Citations

Shear wave elastography generates shear waves with an acoustic radiation force to obtain estimates of the shear wave speed. Shear wave elastography often utilizes time-of-flight calculations that apply cross-correlations or time-to-peak methods to obtain estimates of the shear wave speed in the time-domain. However, these time-domain methods fail to consider the effect of dispersion caused by the shear viscosity, which can introduce substantial errors into estimates of the shear wave speed. To solve this problem, a new viscoelastic method for estimating shear wave parameters in the time-domain is introduced. The performance of the new method, which is applied to shear wave particle velocity waveforms, is established by evaluating a simulated three-dimensional viscoelastic Green's function model for shear waves in the time-domain. Results show that the new viscoelastic time-domain method is applicable to locations outside of the push beam region at the focal depth and throughout a two-dimensional plane. The results also indicate that estimates of the shear wave speed are either comparable to or significantly improved relative to values obtained from cross-correlations while simultaneously providing estimates of the shear viscosity in the time-domain.

BACKGROUND AND OBJECTIVES: Pediatric large-volume brain arteriovenous malformations (AVMs) carry a substantial lifelong hemorrhage risk, neurological symptoms, and treatment morbidity. Single-session stereotactic radiosurgery (SRS) is often unsuitable due to constraints on dose-volume toxicity. Volume-staged SRS (VS-SRS) enables sequential dosing of large nidus volumes, potentially enhancing safety while maintaining efficacy. Evidence in children remains limited. We aimed to evaluate outcomes of VS-SRS for large AVMs in pediatric patients. METHODS: A multicenter retrospective cohort was assembled from 21 centers, including patients aged younger than 21 years treated with VS-SRS for AVMs >10 cm 3 . Clinical and radiological end points included obliteration, hemorrhage, and permanent symptomatic radiation-induced changes (RIC). RESULTS: A total of 103 patients were included (median age 14 years; IQR, 12-17). The median nidus volume at first stage was 18.2 cm 3 (IQR, 12.3-25.6). Median prescription dose per stage was 17 Gy (IQR, 16-18). The median clinical follow-up from the first stage was 57.5 months (IQR, 25-138). Obliteration occurred in 42 of 103 patients (40.8%), with actuarial rates of 6.9% (95% CI: 2.8-14) at 3 years and 29% (95% CI: 20-39) at 5 years. Hemorrhage occurred in 17 of 103 patients (16.5%) during follow-up, and permanent RIC was observed in 9 of 103 patients (8.7%). CONCLUSION: VS-SRS is a reasonably safe, selected option for pediatric large-volume AVMs when microsurgical or endovascular cure is not feasible or prudent. Delivering ≥17 Gy per stage while limiting each treatment volume to <15 cm 3 supports durable nidus control with acceptable toxicity. VS-SRS represents a key modality in multidisciplinary management of this historically difficult-to-treat population.

Renal water reabsorption is classically regulated by vasopressin V2 receptor (V2R) signaling through cyclic AMP and protein kinase A, driving apical accumulation of aquaporin-2 (AQP2). However, collecting duct water handling is also modulated by vasopressin-independent mechanisms. Here, we examined intracellular soluble urate as a vasopressin-independent regulator of AQP2 trafficking. Intracellular urate accumulation in collecting duct cells was mediated by enhanced apical urate uptake via GLUT9b and reduced apical urate efflux through ABCG2, triggering phosphodiesterase-4 activation, reduced cAMP, and downstream AMP-activated protein kinase (AMPK) activation. The resulting AQP2 accumulation at the apical membrane was independent of V2R signaling, required ongoing endocytosis, and was associated with features of postendocytic apical trafficking of internalized AQP2. In vivo ABCG2 inhibition with probenecid increased apical AQP2 abundance and markedly attenuated tolvaptan-induced polyuria in both wild-type and Pkd1 RC/RC autosomal dominant polycystic kidney disease (ADPKD) mice in a uricase-independent manner while preserving tolvaptan’s ADPKD-modifying efficacy. In a phase II trial with tolvaptan-treated patients with ADPKD, probenecid reduced urine volume and nocturia frequency. Together, these findings support a vasopressin-independent urate/AMPK/AQP2 pathway that regulates renal water handling and, in a preclinical ADPKD model, can uncouple cyst growth attenuation from the dose-limiting aquaretic effects of V2R antagonism.

Background: Posterior medial meniscus root tears (PMMRTs) are frequently observed injuries that alter tibiofemoral biomechanics, yet the long-term outcomes are poorly described. Purpose: To perform a systematic review and meta-analysis of the current literature on long-term clinical and radiographic outcomes of operatively managed PMMRTs. Study Design: Meta-analysis and systematic review; Level of evidence, 4. Methods: A systematic review was performed with the inclusion criteria of English-language studies, diagnosis of PMMRT on magnetic resonance imaging, and minimum 5-year radiographic or patient-reported outcome (PRO) metrics. Data analysis included management strategy, surgical technique, meniscal extrusion, medial joint space, PROs, and radiographic measurements. Failure was defined as conversion to arthroplasty, subsequent partial medial meniscectomy (PMM) and/or proximal tibial osteotomy, or clinical failure on PROs. Continuous outcome variables were analyzed with a random effects meta-analysis of mean differences. Chi-square meta-analysis was also used to analyze categorical variables. Results: Twelve studies were identified with >5-year follow-up after PMMRT (mean ± SD, 84.1 ± 11.0 months). Five studies performed PMM, 6 performed medial meniscus root repair (MMR), and 1 utilized either meniscectomy or repair. There were 797 total patients (female, n = 667; 83.7%), with mean ages ranging from 47.2 to 65. Both interventions showed significant PRO improvements after surgery: PMM (pre- vs postoperative Lysholm, 56.1 vs 68.2; P < .01) and MMR (Lysholm, 52.1 vs 83.1; International Knee Documentation Committee [IKDC], 40.0 vs 72.8; P < .01). MMR had significantly lower Kellgren-Lawrence grades (PMM vs MMR, 2.4 vs 1.8; P < .01) and superior IKDC scores (46.5 vs 72.8; P < .01) as compared with PMM. Additionally, PMM had a significantly higher failure rate (23% vs 5.3%) and conversion to knee arthroplasty (20.5% vs 3.5%) as compared with MMR, with odds ratios of 9.8 and 10.2, respectively. Conclusion: This systematic review and meta-analysis of studies with >5-year minimum follow-up found that PMM was associated with a 10-fold increase in clinical failure and conversion to knee arthroplasty relative to MMR in observational studies. In addition, MMR demonstrated superior Kellgren-Lawrence grades and IKDC scores as compared with PMM. The findings of the current analysis suggest that MMR is associated with superior outcomes as compared with PMM at mid- to long-term follow-up.

The NCCN Guidelines for Melanoma: Cutaneous provide strategies for the diagnosis, treatment, and follow-up of patients with cutaneous melanoma, which is among the most common cancers in the United States. The outcome of cutaneous melanoma is significantly influenced by stage at initial presentation. Generally, localized disease and smaller primary tumors have been associated with more favorable prognosis. Thus, the select content featured in this issue focuses on risk factors associated with cutaneous melanoma development and which should be considered during an initial assessment. These include (1) phenotypic predispositions, (2) personal medical history or comorbidities, (3) genetic predispositions, and (4) environmental factors.

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

ABSTRACT The term “clinical anatomy” is widely used in education and research, yet its conceptual boundaries continue to be interpreted in various ways. Prior consensus‐based efforts have emphasized integration, collaboration, and clinical relevance as central features of the field and have provided an important foundation for interdisciplinary engagement. At the same time, ongoing changes in academic structure, medical education, and interdisciplinary biomedical science raise important questions regarding how clinical anatomy can sustain its scientific identity and long‐term relevance. Building upon prior discussions, this article argues that the continued maturation of clinical anatomy depends on the integration of conceptual frameworks with the sustained production of rigorous, reproducible, and clinically meaningful scholarly contributions. Historical and contemporary examples alike demonstrate that the influence of clinical anatomy has been shaped through contributions that directly advanced clinical science and practice. Accordingly, continued emphasis on methodological rigor, reproducibility, clinically meaningful contribution, and educational accountability may be essential to the field's future development and relevance.

Abstract INTRODUCTION White matter lesions on fluid‐attenuated inversion recovery magnetic resonance imaging (FLAIR‐MRI) reflect small vessel disease (SVD) and aid in identifying vascular contributions to impairment and dementia (VCID). Emerging diffusion MRI (dMRI) biomarkers are sensitive to early SVD but the lack of validated approaches for defining dMRI abnormality has limited their clinical utility. METHODS In 3934 participants (8749 observations) from a population‐based sample, we classified 9% as vascular cognitive impairment versus not (VCI+/VCI−) using abnormal FLAIR‐MRI and cognitive testing. We evaluated four distinct dMRI positivity criteria and assessed performance in an independent clinical sample. RESULTS The young referent criterion performed best and yielded an estimated prevalence of dMRI positivity aligned with pathology literature. About 40% of the population were dMRI positive, and these individuals had lower baseline cognition and faster longitudinal decline. Cutpoints were validated in an independent clinical sample. DISCUSSION The proposed dMRI abnormality framework can detect VCID and aid in identification of individuals at risk of VCI.

Background: Alcohol-associated hepatitis (AH) is a severe inflammatory liver condition driven by dysregulated immune responses. CD8 T cells accumulate in the liver during AH, yet their functional role remains poorly defined. Methods: A murine NIAAA chronic-binge model with lipopolysaccharide (LPS) challenge was used. Single-cell RNA sequencing of liver and blood immune cells defined CD8 T cell subsets, followed by pathway analysis and reanalysis of human AH datasets. Spatial relationships were validated by immunohistochemistry of human AH liver tissue with CD8 T RM and liver sinusoidal endothelial cell (LSEC) co-staining. LSEC–CD8 T cell interactions were examined using in vitro co-culture, and signaling pathways were assessed by bulk RNA sequencing and phospho-protein analyses. IL15 function was evaluated by in vivo neutralization. Results: Single-cell RNA sequencing in the murine AH model revealed a distinct population of CD8 tissue-resident memory T cells (T RM ) with heightened activation and proinflammatory cytokine production. Analysis of human AH liver single-cell RNA sequencing data, along with immunohistochemistry validation, supported CD8 T RM enrichment in diseased tissue. IL15 emerged as a prominent pathway linked to T RM activation, and IL15 blockade reduced T RM abundance and attenuated EtOH/ lipopolysaccharide-induced liver injury. Mechanistically, LSECs not only provided a structural niche for T RM retention but also amplified IL15 signalling. In vitro, coculture experiments demonstrated that LSECs intensified activation in pre-stimulated CD8 T cells in a stimulus-dependent manner: under IL15 stimulation, LSECs boosted effector function without inducing cell death, whereas under T-cell receptor stimulation, LSECs drove hyperactivation and activation-induced cell death. Bulk RNA-seq and phospho-protein analysis identified the PI3K-AKT pathway as a shared pathway enhanced by LSEC coculture in activated CD8 T cells. These findings define a context-dependent mechanism in which LSECs promote IL15-driven signaling through AKT pathway amplification, promoting T RM persistence and inflammatory activity in AH. Conclusions: IL15-associated signaling within the hepatic microenvironment, shaped by LSEC-CD8 T-cell interactions, promotes activation and persistence of CD8 T RM cells in AH. Targeting the IL15-LSEC-AKT axis may disrupt pathogenic T RM niches and represent a promising therapeutic strategy for severe AH.

PURPOSE In large B-cell lymphoma (LBCL), use of high-dose methotrexate (HD-MTX) to prevent CNS relapse (so-called CNS prophylaxis) remains controversial. International guidelines continue to recommend HD-MTX in patients deemed ultra high risk (UHR) because of a lack of robust data specific to these subgroups. This study was designed to examine the impact of HD-MTX specifically in UHR patients. METHODS Data from two previous retrospective analyses were combined to produce a cohort of UHR patients (≥1 of the following criteria: CNS international prognostic index score 5-6; testicular, renal/adrenal, or breast involvement; ≥3 extranodal sites), treated with or without HD-MTX. The primary outcome was CNS relapse rate (isolated or concurrent with systemic relapse) measured from diagnosis with additional landmark analysis of all responding patients with no progression event at 6 months. RESULTS Analyses were performed on 1,923 patients meeting UHR criteria. No significant difference in 3-year CNS relapse rate was observed between no HD-MTX (n = 1,051) versus HD-MTX patients (n = 872), including in multivariable analyses adjusting for baseline characteristics (3-year rate, 9.3% v 8.1%; adjusted hazard ratio [HR], 1.13 [95% CI, 0.82 to 1.57]). Analyses restricted to isolated CNS relapse also confirmed no difference (5.9% v 5.7%; adjusted HR, 1.03 [95% CI, 0.69 to 1.53]). In the landmark analysis (no HD-MTX n = 782, HD-MTX n = 773), no difference in 3-year CNS relapse was observed (6.7% v 6.6%, adjusted HR, 0.95 [95% CI, 0.62 to 1.44]). CONCLUSION To our knowledge, this is the largest international comparative data set of patients with LBCL with UHR features showing no significant reduction in CNS relapse with HD-MTX in all UHR or in any individual subgroup. Despite inherent limitations of retrospective analyses, the data strongly support previous studies in suggesting HD-MTX prophylaxis has no meaningful benefit for most patients.