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Importance Cerebral hemodynamic impairment in patients with asymptomatic internal carotid artery (ICA) stenosis is associated with reduced cognition. It is uncertain whether revascularization might be an effective treatment for cognitive impairment in these patients. Objective To test whether any cognitive benefit from revascularization of high-grade, asymptomatic ICA stenosis varies based on the degree of baseline cerebral hemodynamic impairment. Design, Setting, and Participants This substudy was conducted within a multicenter phase 3 randomized clinical trial. Adults (aged 35-86 years) without dementia with eighth-grade education or higher and unilateral asymptomatic ICA stenosis greater than or equal to 70% were enrolled from January 2018 to July 2024 at 61 sites in North America (last follow-up in July 2025). Of 607 participants screened from 2485 in CREST-2, 392 were enrolled. Magnetic resonance or computed tomographic perfusion imaging tested for baseline hemodynamic impairment defined by delayed time-to-peak (TTP) arrival of intravenous contrast in the hemisphere ipsilateral minus contralateral to the stenotic artery. Intervention Carotid revascularization (endarterectomy or stenting) plus intensive medical management (IMM) vs IMM alone. Main Outcomes and Measures The primary outcome was the difference in composite cognitive z score over 1 year based on 5 cognitive tests. The primary analysis tested for an interaction between treatment group (revascularization vs IMM alone) and degree of baseline hemodynamic impairment among those with reduced baseline cognition (cognitive z score ≤−1.0 SD). Results Of 392 participants enrolled (mean age, 71 years; 125 [32%] females), 61 were excluded for missing baseline imaging and 40 for missing cognitive examinations or other covariates, leaving 291 with complete data. Fifty-one had reduced cognition at baseline (25 in the revascularization group and 26 in the IMM alone group). TTP ranged from no interhemispheric TTP delay to a more-than-2-second delay. Mean (SD) cognitive z scores were −1.36 (0.51) at baseline and −1.17 (0.47) at 1 year in the revascularization group and −1.34 (0.83) at baseline and −1.01 (0.97) at 1 year in the IMM alone group. The primary analysis showed no difference in cognition by treatment group over 1 year, adjusting for treatment group × hemodynamic status interaction and other covariates (adjusted difference in cognitive z score, −0.15 SD [95% CI, −0.54 to 0.24]). The interaction was not significant (β estimate = 0.018 [95% CI, −0.025 to 0.061]; P = .40). Conclusions and Relevance In this substudy of a randomized clinical trial, there was no differential effect of revascularization vs IMM alone on cognition over 1 year by cerebral hemodynamic status among those with baseline reduced cognition, suggesting that revascularization does not improve cognitive dysfunction by restoring flow to the brain in chronic asymptomatic carotid stenosis. Trial Registration ClinicalTrials.gov Identifier: NCT03121209

Introduction: Understanding mid-term test-retest reliability and within-subject variability is important for interpreting changes observed in longitudinal and intervention studies. The reliability of resting-state functional magnetic resonance imaging (rs-fMRI) is known to vary across measures and brain regions. However, how reliability differs across functional networks and connectivity- and amplitude-based measures, and whether multi-echo acquisition and processing modify these patterns, remain incompletely characterized. Methods: Twenty-two healthy volunteers underwent two rs-fMRI sessions 15.7 ± 4.0 days apart on a Compact 3T scanner. Multi-echo, middle-echo, and independently acquired single-echo datasets were compared, with multi-echo independent component analysis additionally evaluated as a denoising approach. Functional connectivity (FC) and three amplitude-based measures were evaluated using the Schaefer 400 parcellation. Reliability was systematically assessed using intraclass correlation coefficient (ICC), within-subject standard deviation (wSD), and systematic bias at edge or regional, and network levels. Results: Acquisition-dependent differences in reliability were generally modest. Multi-echo acquisition and processing increased functional connectivity strength and the magnitude of amplitude-based measures and improved inferior cortical coverage, but these enhancements did not consistently translate into substantially higher ICC or lower wSD. In contrast, reliability showed clear network-dependent differences. FC reliability varied markedly across network pairs and was not explained by connectivity strength alone; pairs involving the default mode and control networks generally showed more favorable profiles than several somatomotor and visual network pairs. Fractional amplitude of low-frequency fluctuations (fALFF) also showed network-dependent reliability, with the most favorable regional reproducibility observed in the default mode and control networks and lower reproducibility in the somatomotor and visual networks. Conclusion: These findings provide practical mid-term reliability benchmarks for rs-fMRI on a Compact 3T scanner and show that measurement stability varies more clearly across measures and functional networks than across acquisition approaches.

Abstract Purpose Medical school applicants engage in informal preference signaling by submitting letters of intent (which include a commitment to accept an admission offer) and letters of interest (which include no such commitment). Commitments are unenforceable and are based on an honor system. Applicants submit letters to medical schools before receiving financial aid offers, potentially disadvantaging low socioeconomic status (SES) applicants. This study describes postinterview communication patterns and analyzes associations among applicant demographics, letter submission rates, and admissions outcomes. It tests the hypothesis that low SES is negatively associated with letter of intent submission. Method The authors collected postinterview communications from all interviewees at the Mayo Clinic Alix School of Medicine during 3 admissions cycles (2021-2023). Authors developed and validated codebook definitions for the 2 letter types. SES was defined using the Association of American Medical Colleges education-occupation indicator. Letter submission rates were compared using mixed-effects logistic regression. Results Of 1,313 applicants, 1,109 submitted 1 letter or more. The sample included 257 (19.6%) low-SES and 1,056 (80.4%) non–low-SES applicants. Coders showed excellent interrater reliability (Gwet AC1 range, 0.89-0.995). Low-SES applicants submitted letters of intent with similar frequency to higher-SES applicants (33.9% [87/257] vs 33.5% [354/1,056]; odds ratio, 1.02; 95% CI, 0.76-1.37; P = .88) and submitted letters of interest at similar frequency (55.6% [143/257] vs 59.5% [628/1,056]; odds ratio, 0.86; 95% CI, 0.65-1.13; P = .27). Among 116 applicants who wrote letters of intent and were offered admission, 20 (17.2%) declined the admission offer. Conclusions There was no difference in letter of intent submission based on SES, and letter of intent submission was positively associated with matriculation. Among letter of intent writers who were offered admission, 1 in 6 declined. Undergraduate medical education may wish to consider a formalized preference signaling system to promote an honest and transparent application process.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Abstract Hypoxia constrains cerebral oxygen availability and challenges brain function and stability. Although hypoxia-responsive functional connectivity (HR-FC) reorganizes rapidly with declining arterial oxygen partial pressure, its relationship to local neurovascular activity remains unclear. We examined time-resolved amplitude of low-frequency fluctuations (ALFF) in blood-oxygenation-level dependent (BOLD) fMRI during graded acute hypoxia in healthy adults, performing a continuous cognitive test (Go/No-go task) with concurrent physiological monitoring. Dynamic ALFF and functional connectivity were estimated using a sliding-window approach and analyzed across large-scale brain networks defined by Schaefer’s 17-network parcellation. Severe hypoxia elicited temporally dissociated responses across modalities. Functional connectivity increased monotonically, whereas ALFF exhibited pronounced nonlinear modulation, including phase-dependent divergence across networks. During hypoxic decompensation, the default mode network (DefaultA) showed marked ALFF suppression, whereas a ventral secondary somatosensory-dominant network (SomMotB) exhibited preferential preservation despite similar engagement in HR-FC. Together, these findings indicate that network-level ALFF captures a distinct yet complementary layer of functional dynamics, with a temporal profile distinct from functional connectivity. Spontaneous BOLD dynamics during acute hypoxia reflect structured network-level modulation rather than a uniform suppression attributable solely to reduced oxygen availability. These findings support a conceptual framework of cerebral oxygen budgeting , in which metabolic constraints reshape functional dynamics across brain networks.

ABSTRACT Purpose Active lesion expansion is clinically important because it can indicate disease progression and influence management and treatment planning. However, sequential imaging is often unavailable, and rapid growth can only be inferred from indirect findings such as active perilesional tissue injury. This study aimed to implement and test the feasibility of an MR elastography (MRE)‐based technique for assessing the expansile nature of mass lesions by detecting stiffness changes caused by mechanical strain manifestations in adjacent tissues. Methods A tissue strain mapping (TSM) algorithm was developed using spatial–temporal directional filtering to reveal the presence of perilesional latent strain that is not apparent in conventional MRE inversions. The technical feasibility was tested in tissue‐simulating phantoms containing a mass that was progressively expanded. Preliminary feasibility for clinical application was also demonstrated in representative in vivo examples. Resulting TSM maps were compared with conventional MRE stiffness maps. Results In the phantom experiments, TSM revealed the presence of local strain at the periphery of the expanding mass, with the effect increasing proportionally to the degree of expansion. Conventional MRE did not demonstrate comparable localized stiffening patterns. In vivo examples showed similar perilesional strain features that were not apparent on conventional MRE maps. Conclusion The feasibility of the proposed MRE‐based TSM technique was demonstrated in phantom and preliminary in vivo studies. These findings suggest that the technique is a promising tool for assessing the expansile nature of mass lesions and motivate further development of the TSM processing and exploration of potential clinical applications.

Objective: To explore the existing evidence on novel imaging modalities that may aid in prognostication of vestibular schwannoma (VS) clinical outcomes across various management approaches. Study design: Scoping review. Setting: Not applicable. Patients: Individuals diagnosed with VS. Interventions: Novel imaging techniques. Main outcome measures: Tumor growth and response to medical therapy. Results: A total of 18 articles were included in this review. Of these, 7 focused on pretreatment prognosis, 6 evaluated radiosurgery outcomes, 4 examined microsurgery outcomes, and 1 assessed response to bevacizumab. The imaging modalities investigated included radiomics (n = 10), positron emission tomography (PET; n = 2), dynamic contrast-enhanced MRI (DCE-MRI; n = 2), both PET and DCE-MRI (n = 1), magnetic resonance elastography (MRE; n = 1), contrast-enhanced CT (CE-CT; n = 1), and slip interface imaging (SII; n = 1). Radiomic studies yielded encouraging results in predicting tumor growth after wait-and-scan and radiosurgery, with reported accuracies ranging from 52% to 88%, sensitivities from 13% to 95%, specificities from 50% to 94%, and area under the curves from 0.65 to 0.99. PET studies identified several promising ligands associated with tumor growth during wait-and-scan, suggesting a potential role in prognostication. DCE-MRI also demonstrated associations with tumor growth and treatment response to bevacizumab. Studies on MRE, CE-CT, and SII identified novel imaging parameters associated with tumor stiffness and adhesion. Conclusions: Several emerging imaging modalities hold potential for improving clinical outcome prognostication in VS. Techniques such as radiomics, PET, and DCE-MRI have shown promising results; however, the supporting evidence is still limited and heterogeneous. Further research is necessary to validate and refine these approaches to enhance their clinical utility.