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SUMMARY Aging is accompanied by profound changes in bladder function, leading to increased urinary frequency and incontinence that impair quality of life in humans and are recapitulated in mouse models. Bladder filling and emptying rely on precise mechanosensory feedback, yet how aging alters this sensory control remains unclear. PIEZO ion channels convert mechanical forces into cellular signals essential for bladder fullness sensation. Using inducible smooth-muscle specific Piezo1 deletion, we find that loss of Piezo1 attenuates aging-related bladder dysfunction. Dietary enrichment with margaric acid, a membrane-active fatty acid previously shown to inhibit PIEZO channels, reduced urinary dysfunction in aged mice. In humans, genotype–phenotype analyses reveal an association between a PIEZO1 gain-of-function variant and early-onset neuromuscular bladder dysfunction. Together, these findings define a smooth-muscle, PIEZO1-mediated mechanosensory basis for aging-related bladder dysfunction and introduce a non-invasive strategy for targeting PIEZO channels in vivo .

Background Bedside percutaneous dilatational tracheostomy is a commonly performed procedure in the Intensive Care Unit with a steep learning curve. Checklists and standardized protocols have been established as essential tools for mitigating medical error and enhancing patient safety during critical care procedures. Research Question To assess the feasibility and safety profile of a percutaneous tracheostomy protocol, performed by pulmonary and critical care fellows, which integrates a multi-component checklist, tracheal ultrasound and a unique dual-visualization technique for endotracheal tube management. Study Design and Methods We conducted a retrospective review of all patients (n = 49) who underwent bedside percutaneous tracheostomy using a standardized protocol between November 1, 2022, and October 31, 2024. Key components of the protocol included rigorous pre-procedure assessment with standard tracheal ultrasound stations, a mandatory checklist, and endotracheal tube retraction under dual video laryngoscopy and bronchoscopy. Outcomes analyzed included major bleeding, site infection, and airway complications. Results A total of 49 percutaneous tracheostomy procedures were successfully performed over the 24-month period. No major bleeding episodes or pressure ulcers were identified. There was a single complication involving loss of airway due to endotracheal tube balloon rupture. Critically, the patient was rapidly re-intubated without any hypoxemia or hemodynamic instability, which may be attributed to the immediate availability and use of the dual-visualization safeguard. Interpretation The implementation of this protocolized, checklist-driven approach to bedside percutaneous tracheostomy is feasible and safe within the framework of a pulmonary and critical care fellowship training model. The use of a novel dual-visualization technique (video laryngoscopy and bronchoscopy) during endotracheal tube retraction serves as a robust fail-safe, which may enhance patient safety during airway-compromised events.

ABSTRACT As emergency department (ED) crowding and patient boarding reach critical levels nationwide, the role of the emergency medicine pharmacist (EMP) must be both defined and safeguarded. While EMPs are increasingly valued for their contributions to acute care, their responsibilities often unintentionally expand during periods of operational strain, particularly when admitted patients remain in the ED for prolonged durations. EMPs should ideally be resourced to remain focused on time‐sensitive, high‐risk medication management where their expertise is most impactful and not be used as default providers for all pharmacotherapy needs during ED boarding. This perspective outlines our position on the ideal scope of EMP practice during times of congestion, advocating for clearly defined role boundaries, strategic collaboration with other pharmacy team members, and system‐level support to prevent dilution of emergency care. EMPs must be empowered to prioritize critical ED workflows, support resuscitations, and lead initiatives in education, protocol development, and patient safety, without being overextended by responsibilities that can be absorbed by other team members.

Abstract Rationale Prior studies demonstrate pulmonary artery (PA) enlargement on computed tomography (CT) in pulmonary hypertension (PH). Some patients exhibit markedly enlarged or “aneurysmal” PA dilation, but its clinical relevance remains unclear. We aimed to characterize clinical characteristics, hemodynamics, and survival probability of patients with aneurysmal PA size. Methods Demographics, clinical characteristics, and CT imaging were obtained for individuals with group 1 or 2 PH and matched controls in the Pulmonary Vascular Disease Phenomics cohort. PA diameter was measured using Osirix software. PA diameter was categorized based on previously reported values as normal (<27 mm [females], <29 mm [males]), enlarged (27-39 mm [females], 29-39 mm [males]), or aneurysmal (≥40 mm). Outcomes included mean PA pressure (mPAP) on right heart catheterization (RHC) and time to death or heart/lung transplant. Associations with mortality and mPAP were evaluated using multivariable Cox and linear regression models, adjusting for age, sex, and BMI. Descriptive statistics are presented as median [IQR]. Results 690 subjects met the inclusion criteria for survival analysis (364 WSPH group 1 or matched comparator, 241 group 2 or comparator, 85 healthy control), with 594 undergoing RHC. PA diameter was normal in 163 participants, enlarged in 414, and aneurysmal in 113. Aneurysmal PA, compared with normal or enlarged PA, was associated with younger age (53 ± 14 vs 55 ± 16 and 59 ± 15 years, respectively; p < 0.001), non-White race (18.9% vs 8% and 17.2%; p = 0.034), pro-BNP (1950 ± 5708 vs 531 ±1651 and 110 ± 2258 pg/mL; p < 0.001), PH duration (6.78 ± 6.86 vs 2.24 ± 4.39 and 3.82 ± 5.47 years; p < 0.001), group 1 disease (77% vs 37% and 61%), and congenital heart disease (CHD)-PAH (10.6% vs 0.0% and 4.8%, p < 0.001). Aneurysmal PA subjects had higher mPAP (46 [36-57] vs 19 [16- 25] and 35 [28-47] mmHg, p < 0.001), pulmonary vascular resistance (PVR) (5.5 [3.6-9.4] vs 1.7 [1.0-2.3] and 4.1 [2.4-7.1] Woods units, p < 0.001), cardiac index (CI; 2.73 [2.34-3.29] vs 2.55 [2.13-2.98] and 2.52 [2.12-3.10] L/min/m2, p < 0.02) and likelihood of death or transplant (p < 0.001; Figure 1). Conclusion “Aneurysmal” PA was more common in younger, non-White subjects with longer WSPH group 1 disease duration, CHD, and higher pro-BNP levels. Aneurysmal PA was associated with elevated mPAP, PVR, and CI, and reduced likelihood of survival. These findings highlight the need to further elucidate the pathophysiology and prognostic implications of aneurysmal PA remodeling in PH. This abstract is funded by: NHLBI and the Pulmonary Hypertension Association

Abstract Background We recently reported a strong association between CT markers of pulmonary artery (PA) dilation and mean PA pressure (mPAP) in subjects with World Symposium on Pulmonary Hypertension (WSPH) group 1 and 2 pulmonary hypertension (PH). The relationship between PA size and mPAP in subjects with WSPH group 3 PH, in which parenchymal changes may influence PA dilation, remains uncertain. We sought to investigate this relationship in subjects with and without PH who have significant parenchymal pulmonary disease or hypoxia. Methods We measured PA diameter and PA:aorta (PA:A) ratio on CT for all subjects with WSPH group 3 PH, matched disease comparators, and healthy controls in the Pulmonary Vascular Disease Phenomics (PVDOMICS) cohort. PH and comparator subjects were categorized by group 3 etiology into obstructive (including chronic obstructive pulmonary disease [COPD] and cystic fibrosis), interstitial (including idiopathic pulmonary fibrosis, unspecified interstitial lung disease, combined pulmonary fibrosis and emphysema, and chronic hypersensitivity pneumonitis), and non-parenchymal (including obesity hypoventilation syndrome, obstructive sleep apnea, and extrinsic restrictive disease) subgroups. Primary outcome was mPAP on right heart catheterization (RHC). Association with mPAP was evaluated using multivariable linear regression adjusted for age, sex, and BMI. Results 339 subjects met inclusion criteria (101 WSPH group 3 PH, 153 disease comparators, 85 healthy controls). 83 subjects had obstructive disease, 125 had interstitial disease, and 46 had non-parenchymal disease. PA diameter and PA:A were associated with mPAP in all subjects and in each subgroup (p < 0.001; see figure 1). The association was notably stronger in the non-parenchymal group (ρ = 0.707 for diameter, 0.750 for PA:A) compared to obstructive (ρ = 0.566 for diameter, 0.529 for PA:A) and interstitial (ρ = 0.432 for diameter, 0.373 for PA:A) groups. Change in PA size between 25th and 75th percentile mPAP was lower in the interstitial group (3.88 mm, ratio 0.12) than in the obstructive (4.88 mm, ratio 0.17) and non-parenchymal (4.80 mm, ratio 0.19) groups (see figure 1). Conclusions PA size on CT is associated with mPAP in subjects with chronic lung disease with and without PH. This association is strongest in subjects without parenchymal lung disease but with features of hypercarbia or hypoxia alone. These data suggest that features of parenchymal lung disease in certain patients may limit expected PA dilation in response to elevated PA pressures. Further study is needed regarding the implications of these findings for early identification of PH in patients with chronic lung disease. This abstract is funded by: The NHLBI and Pulmonary Hypertension Association

Abstract Rationale Advances in bronchoscopic technology, including robotic-assisted bronchoscopy (RaB) and cone-beam CT (CBCT), have enabled biopsy of multiple nodules in a single procedure. Here we present the procedural characteristics, safety, diagnostic yield, and use of linear endobronchial ultrasound (EBUS) staging in patients with multifocal pulmonary nodules biopsied under a single anesthesia event. Methods This multi-center, retrospective observational study included adults undergoing RaB biopsy of multifocal peripheral pulmonary lesions and lymph node assessment under a single anesthesia event at six U.S. centers from 11/2019 - 8/2025. Procedures utilized either the Ion (Intuitive) or Monarch (Ethicon) systems under general anesthesia. De-identified demographic, radiologic, procedural, pathologic, and safety data were collected in a secure centralized database. Safety outcomes included pneumothorax and its sequelae, hypoxia, and infectious complications. Diagnostic yield was determined using the 2024 ATS/ACCP consensus statement. NGS adequacy was reported from two health systems with well-defined criteria for sufficiency and standard institutional practices for sending NGS testing on both nodules. Statistical analyses utilized included descriptive statistics, t-tests, chi-squared/Fisher’s tests where appropriate, and logistic regression. Results Among 191 patients, 177 underwent biopsy of two and 14 of three nodules. Lymph nodes were sampled in 167 (87.4%), with 18 (10.8%) positive for malignancy; notably, 17 of 18 (94%) patients with nodal metastases had at least one fully solid nodule. Complications occurred in 20 patients (10.5%), including pneumothorax in 14 (7.3%), with 4 (2.1%) requiring tube thoracostomy. There were no cases of bilateral pneumothorax. Transient hypoxia occurred in 3 patients (1.6%) and 3 developed outpatient-managed bronchitis. Seven patients (3.7%) required unplanned admission. Overall diagnostic yield was 72.2%, with 122 (63.9%) patients having two diagnostic nodules and 33 (17.4%) having two non-diagnostic nodules. Bronchus sign (OR 2.9, p = 0.003), radial EBUS use (OR 2.6, p = 0.025), and CBCT use (OR 2.4, p = 0.021) were associated with procedures having two diagnostic nodules. At sites with standardized NGS adequacy reporting, 74 of 81 malignant nodules (91%) provided sufficient tissue for NGS. Conclusions •Single-procedure biopsy of multifocal pulmonary nodules is feasible, safe, and achieves industry-standard strict diagnostic yield. •Complications are slightly higher than single-nodule procedures. Serious events were rare. •17 of 18 patients with malignant nodal disease had at least one fully solid nodule; no patients with two pure ground glass nodules had nodal metastasis. •NGS testing was feasible and adequate on the majority of samples, aiding clinicians in staging multifocal nodules. This abstract is funded by: None

Abstract Introduction Aminoglycoside antibiotics are well known to cause cochlear and vestibular toxicity when used systemically. Inhaled tobramycin was developed to reduce systemic exposure and is considered safer with only rare reports of ototoxicity have been reported in patients with renal dysfunction. We describe a case of bilateral sensorineural hearing loss (SNHL) and tinnitus associated with inhaled tobramycin in a patient without renal impairment, emphasizing that even inhaled formulations can induce significant auditory toxicity in susceptible individuals. Case A 85 year old woman with Sjogren’s related interstitial lung disease and bronchiectasis who was chronically colonized by Pseudomonas aeruginosa was treated with inhaled tobramycin for recurrent infections. She had normal renal function and no prior aminoglycoside exposure. After approximately three months of inhaled therapy, she noted progressive bilateral hearing decline and high pitched tinnitus without vertigo or otalgia. Physical examination revealed clear ear canals and intact tympanic membranes. Baseline audiometry one year ago had demonstrated mild to moderately-severe bilateral SNHL. Repeat testing after tobramycin exposure showed worsening thresholds and reduced word recognition bilaterally. MRI of the brain and internal auditory canals was unremarkable. Serum creatinine remained normal throughout treatment. Inhaled tobramycin was discontinued, after which hearing loss stabilized. No further progression was observed on follow-up audiometry. Discussion Although systemic absorption from inhaled tobramycin is typically low, elderly and low-body-weight patients may accumulate sufficient serum levels to cause cochlear injury. Mechanisms include reactive oxygen species mediated hair cell toxicity and possible genetic susceptibility involving the mitochondrial 12S rRNA mutation. Prior reports of vestibulotoxicity and cochleotoxicity from inhaled tobramycin primarily involved patients with renal dysfunction, however, this case report demonstrates that toxicity can occur despite preserved renal function. Clinicians should maintain vigilance for otologic symptoms in patients receiving inhaled aminoglycosides. Baseline and periodic audiometric monitoring should be incorporated into chronic treatment protocols. This abstract is funded by: None

Abstract Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor in adults, with median survival remaining approximately 12–15 months despite aggressive multimodal therapy. Therapeutic resistance and tumor recurrence are driven in part by limited drug penetration across the blood–brain barrier (BBB) and the persistence of brain cancer stem cells (BCSCs), highlighting the need for brain-penetrant therapeutic platforms capable of achieving sustained intratumoral delivery. Here, we developed a dendrimer-based nanotherapeutic by conjugating metformin to a fourth-generation hydroxyl-terminated polyamidoamine dendrimer (P4-MET) to enhance intracranial bioavailability and therapeutic efficacy in GBM. P4-MET exhibited favorable pharmacokinetic properties, including prolonged retention within the tumor microenvironment, and demonstrated enhanced cytotoxicity against GBM cell lines relative to free metformin (f-MET). Mechanistical studies with transcriptomic profiling by RNA sequencing revealed distinct treatment-associated molecular signatures, identifying BOLA2B as the most significantly differentially expressed gene between treatment groups. Specifically, BOLA2B expression was markedly elevated in f-MET–treated cells but not so following P4-MET treatment. Given the established association of BOLA2B with mTORC1 signaling and GPX4-mediated ferroptosis resistance, these findings suggest that P4-MET may, at least in part, enhance therapeutic efficacy by modulating ferroptosis-associated pathways. In orthotopic GBM models, combination treatment with P4-MET and radiotherapy (RT) significantly prolonged overall survival and increased tumor cell death compared with either monotherapy alone, consistent with a synergistic radiosensitizing effect. Importantly, P4-MET demonstrated minimal systemic toxicity, supporting its favorable therapeutic index and translational potential. Collectively, these findings establish P4-MET as a brain-penetrant nanomedicine platform that improves metformin delivery, modulates ferroptosis-related signaling networks, and potentiates radiotherapeutic response in GBM. This study highlights the potential of dendrimer-enabled metabolic nanotherapies to overcome therapeutic resistance in malignant brain tumors.

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.