Citations

Background: Vascular endothelial dysfunction is a key antecedent to cardiovascular diseases (CVD) in older adults. Reduced nitric oxide (NO) bioavailability secondary to excess mitochondria-related reactive oxygen species (mitoROS) bioactivity are key mechanisms of endothelial dysfunction with aging. Cellular senescence is a state of largely irreversible cell cycle arrest that drives endothelial dysfunction. This occurs in part through secretion of bioactive factors into serum, collectively referred to as the circulating senescence-associated secretory phenotype (SASP), that promote excess mitoROS and reduce NO. We have shown fisetin improves endothelium-dependent dilation in old mice by reducing cellular senescence and mitoROS. Here, we sought to translate our preclinical findings to older adults. Hypotheses: We tested the primary hypothesis that intermittent fisetin treatment would improve endothelial function in older adults and that this would be mediated by reductions in mitoROS and associated with lower cell senescence. We also determined if fisetin altered the serum to improve endothelial cell (EC) NO and reduce whole-cell ROS and mitoROS ex vivo. Exploratory analyses assessed if fisetin changed circulating SASP factors. Methods: In a randomized, placebo-controlled, parallel-group design pilot trial, 41 older men and postmenopausal women were randomized to fisetin (2 mg/kg/day) (age: 71±1 yrs [mean±SEM], n=22 [13 W]) or placebo (age: 71±1 yrs, n=19 [12 W]) administered in an intermittent manner (2, 3-day dosing periods separated by 14 days). Outcomes were measured at baseline and 1-3 weeks after the final dose. Endothelial function was assessed as brachial artery flow-mediated dilation (FMDBA). The change in FMDBA with an acute supratherapeutic dose (160mg) of the mitochondrial antioxidant MitoQ was used to assess mitoROS-related inhibition of endothelial function. Gene expression of cellular senescence markers Cdkn1a (encodes p21) and Lmnb1 (encodes Lamin B1) were assessed in peripheral blood mononuclear cells (PBMCs) by Q-PCR. Human aortic ECs (HAECs) in culture were exposed to 10% participant serum for 2 hrs; acetylcholine (ACh)-stimulated NO production (DAR-4M-AM) and basal whole-cell ROS (CellROX) and mitoROS (MitoBright Deep Red) bioactivity were assessed via immunofluorescence. Luminex analyses (Biotechne) measured circulating levels of SASP factors in serum. Results: FMDBA was improved by 41% with fisetin (pre: 3.9±0.4%, post: 5.5±0.5%, P< 0.0001), but unchanged with placebo (pre: 4.4±0.5%, post: 4.5±0.4%) (group x time interaction effect: P< 0.01). Similar efficacy was observed in men and women. Acute MitoQ enhanced FMDBA at baseline and after placebo (all P< 0.05) but led to no further improvements in FMDBA after fisetin treatment. Consistent with lower cell senescence, expression of Cdkn1a was reduced (P< 0.05) by 12% and expression of Lmnb1 increased (P=0.06) by 16% in PBMCs collected after fisetin but not placebo. Compared with pre-intervention, serum collected after fisetin, but not placebo, increased HAEC ACh-stimulated NO by 6% (P< 0.01) and lowered whole-cell and mitoROS bioactivity by ~10% (both P< 0.05). Protein levels of CXCL12 in serum were 5% lower (P< 0.05) after fisetin compared with pre-intervention and after placebo. Traditional cardiometabolic risk factors were unchanged. Conclusions: Intermittent fisetin treatment improves vascular endothelial function in older adults in part by suppressing mitoROS. These effects are linked to reduced cell senescence and select changes to the circulating SASP. Funding: AHA 23CDA1056582; NIH F31AG087709; NIH/NCATS CTSA UL1TR002535; Life Extension® provided fisetin (BioFisetin) and placebo. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Accurate assessment of arterial wall mechanics is essential for detecting vascular pathologies. The technique described herein incorporates a commercially available ultrasound system and applanation tonometry to noninvasively evaluate the local mechanical properties of the common carotid artery (CCA). Pressure waveforms were acquired using a tonometer combined with ultrasound-based diameter of the CCA. The signals were temporally aligned, converted to physical units using brachial systolic and diastolic pressure, and interpolated over uniform strain increments. Hoop stress was estimated using thick-wall assumptions, and hoop strain was derived from mid-wall circumferential stretch. Incremental elastic modulus was computed from local linear fits to the stress–strain data, and the area of the resulting hysteresis loop was used as a surrogate for viscoelastic energy loss, quantified by the energy dissipation ratio (EDR). The method was applied to healthy subjects (HS) and those with cardiovascular risk or confirmed atherosclerosis. In HS, pressure–strain elastic modulus (Ep) ranged from 50–55 kPa and EDR from 2%–6%, while non-healthy subjects showed higher EDR values (10%–20%), reflecting increased arterial viscoelasticity. Results revealed nonlinear pressure–diameter relationships with clear hysteresis, reflecting viscoelastic effects. The technique offers potential as a diagnostic tool for evaluating early, localized vascular alterations.

Abstract The lateral and medial meniscus play vital roles in load distribution across the knee joint and in the prevention of knee osteoarthritis. As such, every effort should be made to save and repair the meniscus when possible, as partial and total meniscectomies have been shown to impair the meniscus’ ability to effectively dissipate shock. Recently, an algorithm—coined the “ABCs of meniscal repair”—has emerged as a blueprint for optimizing the success of a meniscal repair. The “ABCs of meniscal repair” refer to anatomic reduction, biologic augmentation, and circumferential compression across the meniscus tear, respectively. In this technique, we describe a modified use of the arthroscopic skid that allows for access to difficult‐to‐reach peripheral meniscal tears while simultaneously aiding in the anatomic reduction of the tear.

Abstract Introduction: Stingray envenomation is a relatively common occurrence among water sports enthusiasts, including swimmers, scuba divers, and surfers, as well as fishermen. However, there is a lack of medical literature on the pathophysiology of immediate and delayed hypersensitivity reactions, and more importantly, on the range of infectious bacterial and mycobacterial infections that can result from these envenomation injuries. This paper aims to provide a general overview of the mechanisms, diagnostic challenges, and management of late hypersensitivity reactions and infections that can occur following stingray stings. Case Report: A 63-year-old man with well-controlled hyperlipidemia presented to the Mayo Clinic with a one-week-old injury from accidentally stepping on a stingray barb while walking on a beach in Ventura, California. Immediate pain was relieved with immersion in warm water. He did not take any over-the-counter or prescription medications, and over the following days, he returned to his usual activities of cycling, running, and swimming with minimal discomfort. There was no initial redness or swelling at the puncture site, but he reported intermittent sharp, localized pain with movement leading up to his hospital visit. A biopsy was performed due to concern for a developing necrotic infection, and he was diagnosed with a hypersensitivity reaction. He was initially treated with IV antibiotics, and steroids were added based on biopsy results. After completing his treatment course, his hypersensitivity reaction fully resolved over several weeks. Conclusion: This case underscores the importance of considering both immediate and delayed hypersensitivity reactions that can result from stingray envenomation. These reactions can be managed with conservative measures, such as warming the affected area in a water bath to denature heat-labile venom, as well as with conventional therapies, including topical or systemic antihistamines and steroids. It also highlights the need for early empiric antibiotic coverage and outlines the infectious agents implicated in early- and late-onset infections following stingray envenomation, including Pseudomonas aeruginosa, Vibrio vulnificus , and Mycobacterium fortuitum . Additionally, it emphasizes the need for tetanus vaccine updates, radiography, and a multidisciplinary approach to treating stingray injuries.

Abstract Neoadjuvant therapy (NAT) with HER2-targeted agents is the standard treatment for patients with HER2-positive early breast cancer (HER2 + EBC). Although high levels of tumor-infiltrating lymphocytes (TILs) are associated with higher pathologic complete response (pCR) rates and improved recurrence-free survival (RFS), the specific immune components responsible remain unclear. In this study, pretreatment tumor biopsies from 188 patients receiving HER2-targeted NAT were analyzed. Univariate analysis revealed that enrichment of TIL-B cells in tumors, high HER2 mRNA and low ESR1 mRNA expression were linked to pCR (both p < 0.01). Multivariate analysis confirmed TIL-B-cell enrichment as an independent predictor of pCR. Mature IgD/IgM-high B cells, but not immature RAG1 + B cells, independently predicted pCR. Transcriptomic profiling identified 265 upregulated genes in pCR tumors enriched in MHC class II antigen presentation pathways. Immunofluorescence demonstrated increased spatial interaction of mature B cells with CD4 + T cells in pCR tumors, consistent with active antigen presentation. The antigen presenting B-cell signature, integrated mature B-cell and MHC II profile, was the strongest independent predictor of pCR (OR = 3.008, 95% CI: 1.196–7.544, p = 0.019) and was also significantly associated with improved RFS (HR = 0.109, 95% CI: 0.014–0.872), highlighting B-cell–mediated antigen presentation as a clinically relevant biomarker in HER2 + EBC.

Abstract Background: Early postoperative mortality remains a major clinical challenge in left ventricular assist device implantation. Accurate preoperative identification of high-risk patients could optimize candidate selection and improve perioperative management. Methods: From February 2021 to March 2025, 60 patients who underwent LVAD implantation at Zhongshan Hospital, Fudan University were included in the present study. Early mortality was defined as death within 2 months postoperatively, a threshold derived from survival analysis showing a distinct early hazard phase. Preoperative demographic, echocardiographic, hemodynamic, and laboratory variables were evaluated. Predictor selection used least absolute shrinkage and selection operator (LASSO) logistic regression with 10-fold cross-validation, followed by multivariable Firth logistic regression. Internal validation employed bootstrap resampling (1,000 iterations). Results: The mean age was 55 ± 10 years, and 50 (83%) patients had dilated cardiomyopathy. Kaplan–Meier analysis indicated an early hazard phase, with all deaths occurring by ~ 1.7 months after implantation. LASSO selected age, MELD-XI, passive cardiac index (PasCI), and mixed venous oxygen saturation (SvO₂) for multivariable modeling. In the final Firth model, lower SvO₂ (odds ratio [OR] 0.92; 95% CI 0.83–1.00; p = 0.048) and older age (OR 1.13; 95% CI 1.00–1.35; p = 0.059) were associated with higher early mortality. Internal validation yielded an optimism-adjusted AUC of 0.84. Conclusions: In this exploratory study, lower preoperative SvO₂ and older age were the principal predictors of early mortality after LVAD implantation. Our internally validated risk assessment model supports preoperative risk prediction and stratification; however, confirmation in larger, multicenter cohorts is warranted before broader adoption. (246/250)

Abstract Femoroacetabular impingement with cam morphology that fails nonoperative management can be addressed with hip arthroscopy and cam resection. There exists a wide variation of cam morphology due to various etiologies that can make some cam lesions more challenging to address. A thorough preoperative evaluation and the utilization of a variety of intraoperative techniques can allow for adequate arthroscopic resection of these otherwise challenging cam lesions. In this technique video, we describe a systematic approach for the preoperative assessment of femoroacetabular impingement due to a cam lesion and consideration of different approaches for arthroscopic resection based on cam‐specific morphology.

Color Doppler twinkling improves visibility and ultrasound-guided localization of biopsy markers made of polymethyl methacrylate (PMMA). This study examines the time- and frequency-domain features of twinkling. We performed beamforming on the raw radiofrequency (RF) data collected using a L7-4 transducer, followed by in-phase/quadrature (IQ) demodulation and wall filtering. Frequency content variations were evaluated both within individual Doppler ensembles (pulse-to-pulse) and across multiple frames. Normalized FFT magnitude spectra were computed for both twinkling and non-twinkling (metal) cases using beamformed RF and IQ data. The median of the normalized FFT magnitude (3–10 MHz) was consistently higher for the twinkling case compared to the metal case across RF (–13.75 dB vs –17.29 dB) and the IQ real component (–12.72 dB vs –16.15 dB), indicating broader and more energetic spectral content in twinkling. The frequency spread above the –20 dB threshold was approximately 2.5 times wider (5.38 MHz vs 1.95 MHz) in the twinkling case compared to the metal case. In time domain, the RMS of the standard deviation for the twinkling signal was approximately 28 times higher than that of the metal case across both RF and IQ data. These findings indicate that the ultrasound data from twinkling exhibits a more distributed frequency profile, consistent with observed aperiodic nature.

Elevated intratumoral interstitial fluid pressure (IFP) can negatively impact the efficacy of neoadjuvant chemotherapy (NAC) of breast cancer. This study aims to predict breast cancer pathological complete response (pCR) to NAC based on IFP measures by 3-D subharmonic-aided pressure estimation (SHAPE). SHAPE uses the inverse linear relationship between hydrostatic pressure and subharmonic signal magnitude from intravascular ultrasound contrast agents. Thirty-eight breast cancer patients undergoing NAC from three clinical sites were enrolled for this study. SHAPE data were collected for each subject at 0%, 10%, and 30% of NAC completion using a Logiq E9 system (GE HeathCare) equipped with an RSP6-16D probe. The contrast agent used was Definity (Lantheus Medical Imaging). The subharmonic signal gradients between tumor and adjacent normal tissue were calculated and compared with patient pathological response outcome using t-test and receiver operating characteristic (ROC) curve analysis. Pressure gradients between pCR (15 patients) and non-pCR (23 patients) groups were significantly different at 0 (p = 0.02), 10 (p = 0.03), and 30% (p = 0.0003) completion of NAC. Area under the curve values of 0.69, 0.77, and 0.86 were achieved at 0%, 10%, and 30% of NAC completion, respectively. Overall, SHAPE pressure gradients may aid prediction of NAC pathological response in breast cancer patients.