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.

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.

Color Doppler twinkling is associated with rough-surfaced objects like kidney stones, some clinical breast biopsy markers, and polymethyl methacrylate (PMMA) bone cement. Microbubbles are theorized as the predominant source of twinkling, supported by decreased twinkling under increased pressure. PMMA, metallic breast markers, a low-twinkling PMMA sample, and a non-twinkling metal rod were scanned in a pressure chamber up to 1000 psi using a General Electric Logiq E9 system and C1-6 probe (1.7–3.6 MHz Doppler transmit frequency). Clinical markers maintained distinct twinkling up to 250 psi. PMMA often twinkled at higher pressures, sometimes up to 1000 psi. The controls showed no twinkling. To understand physical structure associations with twinkling, the samples were scanned in a micro-CT system with a pixel resolution of 2 μm. Analysis of PMMA and Cork internal voids showed no correlation with twinkling. However, a correlation between Sa (average difference between the mean surface profile and actual surface profile) values and twinkling was found. This indicates that internal structure is not important for twinkling, and certain surface roughness is critical, possibly providing sites for surface microbubbles to oscillate from incident ultrasound waves.

Ultrasound shear wave elastography is a medical imaging technique where mechanical properties (e.g., shear modulus) of soft tissue are imaged with the goal of diagnosing disease. However, different sources of noise or error often lead to poor images that exacerbate uncertainty of medical diagnosis based on these techniques. Sources of uncertainty include scatterer positions and strengths (e.g., emanating from the cellular structure of tissue), other surrounding tissue not included in the image, and electronic noise, among others. In this work, we are developing Optimal Experimental Design (OED) techniques based on the simulation of the ultrasound imaging process and particle tracking to identify controls that maximize the quality of elastography images. Specifically, we propose a general formulation for OED where the observation error depends on both uncertain quantities and the variables to be inferred (e.g., shear moduli). Furthermore, we pose a nonlinear OED problem where the main design variables are the angles used in plane wave compounding for ultrasound motion tracking of propagating shear waves. The goal of the OED problem is to find the number and values of compounding angles that minimize bias and variance in the estimated shear modulus image. We will demonstrate our approach through various numerical examples.

PURPOSE For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR) but extends treatment duration. This phase III trial investigated whether boost delivery during WBI versus after WBI provides noninferior IBR and preserves cosmetic appearance. METHODS NRG/RTOG 1005 randomly assigned patients at higher risk for IBR after lumpectomy and axillary surgery to either a sequential boost of 12 Gy in six fractions(F) or 14 Gy in 7F after WBI of 50 Gy in 25F or 42.7 Gy in 16F (sequential arm) or a concurrent boost of 8 Gy in 15F of 0.53 Gy per day with WBI of 40 Gy in 15F (concurrent arm) using 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT. Based on 1.59% 5-year IBR for the sequential arm, defining the noninferiority margin as a hazard ratio upper limit on the 90% CI of 2.12, 2,312 patients provide 80% power for noninferiority of IBR as first recurrence for the concurrent arm. Secondary end points included disease-free survival and overall survival, adverse events (AEs), and cosmetic outcomes. RESULTS Between May 24, 2011, and June 20, 2014, 2,354 patients were randomly assigned, with 2,255 eligible for analysis (sequential arm, n = 1,118; concurrent arm, n = 1,137). With median follow-up of 7.3 years, there were 56 IBR events; 5- and 7-year IBR were 2.1% and 2.2% on the sequential arm and 1.9% and 2.6% on the concurrent arm, respectively. The noninferiority criterion was met: HR (90% CI): 1.31 (0.84 to 2.04), P = .037. No differences were observed in AEs, cosmetic outcomes, or survival between arms. CONCLUSION Concurrent boost during WBI results in noninferior IBR compared with sequential boost without worsening toxicity or cosmetic outcomes and reduces overall treatment time.

BACKGROUND: Free fibula flaps have been widely used for bony reconstruction in pediatric patients. While donor site complications have been well studied in adults, data in the pediatric population remains limited. This study exclusively reports donor-site morbidity following fibula flap harvests in the pediatric and adolescent population. METHODS: We reviewed all patients younger than 18 years with open physes who underwent fibula flap harvests at a single academic institution from 1997 to 2024. Demographics, clinical and surgical characteristics, and donor-site complications were recorded. RESULTS: Fifty-seven free fibula flaps were harvested from 55 pediatric patients (mean age 12 years; 29 female) with a mean follow-up of 6 years. Flaps were most commonly used for lower extremity reconstruction (52%) and following tumor resection (74%). Osteoarticular flaps (n=8) were associated with transient deep peroneal nerve palsy in four cases, all of which recovered antigravity dorsiflexion by 6 months. In standard segmental harvests (n=49), donor-site complications occurred in 38%, most frequently valgus ankle deformity (9%) and neuropathic pain (6%). Valgus deformity was more likely in patients with shorter distal residual fibula and an age–residual fibula index (A-RFI) <16. CONCLUSIONS: Vascularized fibula flaps are safe and versatile for pediatric skeletal reconstruction. Donor-site complications are common but generally manageable, with full recovery of nerve function. Osteoarticular harvests carry the highest risk of peroneal nerve injury, and valgus ankle deformity may occur, particularly with an age–residual fibula index <16. Careful planning and age-adjusted fibular preservation are essential to optimize outcomes.

Background: Managing heart failure (HF) can be challenging for rural dyads, potentially contributing to depressive symptoms. Coping resources may be important components for dyadic interventions targeting depressive symptoms. Purpose: To explore actor and partner effects of coping resources on depressive symptoms in rural HF dyads. Methods: Using a cross-sectional design, data were collected from 42 rural HF dyads using the Interpersonal Support Evaluation List-12, Social Problem-Solving Inventory Revised-Short, Global Family Function, Family APGAR, and the Center for Epidemiological Studies-Depression scales. Data were analyzed using the Actor-Partner Interdependence Model. Results: Patients were 66.42 and caregivers were 60.83 years old. No partner effects noted. Significant actor effects for patients and caregivers between their own social support and depressive symptoms and their own problem-solving and depressive symptoms were found. There was also a significant actor effect between the caregivers’ family satisfaction and depressive symptoms. Conclusions: Dyadic interventions that enhance coping resources are needed.

Summary Renal response (RenR) in light‐chain (AL) amyloidosis is associated with a lower risk of end‐stage kidney disease and improved survival. However, substantial variation exists in the time to and depth of RenR. We investigated variables associated with RenR in a retrospective study of newly diagnosed AL amyloidosis patients ( n = 350) assessable for RenR between 2010 and 2022. RenRs were recorded at 6, 12 and 24 months and best response. Deep RenR was defined as a ≥renal very good partial response (RenVGPR, >60% reduction in 24‐h proteinuria or ≤200 mg). Logistic regression and competing risk methods were used to examine variables associated with RenR. The median age was 64 years, and median follow‐up was 5.5 years. On multivariable logistic regression, obtaining ≥HemVGPR within 6 months, kappa isotype, high baseline difference between involved and uninvolved free light chains (dFLC ≥40 mg/dL), renal stage and autologous haematopoietic stem cell transplant (AHSCT) were significantly associated with deep RenR. Cumulative incidence rates for deep RenR, treating death or renal progression as a competing event, demonstrated that early HemR, first‐line AHSCT, lower renal stage and dFLC ≥40 mg/dL significantly increased the likelihood of deep RenR. Specific clonal plasma cell features, namely light‐chain isotype and baseline dFLC levels, independently influence the timing and depth of RenRs in AL amyloidosis following treatment, in addition to renal stage and HemR.