Publications by Year: 2025

INTRODUCTION: Point-of-care ultrasound (POCUS) is a valuable tool for clinicians, but little data exists regarding the perceptions of ideal POCUS utilization, as compared to actual use, amongst urologists. We aim to assess how perceptions align or diverge with actual practice.

METHODS: An institutional review board (IRB)-approved survey was developed and disseminated by email to 6 of 8 American Urologic Association Sections, program directors via the Society of Academic Urologists, and to 2 residency programs. The primary outcome was to assess differences in current and perceived optimal use. Data was collected via the University of Iowa RedCap system. Descriptive statistics and Chi-squared analyses were performed.

RESULTS: 184 non-trainees and 41 trainees completed the survey. Rates of current POCUS use were significantly lower than perceived optimal usage for renal (58% to 88%, p < 0.001), testis (37% to 74%, p < 0.001), and penile (19% to 37%, p < 0.001) application amongst the urologic organs. Current use was also lower than perceived optimal use with regard to utilization in the emergency room (16% to 39%, p < 0.001) and for diagnostic purposes (53% to 81%, p < 0.001), regardless of organ focus. Sub-analysis found that trainees, compared to non-trainees, identified the inpatient unit (54% to 18%, p < 0.001) and emergency room (81% to 35%, p < 0.001) as optimal locations for use.

CONCLUSIONS: Perceptions of POCUS use differ between trainees and non-trainees, especially the location of use. These results help identify areas for which training could be focused, as well as highlight the need for further research on generational variation in desired POCUS use.

DANFLU-1 was an open-label, pragmatic feasibility trial which randomized persons aged 65 to 79 years to high-dose inactivated influenza vaccine (HD-IIV) or standard-dose inactivated influenza vaccine (SD-IIV). The trial found that HDIV was associated with a reduced incidence of death and hospitalization for influenza or pneumonia as compared to SDIV. Bayesian analysis offers a framework for probabilistic interpretation of trial data and provides a method for incorporating prior information into the analysis. This study presents a post-hoc, Bayesian re-analysis of the DANFLU-1 trial. We conducted a Bayesian re-analysis of the DANFLU-1 trial, which randomly assigned 12,477 adults (65-79 years) 1:1 to HDIV or SDIV during the 2021/2022 season. The trial used Danish nationwide registers for data collection including baseline and follow-up data. This re-analysis applied neutral non-informative, evidence-based, and neutral skeptical priors. The evidence-based priors were informed solely by randomized trials published before DANFLU-1. Relative vaccine effectiveness (rVE) with 95% credible intervals (CrI), and posterior probabilities were estimated using Bayesian log-binomial regression models. Probabilities of rVE >0%, 10% and 20% were estimated. The findings were consistent across different priors. There was a greater than 95% probability of any benefit (i.e. rVE >0%) for all-cause mortality and hospitalization due to pneumonia/influenza, regardless of the prior used. For pneumonia/influenza hospitalization, the probabilities of rVE >10% were at least 95% with the non-informative and evidence-based priors, while it was 93.2% with the skeptical prior. For all-cause mortality, the probabilities of rVE > 10% ranged from 91.1% to 98.4% across priors. For the remaining outcomes, including cardiorespiratory hospitalization and any hospitalization, the probabilities of of rVE >10% ranged from 25.0% to 59.0% across priors. This Bayesian re-analysis of DANFLU-1 demonstrated robust results, with high probabilities of any benefit (rVE >0%) for all-cause mortality and hospitalization due to pneumonia/influenza. We also found high probabilities of an rVE > 10% for both outcomes, indicating robust findings supportive of clinical benefit. As a feasibility trial, the findings warrant further Bayesian investigation of adequately powered trials.

Cohesin plays a central role in three-dimensional genome organization and transcriptional regulation, with functional diversity determined by incorporation of distinct STAG subunits. Pathogenic variants in the X-linked STAG2 gene cause a rare cohesinopathy with variable clinical manifestations. Molecular analyses of fibroblasts from females carrying germline STAG2-truncating variants revealed highly skewed X chromosome inactivation favoring the mutant allele, resulting in loss of STAG2 expression in most cases. STAG2-deficient cells displayed a proliferative advantage and transcriptional alterations without detectable defects in sister chromatid cohesion or DNA repair. Notably, compensatory upregulation of STAG1 and ectopic expression of the germ cell-specific paralog STAG3 were observed, leading to the formation of a previously unrecognized chimeric cohesin complex in somatic cells. These findings suggest that females with STAG2-truncating variants exhibit mosaicism for STAG2 expression and compensatory STAG3 incorporation, providing mechanistic insight into the phenotypic variability observed in STAG2-associated cohesinopathies.

In the evolving landscape of heart failure (HF) management, the identification and analysis of subgroups and special populations within clinical trials are crucial for enhancing clinical decision-making, guiding further research, and understanding heterogeneity in study outcomes. This expert consensus document results from the collaborative efforts of the Heart Failure Collaboratory and the Heart Failure Collaboratory Academic Research Consortium, which brought together stakeholders from academia, industry, the U.S. Food and Drug Administration, and patient representatives. The purpose of this assembly was to propose standardized definitions and critical endpoint considerations essential for shaping the design and conduct of clinical trials for drugs and devices in the field of HF. In this context, we propose definitions and endpoints for specific subgroups and special populations in the spectrum of HF. We enhanced the precision, efficacy, and applicability of clinical research and promote more "personalized" approaches to interpretation of clinical trials. Furthermore, we explore the burgeoning field of gene therapy as a promising avenue for addressing the genetic basis of certain cardiomyopathies within these specialized patient groups. We focus especially on methodological considerations for subgroup analyses in large-scale trials, highlighting the importance of proper interpretation of subgroups and best practices for identifying heterogeneity suggestive of differential treatment effects, including when these analyses should be considered hypothesis-generating and requiring subsequent validation. We advocate for a methodical approach to clinical trial design, one that prioritizes the strategic identification of subgroups and employs appropriate statistical methodologies to ensure the reliability and clinical relevance of findings. Through this lens, we envision a pathway toward more personalized and effective treatments for HF, ultimately aiming to improve patient outcomes by leveraging the insights garnered from meticulously designed and comprehensively analyzed clinical trials.

BACKGROUND: Major adverse cardiovascular events (MACE)-cardiovascular (CV) death, nonfatal myocardial infarction (MI), and nonfatal stroke-are highly relevant clinical outcomes. In global randomized trials, medical records review by a physician clinical events committee (CEC) is the conventional standard for adjudicating MACE but is labor intensive. Automated adjudication with the use of artificial intelligence (AI) could reduce cost and improve reproducibility.

OBJECTIVES: In this study, the authors sought to develop and validate an AI-based adjudication system for MACE and compare its performance with CEC adjudication in a large global randomized trial.

METHODS: We developed an AI-based system ("Auto-MACE") that uses an iteratively refined prompt of the OpenAI o1-mini language model to adjudicate MACE events, and a Clinical Longformer model trained on adjudicated events to assign a confidence level. We validated Auto-MACE against CEC adjudication in the PARADISE-MI global clinical trial comparing sacubitril/valsartan and ramipril in 5,661 patients with MI complicated by systolic dysfunction or pulmonary congestion.

RESULTS: Auto-MACE provided a confident adjudication in 315/455 deaths (69%), 301/659 potential MIs (46%), and 136/167 potential strokes (81%). Auto-MACE agreed with the CEC adjudication in 97%, 89%, and 88% of confident events, respectively. Among all events, Auto-MACE agreed with CEC adjudications in 86% of deaths, 76% of potential MIs, and 84% of potential strokes. The estimated effect of sacubitril/valsartan vs ramipril on composite MACE was similar with Auto-MACE adjudication (HR: 0.91; 95% CI: 0.78-1.07) and CEC adjudication (HR: 0.90; 95% CI: 0.77-1.05).

CONCLUSIONS: AI-based adjudication of MACE showed high agreement with human CEC adjudication, especially for CV death and stroke, and where the model was confident. Initial AI-based adjudication with CEC review of uncertain events may reduce workload while maintaining accuracy.

PURPOSE: To describe a novel Optical Coherence Tomography (OCT) finding called "scolex sign" in cases of central serous chorioretinopathy(CSCR).

METHODS: This retrospective multicenter study included CSCR patients with serous pigment epithelial detachments(PED) greater than 100µm, with or without subretinal fluid(SRF). Eyes showing a distinct hyperreflective focus on the PED wall(scolex sign) were analyzed. An equal number of age-matched controls with PEDs but without the scolex sign were included. Multimodal imaging data were reviewed. A subgroup analysis based on SRF status was also performed.

RESULTS: Of 291 eyes with large serous PEDs, 52 eyes exhibited the "scolex sign" and were compared to 52 age-matched controls. Baseline characteristics including gender, systemic comorbidities, best recorded visual acuity(BRVA) and OCT parameters were similar in both the groups. However eyes with "scolex" sign exhibited more number of central PEDs and shorter distance from foveal centre. On follow-up, eyes with "scolex" sign showed a higher rate of PED flattening and SRF resolution trended to be higher compared to controls.

CONCLUSION: The "scolex" sign represents a novel, benign OCT feature seen in a subset of CSCR cases. While not associated with poorer outcomes or adverse sequalae, it may reflect ongoing reparative changes, indicating a resolving stage of the disease.

Head-to-head research comparing invasive revascularization strategies for chronic limb-threatening ischemia (CLTI) is sparse, partly due to challenges in conducting randomized controlled trials in the CLTI space. These include the expense of head-to-head trials, optimizing patient selection criteria for real-world applicability, and identifying optimal study end points. The Vascular InterVentional Advances (VIVA) Foundation, a 501(c)(3) not-for-profit organization, convened a Vascular Leaders Forum to initiate an open, multispecialty collaborative discussion of these challenges and ways to optimize the design of medical device trials in CLTI. This article summarizes the current landscape of clinical studies of CLTI revascularization strategies and options for designing comparative trials proposed by representatives from vascular surgery, interventional cardiology, interventional radiology, vascular medicine, podiatry, the U.S. Food and Drug Administration, and a medical device manufacturer. Four broad areas to optimize comparative trials of CLTI interventions were identified. First, primary end points should be carefully chosen with attention to clinical, patient-centric, imaging, and hierarchical considerations; standardization; and inclusion of guideline-directed medical therapy. Second, broader eligibility criteria can expand and hasten enrollment and are important for gathering evidence on outcomes in medically complex patients often encountered in real-world practice. Third, extending the primary end point timing to 12 months with additional follow-up out to 24 to 60 months would accommodate a longer period of device evaluation and the ability to enrich clinical end-point rates. Finally, innovative pragmatic trial designs and statistical methodologies are needed to conduct comprehensive, cost effective, relevant trials with sufficient statistical power and without prohibitively large sample sizes and study durations.

Alzheimer's disease (AD) begins decades before clinical symptoms emerge. The "amyloid hypothesis" suggests that amyloid-β (Aβ) deposition initiates a cascade of tau hyperphosphorylation, neuroinflammation, and neuronal loss leading to cognitive decline. The recent success of anti-Aβ therapies such as Leqembi in prodromal or mild cognitive impaired patients underscores the importance of early intervention and Aβ clearance. However, safety and cost limitations highlight the need for alternative therapeutic strategies. Small-molecule modulators of Sigma-1 and Sigma-2 receptors (σ1R and σ2R) have emerged as promising candidates for AD treatment. σ1R agonists exhibit neuroprotective and anti-amnestic effects under pathological conditions without affecting normal cognition. Beyond AD, σ1R is implicated in several neurodegenerative diseases including ALS (amyotrophic lateral sclerosis), Parkinson's, and Huntington's diseases, stroke, and epilepsy. σ1R plays a key role at mitochondria-associated ER membranes (MAMs)-specialized lipid raft-like domains that form functional membrane contact sites between the endoplasmic reticulum (ER) and mitochondria. β-secretase (BACE1), γ-secretase, and their substrates APP and palmitoylated APP (palAPP) localize in the MAMs, promoting amyloidogenic Aβ production. MAMs serve as dynamic hubs for inter-organelle communication, calcium signaling, and lipid metabolism. The "MAM hypothesis" proposes that MAM dysregulation drives early AD pathology and persists throughout disease progression, contributing to neurofibrillary tangle formation, calcium imbalance, and neuroinflammation. This review aims to summarize the current understanding of σ1R-mediated regulation of MAMs and its neuroprotective mechanisms, highlighting potential therapeutic opportunities for targeting σ1R in AD and other neurodegenerative disorders.

Artificial intelligence (AI) systems used in everyday digital spaces often rely on design assumptions shaped by adult patterns of reasoning, which creates specific interpretive gaps for younger users. This editorial examines how narrative-style outputs produced through epistemic automation can make probabilistic estimates appear more authoritative than intended for some adolescents. It also considers how technical opacity and model drift introduce shifts in system behavior that minors may misread as stable clinical logic, since there are few cues that distinguish computational changes from expert reasoning. When adolescents independently consult conversational agents or symptom-oriented tools, these interactions can influence clinical encounters without being systematically discussed. Therefore, this editorial outlines practical ways for clinicians to ask about AI-mediated information seeking and describes developmental design features, such as explicit uncertainty cues, layered explanations, and age-responsive prompting, that can reduce misinterpretation. Treating the pediatric digital ecosystem as a distinct design and regulatory setting allows for more precise alignment between algorithmic behavior, developmental cognition, and clinical practice.