Citations

Abstract Alzheimer’s disease (AD) emerges from multi-scale interactions between molecular pathology and disruptions in large-scale brain network dynamics. Understanding how these processes co-evolve and relate to disease stages is essential for advancing complex systems models of aging and AD, and for developing system-informed interventions. However, progress has been limited by a lack of large-scale longitudinal data. To address this, we examined the longitudinal relationship between subsystems of the default mode network (DMN) (posterior DMN, ventral DMN, anterior dorsal DMN) using task-free functional MRI (fMRI) and amyloid positron emission tomography (PET) imaging in a large longitudinal cohort spanning the clinico-biological spectrum of AD (n = 1,451; 2,763 time points) using mixed-effect models. We also assessed whether patterns of DMN connectivity predicted conversion to amyloid positivity, mild cognitive impairment (MCI), and dementia using Cox proportional hazards models. Our findings reveal a dynamic interplay between amyloid accumulation and connectivity within and between DMN subsystems, with both hyper- and hypoconnectivity emerging across DMN subsystems in association with increasing amyloid burden. Importantly, survival models showed that DMN connectivity patterns predicted conversion to critical stages of the disease, including not only conversion to MCI and dementia, but also conversion to amyloid positivity in otherwise clinically unimpaired individuals who were amyloid negative at baseline. These associations were independent of age, APOE4 status, sex, education, and in-scanner motion. These results support a model in which breakdowns in tightly regulated feedback loops governing DMN physiology represent a core systems-level pathophysiology of AD. Notably, this functional dyshomeostasis precedes detectable amyloidosis on imaging. Future studies should focus on the development of robust biomarkers of brain function that can be applied at the individual level, which could in turn help support the development of therapeutic approaches targeting system-level pathophysiology.

Background: Enteral phosphate replacement offers multiple advantages over intravenous phosphate replacement, but optimal dosing and administration are unclear. Objective: This study aimed to compare 2 different dosing strategies (PRE vs POST) of enteral phosphate replacement for mild hypophosphatemia (serum phosphorus = 2.1-2.5 mg/dL) and to evaluate our dosing strategy for moderate hypophosphatemia (serum phosphorus = 1.5-2 mg/dL) in critically ill patients. Methods: This single-center quasiexperimental, institutional review board–approved study was conducted in adult patients admitted to an intensive care unit (ICU) who received enteral phosphate replacement with a follow-up serum phosphorus level obtained within 24 hours of replacement. Patients were excluded if they had diabetic ketoacidosis, acute kidney injury, or received total parenteral nutrition or targeted temperature management. The mild PRE and POST groups received 48 and 72 mmol of enteral phosphate, respectively. The moderate group received 72 mmol of enteral phosphate. Effectiveness outcomes included normalization of serum phosphorus, defined as 2.6 to 4.5 mg/dL, and median change in phosphorus concentration. Safety outcomes included the incidence of new onset diarrhea and hyperphosphatemia (serum phosphorus >4.5 mg/dL) within 24 hours after phosphate replacement. Results: Of the 138 patients included, the median age was 59 (44-70) years and 69.6% were admitted to the surgical trauma ICU. Normalization of serum phosphorus occurred in 55 (58.2%) patients in mild PRE and 44 (72.7%) patients in mild POST ( P = 0.13). Change in serum phosphorus was 0.4 (0.1-0.9) mg/dL in mild PRE vs 0.7 (0.3-1.2) mg/dL in mild POST ( P = 0.06). Normalization occurred in 39 (66.7%) patients in the moderate group with a change in serum phosphorus of 1.0 (0.6-1.6) mg/dL. Rates of new onset diarrhea and hyperphosphatemia were not significantly different between groups. Conclusion and Relevance: Enteral phosphate replacement appears safe and effective in critically ill patients with mild-to-moderate hypophosphatemia and may serve as an alternative to intravenous phosphate.

Abstract Background: Zedoresertib (zedo) and lunresertib (lunre) are oral, highly selective WEE1 and PKMYT1 inhibitors, respectively. Inhibition of these targets leads to premature mitotic entry, and in the presence of high replication stress causes mitotic catastrophe. In preclinical models, the combination of the zedo and lunre is synthetically lethal, supporting this first-in-class trial combination (NCT04855656). Methods: In this Phase 1 trial, patients (pts) with advanced solid tumors with CCNE1 amplification (amp), or FBXW7 or PPP2R1A deleterious mutations (mut) were treated with zedo (daily dosing) plus lunre (3 days on/4 days off), guided by preclinical modelling of the pharmacological contributions of WEE1 and PKMYT1 inhibition in achieving tumor regression. Objectives included safety, tolerability, recommended doses (RD), pharmacokinetics (PK), pharmacodynamics (PDy), antitumor activity and molecular response rate (MRR; ≥50% decline in circulating tumor DNA). Results: As of 18 Nov 2025, 54 pts (55.6% female ; prior lines of therapy 1 - 9, main cancer types: ovarian (OC) (35.2%), colorectal (31.5%), pancreatic (7.4%) and breast (5.6%)) were treated at 5 dose levels (DL) from 150 mg to 260 mg of zedo plus 60 mg or 80 mg of lunre. The most common ≥G3 treatment related adverse events (TRAEs) were anemia (9.3%), neutropenia (7.4%) and Palmar Plantar Erythrodysesthesia (PPE) (7.4%). There were no G5 TRAEs. 4 (9.3%) of 54 pts had a dose-limiting toxicity (G3 pain in extremity and G1 rash in same pt (zedo 150 mg / lunre 60 mg), G3 rash (200 mg / 80 mg), G3 PPE (260 mg / 60 mg), G3 vomiting (260 mg / 60 mg)). PK/PDy analyses showed dose-dependent exposures for both zedo and lunre and target engagement in most pts, with reductions in pCDK1 Thr14 and Tyr15 and yH2AX induction. 24 (55.5%) of 44 RECIST v1.1 evaluable pts showed tumor shrinkage (3 cCR, 5 uPR, 15 SD and 1 PD). Of 16 evaluable pts with advanced OC (12 platinum resistant , 2 unknown and 2 platinum sensitive) with CCNE1 amp (13 pts) or FBXW7 mut (3 pts), 13 (81.3%) showed tumor shrinkage (3 cCR, 3 uPR and 7 SD); clinical benefit rate (pts with CR, PR or SD) was 93.8%; 7 (43.8%) OC pts were on treatment for at least 16 weeks; 4 (25%) OC pts achieved GCIG CA-125 responses. Of 23 pts with a post baseline ctDNA analysis, a MRR of 39% was seen across all DLs. Conclusion: We report the first disclosure of clinical data of the first-in-field synthetic lethal combination of WEE1 and PKMYT1 inhibitors in a molecularly defined pt population. The safety profile of zedo and lunre was expected and manageable. Promising antitumor activity was observed in pts with CCNE1 amp or FBXW7 mut solid tumors, especially pts with OC. Further dose optimization of this combination is ongoing. Citation Format: Timothy A. Yap, Rahul Aggarwal, Elisa Fontana, Martin Hojgaard, Benedito A. Carneiro, Linda Duska, Patricia LoRusso, Siddhartha Yadav, Stephanie Lheureux, Cara Mathews, Ryan H. Moy, Nehal Lakhani, Mia Weiss, Joan Tymon-Rosario, Gerardo Colon-Otero, Ignacio Garrido-Laguna, Elisabeth K. Lee, Esteban Rodrigo Imedio, Jonathan Wessen, Luke Piggott, Vito Dozio, Noemie Luong, Christophe Mas, Alison M. Schram. First data disclosure of the Phase I trial of the first in class combination of WEE1 inhibitor zedoresertib with PKMYT1 inhibitor lunresertib in patients with advanced solid tumors harboring CCNE1, FBXW7, or PPP2R1A genomic alterations [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 CT022.

■

BACKGROUND: The metabolic mechanisms underlying right ventricular (RV) dysfunction are poorly understood, particularly outside of group 1 pulmonary hypertension (PH). We aimed to identify metabolites and pathways associated with RV systolic function and explored whether associations differed by pulmonary vascular resistance, PH group 1 status, and sex. METHODS: We analyzed data from the multicenter PVDOMICS (Pulmonary Vascular Disease Phenomics) cohort. RV systolic function metrics included fractional area change (echo), global longitudinal strain (echo), and ejection fraction (cardiac magnetic resonance). We used linear regression adjusted for age, sex, body mass index, and PH group to assess associations between metabolites and RV function. Pathway enrichment analyses were used to identify pathways significantly associated with RV function. Interaction terms were assessed to determine whether metabolite associations were modified by pulmonary vascular resistance, group 1 PH status, or sex. Least absolute shrinkage and selection operator regression was used to develop metabolite-based scores for RV function, and prognostic performance was assessed. RESULTS: There were 979 participants with plasma metabolomics and RV function data. Linear regression identified 170 metabolites that were significantly associated with all 3 RV metrics. Androgenic steroid, gamma-glutamyl amino acid, polyamine, vitamin A, fatty acid, and sterol pathways are most strongly associated with RV systolic function. Two metabolites interacted with group 1 PH status, and 6 interacted with pulmonary vascular resistance. Four androgenic steroids are associated more strongly with RV systolic function in women compared with men. Metabolite-based scores were prognostically equivalent to RV systolic function metrics and less accurate than REVEAL Lite 2 scores. CONCLUSIONS: We provide a blueprint of metabolites and metabolic pathways associated with RV systolic function across the spectrum of PH. Novel links to vitamin A and glutathione metabolites were observed. We detected few metabolites that associated with RV systolic function differentially by group 1 PH status or degree of pulmonary vascular resistance elevation. Androgenic steroids may associate more strongly with RV systolic function in women compared with men.

Background: Stable osteochondritis dissecans (OCD) lesions are primarily treated nonoperatively. Nonoperative treatment includes several recommendations, including the use of an unloader brace. However, little is known about the clinical effectiveness of unloader bracing and its influence on OCD healing, return to sports, and patient-reported outcomes (PROs). The purpose of this investigation was to evaluate the impact of unloader bracing on patients with stable medial femoral condyle (MFC) OCD lesions treated nonoperatively. Purpose: To investigate the influence of valgus unloader bracing on the success of treating stable MFC OCD with nonoperative treatment strategies. Study Design: Cohort study; Level of evidence, 2. Methods: The authors used a prospective cohort of patients receiving nonoperative care for stable MFC knee OCD lesions. The primary variable of interest was the efficacy of bracing. The primary outcomes were transition from nonoperative care to surgical intervention, return-to-play (RTP) clearance, and PROs. Bivariate testing was used to determine if there were differences between groups. Chi-square testing was used to determine if there were differences in rates of transition to surgery by group. The timing of the transition by each group was assessed using a Wilcoxon rank-sum test, given the nonparametric nature of the data. Kaplan-Meier survival analysis was used to calculate time at risk, incidence rate, and survival times for each group. Results: A total of 185 knees (bracing group: 123 [66.5%] knees; no-bracing group: 62 [33.5%] knees) were analyzed. Overall, 142 (76.8%) knees were successfully treated nonoperatively. Transition to surgery occurred in 43 (23.2%) knees. There were no differences in transition to surgery by groups, with no differences seen by group. Of the knees that did not transition to surgical care, 65 (71.4%) in the bracing group and 38 (74.5%) in the no-bracing group received RTP clearance ( P = .693). PRO scores were similar between the 2 groups at the time of RTP clearance. Conclusion: The inclusion of an unloader brace in the nonoperative treatment for stable MFC OCD lesions did not decrease the likelihood of patients undergoing surgical intervention or improve their PRO scores at the time of RTP clearance. Registration: NCT02771496 (ClinicalTrials.gov identifier).

Abstract A short diagnosis-to-treatment interval independently predicts inferior outcomes in follicular lymphoma. Using international discovery and validation cohorts, we demonstrate its prognostic value beyond established prognostic indices, with implications for risk stratification, clinical trial design, and interpretation.

Abstract We evaluated outcomes by management type for patients with stage IA nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) in the Global NLPHL One Working Group retrospective database of 2243 patients with stages I to IV disease diagnosed from 1992 to 2021 at 38 international institutions. A total of 779 patients had stage IA disease with median age of 35 years (range, 3-89) and median follow-up of 6.1 years. The 6-year progression-free survival (PFS) and overall survival were 86.3% and 97.7%, respectively. Outcomes were analyzed for the 2 groups: complete resection and unresected disease. Patients with a complete resection and observation alone (n = 99) had a 6-year PFS of 65.5% vs 90.5% for those who received radiotherapy (RT) (n = 53). Patients with unresected disease (n = 627; 80.5%) had a 6-year PFS of 62.0% for rituximab alone (n = 31), 89.6% for RT alone (n = 325), 76.8% for ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) alone (n = 40), and 94.3% for ABVD plus RT (n = 130). A total of 127 patients relapsed (16.3%), of which 25 (19.7%) had transformation. Our analysis suggests the following: (1) RT improves the PFS in patients with completely resected disease; (2) rituximab or ABVD alone does not appear to achieve a durable response; and (3) chemotherapy was not observed to add additional PFS benefit when used in combination with RT. Thus, for stage IA NLPHL, RT alone is likely sufficient for definitive treatment.

Abstract Aims Infective endocarditis (IE) is a serious and potentially fatal complication of mitral valve (MV) intervention. There are limited data comparing the incidence of IE after MV repair compared with bioprosthetic MV replacement. The aim of this study was to analyse the incidence and timing of IE after MV repair compared with bioprosthetic valve replacement, in both surgical and transcatheter patient populations. Methods and results A literature search of Medline, Embase, and Cochrane Library (January 2000—September 2025) was conducted. Pooled IE incidence rates were derived using random-effects models. Eighty-two studies (80 939 patients, total follow-up 350 252 patient-years) were included. The overall incidence rate of IE was 0.97 per 100-patient-years (95% confidence interval [CI] 0.71–1.34). IE was more common after surgical MV replacement (SMVR) than surgical MV repair (SMVr): incidence rate 0.93 (95% CI 0.41–1.81) vs 0.39 (95% CI 0.25–0.62) per 100-patient-years, incidence rate ratio (IRR) 2.34 (95% CI 1.06–5.18), P = .035. The incidence of IE after transcatheter MV replacement (TMVR) was comparable to transcatheter MV repair (TMVr) (2.88 [95% CI 1.91–4.33] vs 1.70 [95% CI 0.84–3.43] per 100-patient-years), IRR 1.56 (95% CI 0.73–3.34), P = .250. The cumulative incidence of IE following SMVR was significantly higher than following SMVr at 1- and 2-years post-procedure, but not at 6 months. Conclusions IE is an infrequent complication of mitral valve intervention. The incidence of IE following SMVR is significantly higher than following SMVr, while the incidence of IE following TMVR is numerically but not significantly higher than following TMVr. Reducing IE risk after mitral intervention is a clinical and research priority.