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Importance Delirium is a state of acute confusion characterized by deficits in attention that occurs commonly during hospitalization and is associated with adverse outcomes; however, the association of delirium with longitudinal cognitive trajectories is not fully understood. Objective To evaluate the association of delirium during hospitalization with subsequent development of mild cognitive impairment (MCI), dementia, and longitudinal cognitive trajectories. Design, Setting, and Participants This cohort study used data from participants with hospitalizations in the Mayo Clinic Study of Aging (MCSA) from October 2004 to December 2023. The MCSA is a prospective, population-based longitudinal study of cognitive aging among residents of Olmsted County, Minnesota. Of participants enrolled in the MCSA between 2004 and 2023, individuals who experienced 1 or more hospitalization prior to their last MCSA encounter were included in this study. Participants with dementia at MCSA enrollment or prior to first hospitalization were excluded. Follow-up continued until development of MCI or dementia, last MCSA visit, or the end of the study. Exposure Delirium was identified using a validated natural language processing algorithm applied to clinical notes from hospitalizations, associated emergency department visits, and follow-up within 30 days after hospitalization. Delirium status was modeled as a time-dependent exposure. Main Outcomes and Measures Incident MCI and dementia were assigned through MCSA expert consensus evaluations, including neuropsychological testing performed every 15 months. Association between delirium and development of MCI or dementia was assessed using Cox proportional hazards regression, adjusted for patient age, sex, level of education, and apolipoprotein E (APOE) ε4 allele carrier status; cognitive trajectories were assessed with linear mixed-effects models. Results Of 7030 participants enrolled in the MCSA, 3542 individuals experienced 1 or more hospitalization prior to their last MCSA encounter and were included, and 41 participants with dementia at enrollment or prior to first hospitalization were excluded. The cohort included 3501 participants with at least 1 hospitalization. Median (IQR) age was 74.1 (66.6-80.9) years, 1676 participants (47.9%) were female, median (IQR) level of education was 14 (12-16) years, and 910 participants (26.0%) were APOE ε4 carriers. During a median (IQR) follow-up of 7.2 (4.1-10.4) years, 75 participants (2.1%) had delirium documented within 30 days of hospitalization. Delirium was associated with increased risk of MCI (adjusted hazard ratio [aHR], 3.67; 95% CI, 2.19-6.15) and dementia (aHR, 5.39; 95% CI, 2.94-9.85) and with accelerated decline in longitudinal cognitive testing. Conclusions and Relevance In this cohort study among adults in the MCSA, including those with unimpaired cognition at baseline, delirium during hospitalization was strongly associated with increased risk of MCI and dementia and accelerated cognitive decline in subsequent years.

Diffuse B-cell lymphomas are the most prevalent canine hematologic malignancies, and their clinical presentation resembles that of human B-cell non-Hodgkin lymphomas (NHLs). However, a lack of a clear subtyping framework perpetuates imprecise treatment approaches that fail to address mechanisms of therapy resistance. Here, we employed deep phenotyping via serial sampling and longitudinal transcriptomics to evaluate intratumoral composition and therapy response in a 6-year-old neutered male goldendoodle with stage 5A marginal zone lymphoma (MZL). Following sequential treatment consisting of a single IV dose of oncolytic vesicular stomatitis virotherapy (VSV) and standard CHOP chemotherapy 30 days later, we performed scRNAseq on seven serial lymph node biopsies and spatial sequencing on a resection taken 10 days post-VSV treatment. B cells (>90%) comprised three transcriptionally distinct and temporally stable subpopulations, with specific copy number profiles and robust spatial organization despite disrupted lymph node architecture. Analysis across subpopulations revealed downregulation of the quiescence program including KLF2, suggesting similarity to KLF2-deficient human MZL. While VSV successfully reached target B cells, downstream transcriptional responses were predominantly localized to the T-cell compartment. T cells (≤6%) showed increased proliferation and upregulation of cytotoxicity markers post-VSV administration, enriching for leukocyte-mediated cytotoxicity pathways consistent with an anti-viral immune response. Ultimately, these results provide an in vivo proof-of-concept for the treatment paradigm in canine lymphoma, while emphasizing the need for improved subtyping frameworks and multidimensional treatment strategies targeting intratumoral heterogeneity.

PURPOSE Detection of bone marrow disease has been a major component of rhabdomyosarcoma (RMS) staging with bilateral bone marrow aspirates/biopsies (BMAB) from the iliac crests considered the diagnostic gold standard. This study's goal was to determine if 2- 18 F-labeled fluorodeoxyglucose positron emission tomography/computed tomography ([ 18 F]FDG PET/CT) or PET/magnetic resonance imaging (MRI) may replace BMAB in RMS staging. METHODS Patients were recruited in Europe and North America. Medical records, FDG PET/CT or FDG PET/MRI (PET), and BMAB reports were collected retrospectively. Images were re-reviewed by nuclear medicine physicians at the patients' home institutions if PET reports indicated increased FDG uptake at bone/bone marrow sites or if tumor cells were detected in bone marrow samples. RESULTS PET imaging and BMAB were performed before chemotherapy and tumor resection in 301 patients with FDG-avid RMS. Bone marrow metastases were detected by PET and BMAB in 54, by PET only in 24, and by BMAB only in one of 301 patients with FDG-avid primary tumors. Absence of bone marrow metastases was confirmed by PET and BMAB in 222 of 301 patients. These observations translated into 98% sensitivity and 90% specificity for PET in detecting bone marrow metastases when BMAB was considered as gold standard. FDG-avid marrow disease was patchy (1-5 foci) in one third of cases. Patients with marrow disease indicated by PET and BMAB had more FDG-avid bone marrow foci, more metastatic sites, and lower survival than those with marrow disease indicated by PET only, suggesting more advanced disease stages. CONCLUSION Bone marrow sampling may be omitted in patients without evidence of FDG-avid bone marrow disease by PET. If there are FDG-avid bone marrow lesions, further investigation by MRI and/or biopsy should be considered.

Abstract The liver is organized into tightly regulated zones with distinct metabolic functions but zonation erodes with age. Cellular senescence contributes to aging and liver diseases, however, its impact on aging biology is ill-defined. As part of The Cellular Senescence Network Consortium, we used multiple spatial transcriptomics approaches (GeoMx, Visium, CosMx) with snRNA-seq to profile senescence signatures, zonation markers, and metabolic pathways in livers from wild-type (WT) mice of multiple ages. We observed a loss of canonical zone signatures in aged mouse livers characterized by “expansion” of midlobular (zone 2) marker gene expression, accompanied by diminished expression of zone 3 marker genes by middle-age (18 months), indicative of loss of cell identity. Multiple analytic approaches identified distinct age-, zone- and sex-specific senescence signatures, which were significantly associated with zonation markers changes. This was recapitulated in Ercc1 mutant models of accelerated senescence, supporting a causal role of senescent cells in liver aging. A “no-zone” hepatocyte-like cluster expanded with age and with the strongest Senescence-Associated Secretory Phenotype (SASP) profile. Gene expression profiles from senescent hepatocytes implicate decreased WNT signaling and increased BMP as contributing to age-related loss of zonation. Together, these data elucidate the role of senescent cells in driving aging biology in non-diseased liver through disruption of cell:cell signaling and the loss of metabolic and cell identity gene expression necessary for hepatocyte function.

By acquiring the first human and equipment radiographs in space, this study demonstrated the feasibility of on-orbit radiography and expanded diagnostic capabilities for crew health and hardware evaluation.

Abstract Objective This study was undertaken to examine acute and chronic electroencephalographic (EEG) and seizure characteristics in new onset refractory status epilepticus (NORSE). Methods Multicenter inpatient and follow‐up clinical and EEG data were analyzed using International League Against Epilepsy definitions and American Clinical Neurophysiology Society (ACNS) EEG terminology. Results Forty‐four patients were included from the Yale NORSE/FIRES Biorepository (median age = 29 years, 33 female, 38 cryptogenic). Nine hundred twenty inpatient EEG days were reviewed (median = 13.5 days/patient). Presenting status epilepticus (SE) types included 24 convulsive SE (CSE), five focal–motor (FMSE), and 15 nonconvulsive (NCSE). Of 39 patients with post discharge follow‐up (median = 14.7 months), 61.5% ( n = 24) had seizures and required more antiseizure medications than seizure‐free patients (median = 4 vs. 1, p < .001). Inpatient EEG captured epileptiform discharges in all and periodic discharges in 38 patients. Seizures were captured in 38 patients: 33 electrographic (11 only electrographic) and 27 electroclinical. Total seizure burden ranged 6.5–29 615.0 min (median = 50.7). Seizures fulfilling ACNS EEG criteria for SE were captured in 20 patients; two had CSE and the remainder NCSE with coma, nine of whom also had FMSE. Inpatient seizure days (median = 50.0 vs. 15.5%, p = .004) and seizure burden (median = 42.9 vs. 0 min, p = .009) were higher in the first half of monitored days. Interictal findings were equally present and did not predict postdischarge seizures, whereas electroclinical seizures (90.9% vs. 45.5%, p = .037), seizure burden (median = 116.8 vs. 32.5 min, p = .045), and proportion of seizure days (36.3% vs. 20.0%, p = .037) did. Among 12 patients with follow‐up EEGs (median = 19.6 months post onset), posterior‐dominant rhythm (PDR) returned in nine; five had periodic discharges, and three had seizure captured. Significance Seizures are most commonly convulsive upon presentation and nonconvulsive or clinically subtle throughout the inpatient course in NORSE. Inpatient seizures, but not interictal abnormalities, occur earlier in the inpatient course and presence of electroclinical seizures, seizure burden, and proportion of seizure days but not interictal findings are associated with postdischarge seizures. Although return of PDR reflects neurological recovery, seizure persistence and EEG abnormalities post‐NORSE are common.

Abstract Spatial transcriptomics has been widely applied to study the spatial distribution of cell types, cell states, and specific gene expression in tissue samples. However, we show that there is a prevalent transcript leakage problem in spatial transcriptomics data, where transcripts expressed by a cell diffuse to its neighborhood and are recurrently detected in the nearby cells. By analyzing published data sets, we show that this problem is general across data produced from different tissues and different species using different imaging-based and sequencing-based spatial transcriptomics platforms. It affects both upstream tasks such as expression quantification as well as downstream tasks such as cell-type annotation and detection of spatially-dependent gene expression. To tackle the transcript leakage problem, we propose a reference-free Bayesian model-based method, DeLeakage, which cleans up the data much more effectively than existing denoising methods. DeLeakage also improves cell-type annotation and avoids false detection of spatially dependent expression.

625 Background: I-SPY 2 is a multicenter phase II adaptive platform trial evaluating novel agents for stage II-III high-risk breast cancer using response-predictive subtypes (RPS) and a sequential neoadjuvant treatment design of up to three blocks (A/B/C). Investigational regimens are given in Block A, followed by response-guided escalation to standard-of-care (SOC) therapy (tx) in subsequent blocks or early surgery for responders. Topoisomerase I (TOPO1) inhibition plus PARP inhibition may enhance DNA damage and tumor response. DAN-222 is a tumor-targeted polymeric camptothecin conjugate designed to improve the therapeutic index of TOPO1 inhibition. Based on favorable phase 1 safety and preliminary activity in metastatic breast cancer, DAN-222 plus niraparib was evaluated as Block A tx in HER2− disease. Notably, the neoadjuvant regimen used a higher dose of niraparib (200 mg daily) than the prior phase 1 metastatic study. Methods: Patients (pts) with HER2− breast cancer were randomized to DAN-222 plus niraparib for up to 12 weeks in Block A. Response was assessed by serial MRI and biopsy. Inadequate responders escalated early to SOC tx in Blocks B/C. Primary endpoint was pathologic complete response (pCR). Secondary endpoints included residual cancer burden, safety, early discontinuation, and treatment-strategy performance versus subtype-specific SOC tx controls. Given established PARPi sensitivity in BRCA mut disease, the key objective was to assess clinically meaningful activity of DAN-222 plus niraparib in BRCA wt pts. Accordingly, a prespecified Bayesian interim futility analysis focused on BRCA wt and tested the probability of the true pCR rate after Block A alone exceeded 15% after 50 pts. Results: Fifty pts enrolled from Sep to Dec 2024. In BRCA wt (n=47), estimated Block A pCR was 3%, with posterior probability of 0.02 that that true pCR exceeded 15%, meeting futility criteria and prompting arm closure. Across all blocks, pCR rate was 57% (8/14) for HR-HER2−; 11% (4/36) for HR+ HER2−, largely after SOC tx. 2/3 BRCA mut pts achieved pCR. Treatment strategies initiating with DAN-222 plus niraparib underperformed subtype-specific controls. 68% discontinued Block A early, mainly due to toxicity. Grade ≥3 cytopenias were common: neutropenia (n=25; 50%), anemia (24%), and thrombocytopenia (18%). Cystitis occurred in 36% (1 grade ≥3). Conclusions: Neoadjuvant DAN-222 plus niraparib showed insufficient activity and no treatment-strategy benefit in BRCA wt HER2− breast cancer, underscoring challenges for TOPO1–PARP inhibitor combinations. Although not supported for further development in this setting, these results highlight the strength of I-SPY 2 in rapidly enrolling patients and quickly distinguishing ineffective from promising therapeutic strategies to accelerate progress toward improved outcomes for patients with curable breast cancer. Clinical trial information: NCT01042379 .