Citations

Abstract Asthma in the elderly (AIE) represents a unique challenge, necessitating better understanding of the mechanisms that drive airway hyperreactivity and remodeling (thickened, fibrotic airways). Normal aging is associated with increased lung stiffness, and thus the influence of mechanical forces on bronchial airways (breathing, sighs, CPAP) likely changes, potentially increasing with AIE and resultant remodeling, overall highlighting the need to understand the importance of mechanobiology in aging and AIE. Here, mechanosensitive Piezo (Pz) channels are highly expressed in the lung, including within airway epithelium and smooth muscle (ASM) but their specific roles particularly with aging remain largely unexplored. In this study, we used human ASM cells from young vs. old (≥65 y) non-asthmatics vs asthmatics to test the hypothesis that normal aging blunts Pz expression and functionality at baseline as well as in response to mechanical stretch, whereas asthma, particularly, AIE ASM leads to enhanced Pz expression promoting fibrosis and remodeling. Both Pz1 and Pz2 were expressed in ASM and increased in AIE. Oscillatory mechanical stretch mimicking breathing with superimposed static stretch increased Pz, especially in AIE: effects exacerbated by Pz activator Yoda1 and blunted by Pz inhibitor GsMTx4. Stretch or Yoda1 increased Wnt3a, β-catenin and GSK3β activation particularly in AIE, while ASM proliferation and extracellular matrix production remained preserved or even heightened in elderly ASM. Conversely, Pz1 inhibition by GsMTx4 potently reduced ECM deposition, particularly in AIE cells, highlighting Pz1's pivotal role in modulating ECM deposition. Overall, our findings indicate Pz1 as a mechanosensitive regulator of airway remodeling in AIE.

ABSTRACT Background Antiplatelet management in patients hospitalised for gastrointestinal bleeding (GIB) after percutaneous coronary intervention (PCI) requires balancing risks of rebleeding and clinical vascular events. Aims Evaluate the impact of antiplatelet resumption timing post‐endoscopy on rebleeding and clinical vascular events. Methods We performed a retrospective nationwide cohort study of patients hospitalised with post‐PCI GIB on dual antiplatelet therapy (DAPT) using the Vizient Clinical Database. Co‐primary outcomes were 30‐day rebleeding and 90‐day clinical vascular events after endoscopy. Multivariable Cox proportional hazards regression analysis was performed. Results Among 2979 patients with both antiplatelet agents held before endoscopy for GIB (46.0% upper; 34.8% lower), antiplatelet resumption > 7 days post‐endoscopy was associated with decreased 30‐day rebleeding (hazard ratio [HR] 0.66; 95% confidence interval [CI] [0.49–0.87]) and increased 90‐day clinical vascular events (HR 1.18 [1.02–1.36]) compared to restarting ≤ 1 day post‐endoscopy. Among 869 patients with one antiplatelet agent held before endoscopy for GIB (47.3% upper; 36.3% lower), resumption at > 7 days vs. ≤ 1 day had HR 0.69 (0.41–1.14) for rebleeding and HR 1.41 (0.97–2.04) for clinical vascular events. HRs for antiplatelet resumption > 3 days vs. ≤ 1 day post‐endoscopy were similar. Conclusions Antiplatelet resumption > 7 days after endoscopy in patients hospitalised with post‐PCI GIB is associated with decreased 30‐day rebleeding but increased 90‐day clinical vascular events compared with resumption ≤ 1 day post‐endoscopy. Similar tradeoffs were noted with antiplatelet resumption > 3 days post‐endoscopy. To optimise competing risks of rebleeding versus clinical vascular events, antiplatelet therapy should be resumed no later than 7 days post‐endoscopy, and preferably within 3–4 days.

Abstract Neuromodulatory subcortical systems (NSSs) are uniquely susceptible to dementia‐related pathology, leading to frequent molecular and behavioral impairments associated with altered function of these nuclei. Some of these systems display clear sex‐specific cytoarchitecture and signaling leading to distinct physiology and behavioral outputs in males and females, while other regions display nominal sex differences. However, the relevance of sex differences in modulating dysfunction of NSSs in Alzheimer's disease (AD) and related dementias is not well understood. This review is a joint effort by the Neuromodulatory Subcortical Systems and Sex and Gender Differences in Alzheimer's Disease Professional Interest Areas of the Alzheimer's Association. We review sex differences in NSSs, both in non‐disease states and in AD models and patients. We highlight the possible role of NSSs in driving sex‐specific AD susceptibility and potential footholds for sex‐based interventions targeting these systems. We conclude by outlining immediate and long‐term actions to address the intersection of NSSs, sex, and AD.

Abstract Purpose Although the Woven EndoBridge (WEB) device is increasingly used for the treatment of wide-neck intracranial aneurysms, including in the acute rupture setting, comparative evidence assessing the impact of rupture status remains limited. This study compared angiographic, safety, and clinical outcomes between ruptured and unruptured intracranial aneurysms treated with WEB. Methods We conducted a retrospective analysis of prospectively collected data from the multicenter cohort registry WorldWideWEB, including consecutive adult patients with intracranial aneurysms treated with the WEB. Patients were stratified into groups of ruptured and unruptured aneurysms. Propensity score matching was used to balance baseline characteristics between both groups. Retreatment rate was the primary outcome. Secondary outcomes included mRS, safety events (thromboembolic complications) and angiographic outcomes (periprocedurally and last follow-up). Results Among 1,220 patients, 342 (28.0%) presented with ruptured aneurysms. There was no significant difference in the rate of thromboembolic complications between groups (11.8% vs 5.9%, p = 0.056). At follow-up, adequate occlusion was lower (82.2% vs 93.3%, p < 0.002) and functional outcomes were worse (mRS ≥2 in 34.1% vs 21.9%, p = 0.012) among patients with ruptured aneurysms. Periprocedural adequate occlusion (53.3% vs 53.8%, p>0.9) and retreatment rates (11.8% vs 7.1%, p = 0.14) did not differ between groups after matching. Conclusion Ruptured aneurysms demonstrated expected inferior follow-up functional and angiographic outcomes when compared with unruptured aneurysms, but no difference in retreatment rate and procedural safety. These findings support WEB as a safe and effective treatment option for appropriately selected ruptured intracranial aneurysms in routine clinical practice.

Abstract Aims Early detection of structural heart disease (SHD) improves patient outcomes. However, population-based screening is not recommended due to the lack of accurate and cost-effective tools. We evaluated the costs of artificial intelligence–enabled electrocardiogram (AI-ECG) alone vs. AI-ECG followed by handheld cardiac ultrasound (HCU) for SHD screening. Methods and results We performed a model-based cost analysis using data from 286 adult patients who underwent ECG and same-day HCU performed by a novice operator. Transthoracic echocardiogram (TTE) was the reference standard. We compared two screening strategies: (i) AI-ECG alone and (ii) a stepwise approach (AI-ECG followed by HCU). We assessed costs per diagnosis of aortic stenosis (AS), increased left ventricular wall thickness (ILVWT), and left ventricular systolic dysfunction (LVSD). Sensitivity analyses were conducted for varying disease prevalence. The stepwise approach decreased the cost per diagnosis of AS from $6386 (AI-ECG alone) to $2746 (57.0% savings), ILVWT from $4448 to $2895 (34.9% savings), and LVSD from $1469 to $1296 (11.8% savings). Overall, the cost per diagnosis for all SHDs combined decreased from $1940 to $1570 (19.1% savings). Sensitivity analysis demonstrated that cost savings were inversely proportional to disease prevalence. Nevertheless, stepwise screening remained cost-saving compared with AI-ECG alone until prevalence exceeded ∼55.9% for AS, 28.9% for ILVWT, 20.7% for LVSD, and 40.8% for all SHDs combined. Conclusion A stepwise screening strategy incorporating HCU after a positive AI-ECG reduces the immediate costs of SHD detection by minimizing unnecessary TTEs. This approach may enhance the feasibility of population-based SHD screening, particularly in lower-prevalence settings.

ABSTRACT Introduction Cardiac myosin inhibitors (CMIs) improve hemodynamics and symptoms in hypertrophic cardiomyopathy (HCM), but recent real‐world data have raised concerns regarding an increased risk of atrial fibrillation (AF). We sought to reassess AF risk using randomized controlled trial (RCT) evidence and to contextualize discrepancies with observational reports. Methods and Results We performed a systematic review and random‐effects meta‐analysis of RCTs evaluating the effect of CMIs on incident AF in HCM. MEDLINE, Scopus, and CENTRAL were searched through November 25, 2025. Eight RCTs ( n = 1581) comparing mavacamten or aficamten with placebo or active control were included. Event counts were pooled as risk ratios (RRs) with 95% confidence intervals (CIs). CMIs were not associated with increased AF risk (RR 1.11, 95% CI 0.62–1.98; heterogeneity I 2 = 0%). No differences were observed between mavacamten and aficamten, with consistent findings across HCM subtypes (obstructive and non‐obstructive). Importantly, most trials (7/8) excluded patients with uncontrolled, persistent, or permanent AF, five excluded paroxysmal AF at screening, and one excluded any AF history. Baseline left atrial enlargement was generally in the mild to moderate range across trials, suggesting limited representation of high‐risk AF phenotypes. Conclusion Randomized evidence to date does not demonstrate an increased AF risk with CMIs. Differences between RCT populations and real‐world cohorts, including restrictive AF eligibility criteria, lower baseline atrial remodeling, and limited rhythm surveillance may explain discordant observational findings and highlight the need for longitudinal monitoring in clinical practice.

ABSTRACT Purpose To simultaneously measure skeletal muscle energetics and blood flow (BF) before, during, and after dynamic plantar flexion exercise (PFE). Methods Non‐localized pulse‐acquire phosphorus‐31 magnetic resonance spectroscopy ( 31 P MRS) and phase contrast flow magnetic resonance imaging ( 1 H MRI) using golden‐angle rotated spiral readouts were acquired in an interleaved fashion. Data were collected at rest, during PFE to volitional fatigue, and post‐exercise recovery in 10 healthy adults. Interleaved popliteal artery BF was validated against conventional cine phase‐contrast measures at rest and post‐exercise recovery, while calf muscle energetics were validated by comparing to conventional 31 P MRS‐only measures at rest. To minimize motion artifacts during dynamic PFE, flow data were resolved in 3 dimensions (cardiac phase, pedal position, and exercise stage). Results Resting phosphocreatine (PCr) and inorganic phosphate concentrations were similar between both techniques (both p > 0.05). During PFE, PCr declined to 46% ± 10% of rest. PCr recovery time was 43 ± 15 s. Resting BF was 132 ± 43 mL/min and increased up to four‐fold during PFE depending on exercise stage and pedal position. Notably, there was excellent agreement between the interleaved and conventional BF measures ( r 2 = 0.95, slope = 0.977, p < 0.0001) with minimal bias (12.62 mL/min) over a wide range of physiologically relevant BF values (from ∼60 to 600 mL/min). Conclusion The feasibility of simultaneous assessment of skeletal muscle energetics and BF during dynamic exercise by interleaved 31 P MRS/ 1 H flow MRI was demonstrated along with good agreement between interleaved and conventional techniques during rest and recovery. One can now simultaneously quantify critical BF‐metabolism relationships and use this to probe disease‐related adaptations.

ABSTRACT Objective Surgical repair and 3D‐printed customized septal prosthesis (3D‐PCSP) are options for septal perforation treatment. We performed a study to compare the clinical outcomes of surgery and 3D‐PCSP using the NOSE‐Perf Scale (NPfS). Methods A chart review was performed on patients undergoing surgical repair or 3D‐PCSP placement between January 2018 and July 2024. The change in NPfS was used as primary endpoint. Demographics, ASA score, perforation size, etiology, and follow‐up duration were reported. Results Thirty‐five patients, 23 for surgical repairs and 12 for 3D‐PCSP, were included in this review [median (IQR)]. In the surgical repair group, perforation length and height measured 12 (10–18) mm and 10 (8–15) mm, respectively. Baseline NPfS was 24 (16–32), and this decreased to 8 (6–13) following surgical repair ( p < 0.001). Follow‐up time was 12 (5–21) months. In the 3D‐PCSP group, septal perforation length and height measured 25 (15–30) mm and 17 (15–20) mm, respectively. The baseline NPfS was 17 (3–24.5), and this decreased to 9.5 (7–13) following 3D‐PCSP placement ( p = 0.001). The follow‐up was 18.4 (16–23) months. NPfS reduction was greater for surgical repair ( p = 0.018). Conclusions Surgery and 3D‐PCSP offer meaningful symptom relief for NSP patients. Treatment decisions should be individualized through shared decision‐making that considers patient comorbidities, preferences, surgeon experience, and risk tolerance. In this cohort, surgical repair was associated with greater NPfS reduction compared with 3D‐PCSP placement. Level of Evidence 3.