Citations

Dynamic fluid and solute transportation across the arachnoid barrier in the meninges of healthy participants was measured by tracking intravenous gadolinium-based contrast agent entering cerebrospinal fluid from dural blood vessels using dynamic dual-spin-echo perfusion MRI.

Background Multimorbidity is common in patients with atrial fibrillation (AF); however, the impact of the number and type of comorbid conditions on outcomes remains uncertain. Methods This cohort study included patients with new‐onset AF from a Midwest region between 2013 and 2017. Eighteen chronic conditions at the time of AF were classified into groups: cardiometabolic, other somatic, and mental health. Cox regression determined associations between the number of each condition type with death, ischemic stroke/transient ischemic attack, and congestive heart failure, stratified by age. Results Among 16 509 patients with AF (mean age, 74 years; 43% women), the mean number of cardiometabolic, other somatic, and mental health conditions was 2.7, 1.4, and 0.5, respectively. The number and type of conditions had a varying impact on outcomes and differed by age. A higher number of cardiometabolic conditions were associated with increased risk of death within 90 days only in people aged ≥85 years (≥4 conditions versus 0: hazard ratio [HR], 1.74 [95% CI, 1.05–2.87]), whereas for death after 90 days, associations were strongest in the youngest age group (<65 years: HR, 1.83 [95% CI, 1.35–2.46]; 65–74 years: HR, 1.34 [95% CI, 1.04–1.73]; 75–84 years: HR, 1.32 [95% CI, 1.09–1.60]; ≥85 years: HR, 1.14 [95% CI, 0.96–1.35]). Associations with outcomes were generally strongest in the youngest age group and attenuated with older age for higher number of other somatic conditions, whereas the pattern was less consistent for mental health conditions. Conclusions Along with cardiometabolic‐related conditions, other somatic and mental health conditions are important predictors of outcomes in AF, with effects differing by age, and should be considered when caring for these patients.

BACKGROUND: Guidelines acknowledge that discordant low-gradient (LG) aortic stenosis (AS) may be severe, but verifying this can be challenging. Right heart catheterization during exercise is considered the gold standard for evaluating ventricular hemodynamics. No invasive studies have compared the hemodynamic response of discordant LG and severe AS during exercise. The aim of this observational study was to describe exercise hemodynamics in patients with asymptomatic discordant AS and left ventricular ejection fraction ≥50%. METHODS: Patients with aortic valve area ≤1.5 cm 2 underwent right heart catheterization at rest and during maximal exercise, measuring pulmonary capillary wedge pressure (PCWP), cardiac output (CO), and the PCWP/CO-slope. Patients were stratified into 3 groups: discordant LG AS (aortic valve area ≤1.0 cm 2 and mean gradient <40 mm Hg); moderate AS (aortic valve area >1.0 cm 2 ); and high-gradient (HG) severe AS (aortic valve area ≤1.0 cm 2 and mean gradient ≥40 mm Hg). RESULTS: Among 86 patients, 17 (20%) had discordant LG, 49 (57%) moderate, and 20 (23%) HG severe AS. The median PCWP/CO-slope was significantly steeper in discordant LG (3.3 [interquartile range, 2.1–4.3] mm Hg/L/min) and HG severe AS (2.7 [1.9–3.4] mm Hg/L per minute) compared with moderate AS (1.9 [0.7–2.8] mm Hg/L per minute), P =0.004. In a regression model adjusted for age, sex, and rest PCWP, systemic arterial compliance and AS severity were significantly associated with the PCWP/CO-slope. Furthermore, patients with discordant LG AS had a leftward-upward shift in the PCWP/CO-curve. CONCLUSIONS: Discordant LG and HG severe AS had similar hemodynamic responses to exercise with steeper PCWP/CO-slope than in moderate AS, suggesting that discordant LG AS is a severe form of AS. In addition, the left upwards shift in PCWP/CO-curve for discordant LG compared with HG severe AS indicates that this group also has heart failure with preserved ejection fraction physiology. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT04913870 and NCT02395107.

Abstract Total wrist arthroplasty (TWA) is a motion-sparing surgical alternative to wrist arthrodesis for patients with radiocarpal arthritis, but prior reports have indicated that its utilization remains limited. This study aimed to quantify Medicare and Medicaid reimbursement for TWA, along with utilization trends for the procedure using Medicare data. Medicare and Medicaid reimbursement rates for three TWA Current Procedural Terminology (CPT) codes—25446 (TWA), 25332 (TWA with interposition), and 25449 (revision TWA)—were collected for all states except Tennessee for the year 2024 and compared with each other. Prior Medicare rates from 2000 to 2023 were also obtained, adjusted for inflation to represent 2024 dollars, and analyzed for reimbursement trends with a two-tailed t-test between average inflation-adjusted 2000 and 2024 reimbursement. Utilization data from 2000 to 2022 were obtained from the Medicare Part B database. Medicaid reimbursement averaged 16.8% less than Medicare across the three TWA codes, with high variability between states. Inflation-adjusted Medicare reimbursement decreased by an average of 44.2% from 2000 to 2024, with the greatest decline seen in CPT 25446 (TWA) with a 45.1% decrease. Reimbursement for all three codes had decreased significantly from 2000 to 2024 via the two-tailed t-test. Besides an initial dramatic fall from 2000 to 2021 for revision TWA, Medicare utilization gradually increased, with 25332 (TWA with interposition) being the most commonly billed code. TWA reimbursement has decreased significantly over the past two decades for Medicare. Current Medicaid reimbursement is substantially less than Medicare. Although utilization has increased modestly, low reimbursement, along with a variety of other factors, may contribute to a limited adoption of TWA. Addressing these disincentives may encourage further innovation and technological development in TWA.

According to the current WHO classification, noninvasive germ cell neoplasia of the testis comprises germ cell neoplasia in situ (GCNIS), specific forms of intratubular germ cell neoplasia, and gonadoblastoma. Because type II germ cell tumors (GCT, type II) arise from GCNIS, accurate detection of precursor lesions is diagnostically important. In preparation for the 2024 International Society of Urological Pathology (ISUP) Consensus Conference on genitourinary precursor lesions, which took place in Florence, Italy, an anonymous survey was distributed to ISUP members to assess current diagnostic practices regarding testicular precursor lesions. The literature and current WHO classification affirm the significance of precursor lesions in testicular tumours. Working Group 4—Precursor Lesions of the Testis—focused on their practical application by individual pathologists rather than establishing consensus from scientific data. There is strong agreement that GCNIS is the preferred and appropriate term for GCT precursor lesions and that its presence should be reported in cases of invasive GCT. Respondents also agree that “seminoma with intratubular nonseminoma” is the appropriate terminology for seminoma with an associated noninvasive nonseminomatous (embryonal carcinoma, yolk sac tumor, trophoblasts, or teratoma) component. Most pathologists prefer to use OCT3/4 as the primary immunohistochemical marker, and a panel was generally not considered necessary. No consensus is reached regarding the requirement for immunohistochemistry to confirm GCT precursor lesions in the testis. Three questions remain open: the value of subtyping intratubular lesions, the immunohistochemical approach to gonadoblastoma, and the criteria distinguishing Sertoli cell nodules from Sertoli cell tumors.

Abstract Objective To investigate the ability of artificial intelligence‐enabled electrocardiogram (AI‐ECG) atrial fibrillation (AF) prediction model output and delta age, defined as AI‐estimated age minus chronological age, to predict adverse vascular outcomes in patients with migraine. Background Migraine, especially migraine with aura, is associated with an increased risk of cardiovascular events. Using normal sinus rhythm ECG, our institution has developed AI‐ECG models that predict the probability of AF and estimate patients' age, and from that, delta age (estimated age minus actual age) has been shown to reflect cardiovascular health and physiologic aging. Methods We conducted a retrospective cohort study that included adult patients with migraine who had at least one digital, standard 12‐lead ECG from 2000 to 2020 at any Mayo Clinic site. The first normal sinus rhythm ECG was defined as the index ECG, and those with adverse vascular events or AF prior to, or within 3 days after, index ECG were excluded. AI‐ECG AF prediction model output and delta age were obtained from the index ECG. The primary outcome was a composite endpoint of adverse vascular events that included acute myocardial infarction, acute ischemic stroke, venous thromboembolism, and death. New‐onset AF was also recorded as a secondary outcome. Results A total of 29,928 patients were included. The mean age was 44.3 ± 14.5 years, and the median follow‐up time was 54 months. During the study period, 4662 (15.6%) patients had adverse vascular events, and 1384 (4.6%) patients developed new‐onset AF. A higher AF prediction model output was associated with a higher risk of adverse vascular outcomes (adjusted hazard ratio [aHR]:1.15 [95% confidence interval: 1.12 to 1.18] for every 10% increase in prediction model output), as was a larger delta age (aHR:1.16 [1.12 to 1.21] for every 10‐year increase in delta age). Moreover, AI‐ECG AF prediction model outputs of ≥1% (aHR: 1.45 [1.36 to 1.54]) and delta age ≥−1 years (aHR: 1.09 [1.02 to 1.16]) were found to be the optimal cutoffs to dichotomize patients into high‐risk and low‐risk groups for adverse vascular events. Higher AI‐ECG AF prediction model output at baseline also predicted a higher likelihood of having new‐onset AF during the study period (aHR: 1.31 [1.26 to 1.37]), and the development of new‐onset AF was associated with a higher risk of adverse vascular events (aHR: 2.43 [2.17 to 2.73]). Conclusions For patients with migraine, a higher AI‐ECG AF prediction model output and delta age are predictive of adverse vascular outcomes. A higher AF prediction model output is also predictive of future AF development. Furthermore, we identified the cutoffs for both AI‐ECG models that can distinguish patients between high‐ and low‐risk groups. Our results showed that AI‐ECG models could inform clinical practice and identify patients with migraine at risk for future adverse vascular events.

Abstract Background: Stromal tumor infiltrating lymphocytes (sTILs) are associated with improved response to chemotherapy and better overall survival (OS) in triple-negative breast cancer (TNBC). Quantification of sTILs via hematoxylin and eosin (H&E) tumor slides offers a widely available method to define a simple, effective surrogate for host anti-tumor immunity. Digitization of H&E slides has rapidly gained acceptance for use in diagnostic pathology and research, opening the door for image-based computational approaches to enumerate sTILs, among other features. Methods: We describe QuTILs - a multilayer perceptron-based framework to detect/enumerate TILs trained on &gt;700,000 cells via The Cancer Genome Atlas Program (TCGA) slide images, implemented in the widely used open-source QuPath digital pathology suite. QuTILs was applied to digital H&E images using standard computing in primary breast tumors from phase 3 breast cancer clinical trials - CALGB 40502 (testing), CALGB 40601 and 40603 (validation) - in total 1,729 total images from 962 unique patients. The aims of this investigation were: 1) to assess the relationship between TIL patterns with overall or event-free survival outcomes; 2) to benchmark diverse image-based characteristics of TIL abundance and spatial architecture; and 3) to evaluate the association between image-based TIL levels and RNA-seq-based immune deconvolution metrics (CIBERSORT, EPIC, quanTIseq). Results: QuTILs average processing time was 7.9 minutes for whole-slide total TIL count and area density on a standard laptop workstation. In CALGB 40502, there was positive but modest correlation between pathologist TILs and QuTILs total TILs %, higher in the TNBC subgroup of CALGB 40502 (Pearson r = 0.55). In Cox proportional hazards models, the CALGB 40502 TNBC cohort showed significant univariate association for total TILs % with increasing decile (higher total TIL%) associated with reduced hazard (hazard ratio [HR]: 0.712, 95% CI: 0.559-0.906; P = 0.006), which remained significant in multivariable model incorporating age, race, and treatment arm (HR: 0.713, 95% CI: 0.556-0.915; P = 0.008). In validation TNBC clinical trial CALGB 40603, marginal TILs % was significant in the univariable Cox model (HR: 0.786, 95% CI: 0.639-0.966). Evaluation of TILs % by QuTILs with RNAseq-based deconvolution metrics in cohort-stratified and deconvolution method-stratified multivariable models showed that decile total TILs % by QuTILs was shown to significantly predict outcome in the EPIC (HR: 0.668, 95% CI: 0.466-0.957) and quanTIseq (HR: 0.646, 95% CI: 0.446-0.936) sets, with a similar magnitude as in clinical Cox, suggesting that RNA-based deconvolution estimates may not supplement the prognostic power of image-based TIL estimates. Exploratory analyses of pre- versus post-neoadjuvant therapy H&E images in CALGB 40603 and CALGB 40601 revealed a significant decrease in QuTILs total TIL% in CALGB 40603 for all pairs (n = 118 pairs, pre-median=9.52%, post-median=6.33%; Wilcoxon signed rank P &lt; 0.001) but no significant change in QuTILs total TIL% among all pairs in CALGB 40601 (n = 82 pairs, pre-median=15.92%, post-median=15.10%; P = 0.886). Conclusions: QuTILs provides a computationally efficient open-source workflow for sTIL identification from digital H&E images that can be deployed on a standard laptop. We present the first evaluation of digital sTIL enumeration in CALGB 40502, CALGB 40603, and CALGB 40601 phase III breast cancer clinical trials and demonstrate significant prognostic association with QuTIL total TIL % among TNBCs across studies. Citation Format: M. Vater, R. Salgado, E. Blige, H. Lefebvre, A. Strahan, M. Gatti-Mays, H. Rugo, K. Ballman, M. Watson, Y. Wen, R. Leon-Ferre, K. Niazi, W. Symmans, L. Carey, K. AbdulJabbar, Z. Li, D. Stover. Qutils: open-source image-based infiltrating immune cell detection and outcomes in calgb 40502, calgb 40603, and calgb 40601 phase iii breast cancer clinical trials [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS2-07-27.

BACKGROUND: While health systems have implemented resources to improve lipid management in people with atherosclerotic cardiovascular disease, the population-level effectiveness is unclear. METHODS: Electronic health record data from patients with atherosclerotic cardiovascular disease between January 1, 2021, and December 31, 2023, across 16 US academic health systems were analyzed. Atherosclerotic cardiovascular disease (defined by diagnosis and procedure codes) was established on or before the index date defined as the date of the most recent LDL-C (low-density lipoprotein-cholesterol) or the last day of the study period for those without an LDL-C available. Systems were surveyed to identify lipid management programs (eg, prevention/lipid clinic, electronic health record–based tools, and lipid management algorithms). Sequential multilevel multivariable logistic regression modeling was used to (1) assess the system-level association between an LDL-C <70 mg/dL and the presence of lipid management programs, adjusting for patient-level demographic and clinical characteristics, and (2) whether system-level uptake of statin or nonstatin lipid-lowering therapy was associated with an LDL-C <70 mg/dL. RESULTS: We included 1 738 042 patients with atherosclerotic cardiovascular disease (median, 88 365 per system; range, 17 086–2 48 371). About 81% of the health systems had prevention or lipid clinics. The proportion of those on statins ranged from 31.0% to 60.4% across health systems (median, 46.3%). Lower proportions were observed in the use of high-intensity statins (16.2%–33.1%), nonstatins (2.6%–8.1%), and combination lipid-lowering therapy (1.7%–6.3%). Among those with an LDL-C level available (n=890 521), 42.5% had an LDL-C <70 mg/dL, ranging 35.8% to 49.4% across systems. There was no association between the odds of achieving LDL-C <70 mg/dL and health system lipid management algorithm, prevention clinics/lipid clinics, or electronic health record–based tools. Neither system-level high-intensity statin utilization nor nonstatin use was associated with an LDL-C <70 mg/dL. CONCLUSIONS: Despite variability in lipid management resources and lipid-lowering therapy use across systems, many did not reach an LDL-C <70 mg/dL, and there was low uptake of lipid-lowering therapy. Innovative implementation strategies are needed for system-level lipid management.