 [14-75] miles vs 47 [16-96] miles for BMT CTN 1703 participants and 49 [21-104] miles for PRO Protocol participants). Conclusions and Relevance This cross-sectional study of clinical trial participants and a clinical cohort found that the ACCESS trial enrolled a more racially and ethnically diverse and socioeconomically disadvantaged population. Trial designs that broaden eligibility could expand access to HCT, highlighting the need for systemic interventions to ensure equity.

Importance Seizure-induced brain injury is central to the treatment urgency of new-onset refractory status epilepticus (NORSE). Identifying biomarkers that reflect ongoing neuronal damage could inform therapeutic timing and improve outcomes. Objective To quantify acute brain injury in patients with cryptogenic NORSE (cNORSE), etiology-defined status epilepticus (eSE), and chronic epilepsy. Design, Setting, and Participants This was an international cross-sectional study conducted between 2013 and 2025. Patients were enrolled at 36 hospitals in the US, 2 in Canada, and 1 in Italy, France, and Belgium. Patients with cNORSE and eSE for which biological samples were obtained during ongoing seizure activity were enrolled in the study. Comparison groups without status epilepticus comprised individuals with chronic epilepsy and healthy participants. None were excluded. Exposures Neurofilament light chain (NfL) and S100-beta (S100B) protein concentrations in serum and cerebrospinal fluid (CSF). Main Outcomes and Measures Degree of neuronal and glial damage, indexed by NfL and S100B levels, and their association with short-term functional outcomes. Results A total of 78 patients with cNORSE (mean [95% CI] age, 37 [30-41] years; 44 female [56%]) and 2 independent cohorts of 211 patients (mean [95% CI] age, 69 [66-71] years; 128 female [61%]) and 73 patients (mean [95% CI] age, 56 [45-65] years; 39 male [53%]) with eSE were included. NfL concentrations were markedly elevated in cNORSE—approximately 10-fold higher in CSF and 4-fold higher in serum—compared with the eSE cohorts (CSF: median [IQR], 6408 [1503-22 963] pg/mL compared with 694 [219-2389] pg/mL; serum: median [IQR], 231 [99-855] pg/mL compared with 55 [20-135] pg/mL; P <.001). Serum NfL levels were nearly 20-fold higher in cNORSE than in the cohort with epilepsy and in healthy controls (median [IQR], 11 [7-19 ] and 7 [5-14 ] pg/mL, respectively). Serum and CSF NfL levels were strongly correlated (Spearman ρ = 0.75; P < .001) and rose sharply between week 1 (median [IQR], 101 [51-137] pg/mL), week 2 (median [IQR], 197 [117-324] pg/mL), and week 3 (median [IQR], 598 [163-1000] pg/mL) after onset ( P < .001). In contrast, S100B concentrations did not differ between groups and showed no consistent temporal pattern. NfL discriminated cNORSE from eSE (area under the receiver operating characteristic curve [AUROC], 0.79; 95% CI, 0.68-0.90) and from cohorts without status epilepticus (AUROC, 0.99; 95% CI, 0.78-1.00). Higher serum NfL was independently associated with poor functional outcome at discharge (Glasgow Outcome Scale extended score, 1-4; odds ratio, 1.01; 95% CI, 1.00-1.03; P = .03). Conclusions and Relevance Results of this cross-sectional study suggest that acute neuroaxonal injury, as reflected by elevated NfL levels, was substantially greater in cNORSE than in the cohorts with eSE and in controls without status epilepticus. The rapid early rise in NfL highlights a narrow therapeutic window, emphasizing the need for prompt, effective, and potentially neuroprotective interventions in cNORSE.

ABSTRACT Epithelial ovarian cancer (EOC) incidence and mortality increase with age, driven in part by chronic inflammation, diminished T cell output, and heightened regulatory T cell (Treg) mediated immunosuppression. In aged EOC‐bearing mice, we observed reduced survival, accompanied by impaired CD4 + and CD8 + T cell responses and a marked expansion of FOXP3 + Tregs exhibiting elevated IL‐10 and TGFβ expression. Metabolic profiling revealed enhanced oxidative phosphorylation in Tregs from aged mice, along with a fivefold increase in intracellular succinate levels. This accumulation of succinate within the aged tumor microenvironment was found to potentiate Treg suppressive function. Notably, pharmacologic inhibition of α‐ketoglutarate dehydrogenase reversed this effect, restoring effector T cell activity. These findings highlight succinate‐driven metabolic reprogramming as a central mechanism of age‐related Treg dysfunction in EOC and suggest that targeting succinate metabolism may offer a promising strategy to rejuvenate antitumor immunity in elderly patients.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Abstract Background: Black men experience the highest burden of prostate cancer (CaP) incidence and mortality in the United States. The reasons documented for the significant burden of CaP in Black communities include health systems, care process, and individual/personal level factors, such as cultural factors, psychosocial factors, decision making/preferences, comprehension, past experience, and perceived behavioral control. The Community Living Lab (CoLLab) Learning Health System (LHS) was established within three American Legion Posts (ALP) in Northeast Florida to address these factors. Study Objective: This clinical trial study evaluated the impact of the CoLLab LHS on the knowledge, attitudes, beliefs, and cues to action of Black men who received Resources, Education, Amenities, and Community Health (REACH) services at the ALPs. Methods: The design was guided by the Intervention Mapping Framework and the Social Ecological Model. CoLLab REACH services were made available to participants through trusted community infrastructures. Services integrated include CaP resources and materials, social determinant of health navigation, healthy grocery distribution, cancer advocacy programs, and research participation. Participants were recruited at three ALPs and were asked to visit their respective CoLLab LHS site at least twice a month and up to 24 times over one year to use any of the services. The impact was measured using baseline and quarterly surveys assessing CaP awareness, knowledge, attitude, health beliefs, perceived control, intentions, and cues to action. Descriptive statistics were used to compare participants' information at baseline and at 3-month follow-up. Results: A total of 173 participants were included in this analysis; 57.9% were ≥ 60 years, and 92.2% were US-born Black men. Prostate cancer knowledge increased from baseline to 3-month follow-up. The median score rose from 4±1.29 at baseline, with the mean increasing to 4.24±1.10. Attitudes towards Cap screening declined marginally from 12.58±2.15 to 12.27±2.40. Health beliefs showed a clear upward shift, with the mean increasing from 22.86±3.0 at baseline to 23.20±2.82 after 3 months of intervention. Additionally, cues to action also improved, with the mean increasing from 2.78±1.67 to 3.25±1.45. Only the cues-to-action index showed a statistically significant difference (p = 0.018), with higher scores observed after 3 months of intervention. Conclusion: Across the four core constructs—prostate cancer knowledge, testing attitudes, health beliefs, and cues to action—outcomes at follow-up demonstrated modest but consistent improvements compared to those of baseline, alongside slightly reduced variability for most domains. Overall, the evaluation showed that CoLLab REACH services improved knowledge, enhanced stronger health beliefs, and significantly increased cues to action, while testing attitudes remained comparatively stable. Citation Format: Folakemi T. Odedina, Opeyemi Oreoluwa Bolajoko, Quincy A. Wimberly, Daniel W. Lee, Floyd B. Willis, Toshiko Moultrie, Wayne Ford, Derry Green, Arnold J. Merriweather, Michelle Fudge. The impact of the Community Living Lab learning health system on the prostate cancer knowledge, attitudes, beliefs, and cues to action of Black men [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(8_Suppl):Abstract nr LB324.