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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.

Abstract Progressive supranuclear palsy (PSP) and corticobasal degeneration (CBD) are both neurodegenerative diseases characterized by aggregates composed of 4‐repeat (4R) tau protein. They have distinct neuropathological features and classic clinical symptoms; however, the signs and symptoms overlap across the two syndromes. Accumulating evidence suggests that dysregulated immune response is a major contributing factor to neurodegeneration but its role in 4R‐tauopathies remains undetermined. The aim is to explore the involvement of neuroinflammation from a vascular perspective in 4R‐tauopathies. Autopsies from four controls, three PSP, and three CBD cases were assessed. Samples were obtained from the superior/middle frontal gyrus (S/M‐FG) and basal ganglia (BG). Immunofluorescence staining included neuroinflammatory markers: glial fibrillary acidic protein (GFAP), ionized calcium‐binding adapter molecule 1 (Iba1), cluster of differentiation 68 (CD68); vascular markers: collagen type IV (ColIV), monocarboxylate transporter‐1 (MCT1), and α‐smooth muscle actin ( α SMA). Maximally projected confocal z‐stack images of vasculature were used as a mask to quantify total perivascular GFAP+/Iba1+/CD68+ labeling. GFAP immunoreactivity ratio between MCT1 and α SMA double labeled arteries and veins was quantified to further differentiate venular and arteriolar involvement into proinflammatory activation. Both PSP and CBD had widespread perivascular proinflammatory changes, although greater in CBD. The activated GFAP+ astrocytes and microglia/macrophages in CBD were distributed extensively in S/M‐FG and BG, with S/M‐FG WM more affected. In PSP, abundant neuroinflammation was found in BG. The involvement of vasculature type was distinct among the two 4R‐tauopathies, while CBD showed comparable proinflammatory changes in arterioles and venules, PSP exhibited predominant proinflammation in venules. The regional pattern of perivascular proinflammation differed between PSP and CBD, corresponding to the characteristic affected brain regions. CBD had more severe perivascular proinflammation that involved both arterioles and venules, while venules were more affected in PSP. Perivascular proinflammation may be a critical pathophysiological process in 4R‐tauopathies.

Background & Aims: To evaluate safety and efficacy of FGFR1–3 kinase inhibitor derazantinib, in advanced intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 fusions or rearrangements ( FGFR2 F ), mutations ( FGFR2 M ), or amplifications ( FGFR2 A ), previously treated with chemotherapy. Approach & Results: Open-label, non-controlled Phase 2 trial. Patients with advanced iCCA, ≥1 prior chemotherapy, and FGFR2 F (Substudy 1) or FGFR2 M /FGFR A (Substudy 2), received once-daily oral derazantinib 300 mg until disease progression, unacceptable toxicity, consent withdrawal or investigator decision to stop. Efficacy was assessed by central radiology review using RECIST v1.1. Primary endpoints were objective response rate (ORR; Substudy 1) and 3-month progression-free survival (PFS3; Substudy 2). Other endpoints were PFS, ORR (Substudy 2), disease control rate (DCR), duration of response (DOR), and overall survival (OS). In Substudy 1, ORR and DCR were 22.3% (23/103 partial responses) and 75.7%, respectively; median (95% CI) PFS was 8.1 (5.5,8.3) months, DOR was 6.5 (4.6,9.2) months, and OS was 17.2 (12.5,22.4) months. In Substudy 2, PFS3 was 63% (27/43), ORR was 9.3% (3 partial, 1 complete response), DCR was 69.8%, and OS was 11.9 (8.4,15.9) months. There were no Grade 4 or 5 drug-related events. FGFR inhibitor class-specific toxicities included drug-related hyperphosphataemia (38%, Grade 3: 3%) and dry eye (36%). Nail disorders (10%, any grade or causality), stomatitis (5%), retinal events (5%), and palmar-plantar erythrodysesthesia (1%) were infrequent. Conclusions: In previously chemotherapy treated, FGFR-inhibitor-naïve patients with iCCA harboring FGFR2 fusions, mutations, or amplifications, derazantinib showed clinically meaningful efficacy with durable objective responses, and a manageable safety profile.

PURPOSE Patients with breast cancer requiring postmastectomy radiation therapy (PMRT) often desire breast reconstruction. Reconstructions can be adversely affected by PMRT, and fear of reconstruction complications has discouraged adoption of short-course radiation therapy used after lumpectomy. To fill the evidence gap, we conducted a noninferiority trial of hypofractionated versus conventional PMRT in patients undergoing breast reconstruction. The primary outcome was reconstruction complication rate, a composite of wound healing, readmission, capsular contracture, unplanned reoperation, and reconstruction failure. METHODS Women with unilateral invasive breast cancer with planned immediate or delayed reconstruction and PMRT were randomly assigned (1:1) to 50 Gy (25 fractions/5 weeks) or 42.56 Gy (16 fractions/3 weeks). This study was designed with a noninferiority margin of 10%, assuming a 2-year reconstruction complication rate of 25% with conventional PMRT. Randomization was stratified by immediate versus delayed and autologous versus implant-only reconstruction. RESULTS Between 2018 and 2021, 898 patients enrolled with a median follow-up of 3.9 years; 825 patients were evaluable for the primary end point. The 24-month reconstruction complication rates were 12.3% (52/422) with hypofractionated PMRT and 10.2% (41/403) with conventional PMRT, corresponding to an estimated difference of -2.1% (95% CI, -6.5 to 2.2). The complication rate was higher (regardless of arm) with implant-only versus autologous reconstruction (odds ratio = 1.65). There was no statistically significant difference in 36-month locoregional recurrence rates: 1.5% (95% CI, 0.7 to 3.2) with hypofractionated and 2.2% (95% CI, 1.1 to 4.3) with conventional PMRT. Acute and late toxicity rates were not statistically different. CONCLUSION A 16-fraction course of hypofractionated PMRT is safe and noninferior to conventional PMRT in women undergoing breast reconstruction after mastectomy.

Systematic reviews of randomized controlled trials (RCTs) support evidence-based clinical advancement. Clinical trial reporting guidelines, including CONSORT, establish common data elements that support systematic synthesis of published trial outcomes. However, the rapid rise of digital health technologies presents new challenges for reporting guidelines, and substantial real-world reporting heterogeneity has been observed. Therefore, machine-assisted evaluation of reporting adherence offers a pathway for more agile information management to accommodate the diverse and disruptive nature of digital health technology-enabled RCTs. Here, we propose an accelerated retrieval-to-abstraction literature synthesis framework to conduct article screening, text and table data preprocessing, and full-text review using an unmodified pretrained large language model. We apply this methodology in two digital health technology-enabled RCT case studies evaluating adherence to technology and digital health equity guideline reporting items. Large language model performance was on par with inter-annotator agreement F1 scores (≥0.9) in both screening and information-extraction tasks. These findings support the scalability and rigor of accelerated evidence synthesis and demonstrate the importance of common reporting elements across digital health technology-enabled RCTs.

Abstract Glioblastoma (GBM) is a lethal, treatment-resistant brain cancer characterized by diffuse brain invasion, complex neuron-glioma signaling, and cellular, molecular, and spatial heterogeneity. Surgery is the current mainstay of treatment, aimed at maximizing tumor cytoreduction, decompressing the brain to improve neurological function, and providing material for analyses to inform prognostication and adjuvant treatment selection. To accurately model GBM surgical resection and tissue sampling in preclinical animal models, we developed the Maximal Safe Intracranial Surgery (MSIS) system. MSIS integrated a miniaturized neurosurgical resection device and enabled a safe, tunable, and reproducible approach for intracranial tumor resection, multi-regional biopsy, and longitudinal tissue sampling in murine models, with stereotactic, sterile, and high-viability tissue collection. MSIS was applied across five distinct orthotopic brain tumor models to reproducibly generate histologically and radiologically representative models of post-surgical GBM. Similar to humans, increasing the extent of resection correlated with improved animal survival, and recurrent growth patterns varied significantly by model type. Transcriptional profiles of matched primary vs. post-surgical recurrent tumors revealed enrichment of margin-associated transcriptional states consistent with neuron-glioma signaling. Overall, the MSIS system offers opportunities to model the standard-of-care, dissect the spatial and temporal dynamics of GBM, and pair therapeutic discovery with contextual tumor pathobiology.

Abstract Context Menstrual irregularities have been associated with cardiovascular disease (CVD) risk, but underlying etiologies may confer distinct risk profiles. Functional hypothalamic amenorrhea (FHA) has not been evaluated as a separate risk phenotype. Objective To assess the association between FHA phenotype and incident CVD and cardiometabolic risk factors. Design Prospective cohort study with biennial follow-up from 1993 to 2019. Setting Nurses’ Health Study II cohort. Participants The sample included 52,655 premenopausal women free of CVD in 1993. FHA phenotype was defined as irregular or absent cycles without PCOS traits combined with low body mass index and/or high physical activity. Intervention None Main Outcome Measures Incident CVD (coronary heart disease [CHD; myocardial infarction or coronary revascularization] and stroke) and incident elevated cholesterol, hypertension, and type 2 diabetes (T2DM). Results During up to 26 years of follow-up, 1,007 CVD events occurred. Among women who developed CVD, the median time to the first CVD event was 17.0 years (IQR, 11.3-21.0). FHA phenotype in mid-adulthood was associated with a 62% higher risk of CVD (95% confidence interval [CI]: 1.01–2.59), driven by an almost two-fold higher risk of CHD (hazard ratio [HR] = 1.91; 95% CI: 1.11–3.27), compared with women with regular cycles. FHA was also associated with T2DM (HR = 1.86; 95% CI: 1.41–2.47), but not hypertension or elevated cholesterol. Non-FHA menstrual irregularity was associated with elevated cholesterol, hypertension, and T2DM, but not CVD. FHA in early adulthood was not associated with outcomes. Conclusions FHA phenotype in mid-adulthood was associated with increased CHD risk independent of traditional risk factors. Menstrual history may serve as an early marker of cardiometabolic risk.

Background/Objectives: The role of iron in Alzheimer’s disease (AD) and frontotemporal lobar degeneration (FTLD) has been debated. However, the effects of iron on protein burden in these diseases remain poorly elucidated. We hypothesized that there is an association between iron deposition and tau and beta-amyloid deposition in deep grey matter (GM) regions in FTLD. Methods: Neuropathological samples were collected from two control subjects and 10 disease subjects. This included 12 subjects, with several pathological subgroups represented by only one or two cases. Of the 10 disease subjects, one had low-level AD neuropathology (L-AD), and one had high-level AD neuropathology (H-AD), whereas the remaining eight subjects had FTLD-tau pathology, including progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), globular glial tauopathy (GGT), and Pick’s disease (PiD). Neuropathological samples were stained for iron with Prussian blue (PB) and ferritin, tau, and beta-amyloid in the basal ganglia (BG). All 12 subjects had also undergone diffusion MRI, amyloid-PET (PiB-PET), and Tau-PET (flortaucipir) before death. Diffusion tensor imaging mean diffusivity (MD) from BG was examined in each subject. Spearman’s rank correlations between imaging and histology were calculated. Results: Increased BG iron was observed in PSP subjects. Prussian blue and ferritin measures were associated with higher tau- and β-amyloid pathological burden. Tau-PET uptake correlated with iron in the BG. Conclusions: The results of this exploratory study suggest associations between iron burden and tau- and β-amyloid-related measures within basal ganglia regions that may help to explain increased PET signals in AD and FTLD-Tau. Our findings should be considered to be hypothesis-generating and require validation. These preliminary findings require validation in larger cohorts.