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Background: Etripamil nasal spray is a fast-acting, calcium channel blocker in development for the conversion of paroxysmal supraventricular tachycardia (PSVT) outside of a health-care setting. Studies have demonstrated the favorable safety and efficacy of self-administered etripamil in restoring sinus rhythm (SR) and reducing emergency department visits. Purpose: This report analyzes the efficacy, safety, and test-dose tolerability of etripamil across PSVT clinical studies. Methods: We systemically examined randomized, controlled and open-label trials evaluating etripamil in patients with PSVT. Efficacy measures included the proportion of patients converting from PSVT to SR within 30 minutes and the median times to conversion across all Phase 3 studies. Safety data for treatment-emergent adverse events (TEAEs), serious AEs, and test dose tolerability from Phase 2/3 studies were summarized descriptively. Results: NODE-1, NODE-301 Part 1, NODE-301 Part 2 (RAPID, including RAPID Extension, RAPID Open Label, RAPID Open Label Extension periods), NODE-302, and NODE-303 studies were analyzed (Table 1). The Kaplan-Meier estimate of etripamil exposed patients converting to SR within 30 minutes (n= 622) was 59.6% (range, 53.6% to 64.3%) with a median time to conversion of 18.5 minutes (95% CI, 15.7 to 21.0). The proportions of RCT placebo group patients converting from SVT to SR by 30 minutes ranged from 26.7% to 34.7%. Estimates of conversion of SVT to SR with etripamil at 60 minutes for individual studies ranged from 63.2% to 73.5% (Figure). Combined analysis showed mainly the occurrence of mild, transient TEAEs, primarily nasal discomfort, nasal congestion, rhinorrhea, throat irritation, and epistaxis (Table 2). 1,107 patients took at least one etripamil test dose while in SR; no significant change in average baseline heart rate or blood pressure was observed within 45 minutes of administration, and test dose failure occurred in only 16 patients (1.4%). Conclusions: Across multiple clinical studies of acute PSVT management, self-administered etripamil consistently demonstrated robust efficacy and a favorable safety profile for acute PSVT management. Safety data and the low rate of test dose failures indicate favorable tolerability, suggesting no need for a pretreatment test dose. These findings support the potential of etripamil as a patient-administered therapy for PSVT, which may reduce reliance on emergency care.

Background: Dofetilide, a commonly prescribed class III antiarrhythmic for atrial fibrillation (AF), currently requires a 3-month amiodarone washout period per FDA guidelines. We evaluated the safety of initiating dofetilide within this 3-month washout period. Methods: We performed a retrospective cohort study across all Mayo Clinic sites and identified patients using centralized datamart that were transitioned from amiodarone to dofetilide in less than 90 days. Patients were included and confirmed by manual chart review if they had been on amiodarone for ≥ 12 weeks and if available amiodarone level >0.3 mg/ml at the time of dofetilide initiation. Serial ECGs were assessed during the hospitalization for dofetilide initiation and at 3-, 6-, and 12-months follow-up to evaluate QT interval. Primary safety end point was torsade de pointes. Results: The final cohort included 66 patients with a mean age of 65 ±14 years; 71.0% were male; and the average BMI was 29.6 ±5.1 kg/m 2 . Of the 66 patients, 65 had a history of AF: 31.8% paroxysmal, 54.5% persistent, and 12.1% long-standing persistent. Permanent pacemakers and ICDs were present in 27.3% and 22.7% of patients. Patients received amiodarone for a median of 7.8 months at a mean daily dose of 187.1±48.3 mg (range: 100 – 400 mg), with a mean transition period of 44.2±20.3 days. Of 66 patients, 16 (24 %) transitioned within 30 days of stopping amiodarone—including 5 (8 %) within 14 days—while the remaining 50 (76 %) was between 30 and 90 days. A total of 24.2% (16/66) patients required dofetilide dose reduction due to QT prolongation and 10.6% of patients (7/66) required drug discontinuation. There was no difference in either discontinuation rate or dose reduction rate in patients with a transition period ≤30 days vs > 30 days [6.25% vs. 12% (p=0.85) and 12.5% vs. 28% (p=0.36), respectively]. No cases of torsades de pointes were observed during dofetilide initiation or follow up. Conclusion: In this cohort, dofetilide initiation less than 90 days after amiodarone discontinuation was not associated with increased torsades de pointes risk. These data challenge and support reconsideration of the blanket 3-month washout and suggest that a monitored, expedited rhythm-control transition is feasible and safe.

Introduction: Patients with transthyretin amyloid cardiomyopathy (ATTR-CM) typically have low serum transthyretin (sTTR) levels, worsening heart failure, and increased mortality. A recent study has shown the association of sTTR levels ≥20mg/dL with reduced risk of all-cause mortality and cardiovascular mortality (CVM). It has also been shown that regardless of baseline sTTR level, greater increases in sTTR levels are associated with greater improvements in cardiovascular outcomes. Acoramidis, a near-complete (≥90%) TTR stabilizer, demonstrated a rapid and sustained increase from baseline in sTTR by Day 28 and reduced risk of cardiovascular outcomes in patients with ATTR-CM. Hypothesis: Acoramidis-mediated early increase in sTTR levels ≥20 mg/dL (lower limit of normal) at Day 28 reduces risks of CVM and cardiovascular-related hospitalizations (CVH) in patients with ATTR-CM. Methods: Analyses were conducted in the ATTRibute-CM modified intention-to-treat (mITT) population (acoramidis: 409; placebo: 202). The sTTR concentrations (normal range is 20-40 mg/dL) were assessed using an immunoturbidimetric method (Abbott ARCHITECT system) in a central laboratory. The proportion of participants with sTTR levels below normal at baseline and Day 28 were determined. The relationship between sTTR levels <20 or ≥20 mg/dL, at Day 28 across the pooled acoramidis and placebo treatment groups, and subsequent risk of CVM and of CVH over 30 months were analyzed using a stratified log-rank test. Results: At baseline about 25% of study participants had sTTR levels below normal in both treatment groups. At Day 28, less than 2% of participants had sTTR levels <20 mg/dL in the acoramidis arm compared with 26% in the placebo arm ( Table 1 ). When acoramidis and placebo treatment groups were pooled based on sTTR levels <20 or ≥20 mg/dL at Day 28, participants with sTTR ≥20 mg/dL were associated with a lower risk of the composite endpoint of CVM or first CVH at Month 30 in comparison with <20 mg/dL ( p <0.0001) ( Figure 1A ). Comparable findings were observed for the individual components (CVM, first CVH) ( Figure 1B and C ). Conclusion: Across treatment groups, sTTR levels above normal range (≥20 mg/dL) at Day 28 were associated with a lower risk of cardiovascular outcomes at Month 30, when compared with sTTR levels below normal range (<20 mg/dL). Thus, these observations demonstrate that higher sTTR levels over time may have the potential for clinical benefits in both CVM and CVH.

Abstract Clinical flow cytometry laboratories are facing rising test volumes, greater assay complexity, and increasing requirements for quality control and assay validation. In response, the International Clinical Cytometry Society (ICCS) conducted a workload survey in early 2023 to gather updated information on assay volumes, complexity, staffing, and technology. Data analysis focused on identifying correlations between length of time to introduce new assays and other factors as a means to gain insight about laboratories that seem to be either adapting or struggling. Flow cytometry assays were categorized into 3 levels of technical/interpretative complexity: high (e.g., measurable/minimal residual disease (MRD assays)), moderate (e.g., leukemia/lymphoma assays (Assays L&L ), excluding MRD assays), and low (e.g., CD4 count). Annual assays per staff member were calculated according to staff involved in case sign‐out (Staff Signout ) or other laboratory operations (Staff LabOps ). Respondents were from 101 laboratories in the United States (69.3%), Canada (4.0%), and other countries (26.7%). Low, moderate, and high technical/interpretative complexity assays were performed in 85.1%, 97.0%, and 47.5% of all laboratories, respectively. Median annual total assays (Assays Total ) per laboratory were 3515 and, based on complexity, were 1518.5 (low), 1808.8 (moderate), and 350 (high). Among all laboratories, the median time (interquartile range) to introduce new Assays L&L was 6 mos. (4–12 mos.), to introduce MRD assays was 11 mos. (5–12 mos.), and to validate/go‐live with new cytometers was 8 mos. (4–12 mos.); these times positively correlated with each other. This study confirmed significantly increased workload since the prior ICCS 2013 workload survey with a concurrent decrease in Staff LabOps . Faster introduction of new assays correlated with other successes, including quicker validation of and going live with new cytometers. Among all laboratories, those that performed myeloid MRD assays versus those that did not were also found to be faster to introduce new assays. The need for sufficient staffing has been emphasized because laboratories with both higher annual volumes of myeloma MRD assays and higher ratios of Assays Total per Staff LabOps were slower to introduce new assays. “Lack of staff and/or time dedicated or protected for assay development” and, more generally, “staff number” were the most commonly identified major barriers for new assay development, with the former specifically linked to slower introduction of new assays among all laboratories.

ABSTRACT Suicidality contributes substantially to global morbidity and mortality, yet despite its heritability, its biological etiology remains largely elusive. We conducted multi-ancestry genome-wide association study meta-analyses of suicidal ideation (259,747 cases), suicide attempt (64,993 cases), suicide death (9,197 cases), and suicidal behavior (suicide attempt/ death, 75,300 cases), across 54 cohorts (e.g., the Psychiatric Genomics Consortium, Million Veteran Program, UK Biobank). We identified 77 significant loci across meta-analyses, including 59 previously unreported for suicidality. SNP-based heritability ranged from 2.0-6.7% and there were strong, yet incomplete, genetic correlations between suicidality phenotypes (0.70-0.88). Fine-mapping prioritized putative causal SNPs and 20 credible genes. Enrichment analyses implicated synaptic pathways and neuronal populations predominantly in subcortical brain regions (e.g., amygdala excitatory, medium spiny, hippocampal CA1-3). Together, these findings establish suicidality as a polygenic set of traits with both shared and distinct genetic influences, providing a foundation for future studies of suicide biology and etiology.

Abstract Disclosure: B. Salama: None. O. Hamidi: None. T.S. Wang: None. A. Sada: None. M.A. Habra: None. P. Dogra: None. A.P. Dackiw: None. S.C. Oltmann: None. S. Mirfakhraee: None. I. Lingvay: None. T. Mckenzie: None. T. Foster: None. M. Lyden: None. B. Dy: None. V. Balderrama Brondani: None. I. Bancos: None. Background: Patients with mild autonomous cortisol secretion (MACS) are at risk for adrenal insufficiency (AI) after unilateral adrenalectomy. Guidelines recommend initiating glucocorticoid replacement post-adrenalectomy. However, identifying patients at risk and accurately diagnosing AI can enable individualized management. Objectives: Determine the prevalence, duration and predictors of postoperative AI after unilateral adrenalectomy for MACS and compare baseline and peak cortisol post cosyntropin stimulation test (CST) In diagnosing AI. Methods: We conducted a multicenter retrospective cohort study of patients with MACS who underwent unilateral adrenalectomy and post-operative CST evaluation between January 1, 2013, and August 31, 2024. MACS was defined as cortisol &gt;1.8 mcg/dL following overnight administration of 1 mg dexamethasone (DST-cortisol). AI was diagnosed when post-operative day 1 early morning baseline cortisol was &lt;10 μg/dL and/or CST peak cortisol was &lt;18 μg/dL. Baseline and peak cortisol levels were considered concordant when both met cut-offs. Biochemical (BSS) and clinical (CSS) severity scores were calculated. Results: Among 281 adults with MACS (80% women, median age 57 years, interquartile range [IQR] (47-64), the median adenoma size was 3.0 cm (IQR, 2.3-3.9), and 62 (22%) had bilateral disease. The median BSS was 4 (IQR, 3-5), and the median CSS was 6 (IQR, 2-11). Postoperative AI was diagnosed in 153 (54.5%) patients. A multivariable analysis showed that a higher BSS (OR = 1.17, 95% CI 1.01-1.36) and younger age at diagnosis (OR = 0.64, 95% CI 0.50-0.81), but not sex, BMI, or laterality, were associated with AI. Diagnosis of AI was concordant based on the baseline and peak CST cortisol cutoffs in 78% of patients. Diagnosis of AI was discordant in 22%: in 35 patients (12%), baseline cortisol was &lt;10 μg/dL, but CST peak cortisol was ≥18 μg/dL, and in 28 cases (10%), baseline cortisol was ≥10 μg/dL, but CST peak cortisol was &lt;18 μg/dL. Patients with bilateral MACS were more likely to have discordant results (32% vs. 19%, P &lt; 0.001). During a median postoperative follow-up period of 15.4 months, 108 patients (70.6%) recovered from AI. The median time to recovery was 3.9 months (IQR, 3-5.9), with 41% recovering by 3 months, 60% by 6 months, and 73% by 12 months. The median time to recovery was associated with baseline BSS: mild: 3 months, moderate: 4.7 months, and severe: 14.5 months. Conclusion: We found that more than half of patients with MACS develop postoperative AI, with 50% recovering by 4 months post-surgery. BSS was associated with both the development and duration of AI. Baseline and CST peak cortisol results were concordant only in 78% of patients, thus performing both should be considered for an accurate diagnosis of AI. Presentation: Sunday, July 13, 2025

ABSTRACT At the 42nd Annual Meeting of the American Association of Clinical Anatomists (AACA) in Bellevue, Washington, June 2025, two inaugural events—the Clinical Anatomy Fireside Chat (CAFC) and the Clinical Anatomy Symposium: Head and Neck 2025 (CAS)—fostered rich dialogue on the evolving role and operational definition of clinical anatomy. Experts from various clinical and anatomical disciplines explored the meaning of clinical anatomy, highlighting the absence of a universal definition despite its frequent use in education and research. Through these interdisciplinary discussions, a consensus emerged: clinical anatomy is not defined solely by the possession of clinical credentials but by the integration of anatomical knowledge and clinical relevance, achieved most effectively through collaboration. Clinical anatomy education and research require different depths of clinical knowledge depending on the audience and objective, and meaningful collaboration can bridge gaps in expertise. The symposium further illustrated that high‐quality clinical anatomy emerges from mutual respect and reciprocal insight between clinicians and anatomists. This article presents a consensus statement developed by AACA representatives and invited speakers, affirming that collaboration is not only foundational to the practice of clinical anatomy but also fundamental to its definition. These conclusions aim to guide future educational models, research strategies, and interdisciplinary partnerships in the field of clinical anatomy.

Objectives: This trial served as a proof-of-concept for whether inhibition of protein kinase C iota (PKCι) with auranofin and sirolimus provide antineoplastic effects in patients with recurrent high-grade serous ovarian cancer. Methods: This drug combination was administered to patients with recurrent high-grade serous ovarian cancer. Dosing was based on unpublished phase 1 data and consisted of auranofin 6 mg and sirolimus 5 mg both orally per day of a 28-day cycle. The primary endpoint was tumor response. Available tumor tissue was assessed for PKCι protein expression by immunohistochemistry (IHC) and PRKCI copy number by fluorescence in-situ hybridization (FISH) after the start of cancer therapy. Results: Twenty-two patients were enrolled, and 21 were evaluable for all clinical trial endpoints. One patient was unevaluable because she did not receive a full chemotherapy cycle. No tumor responses were seen in the first 21 patients, resulting in early trial termination per a priori trial design. The median progression-free survival was 2.1 months (95% CI: 1.8-3.7). The median overall survival was 4.4 months (95% CI: 2.6-12.5). Fourteen (67%) patients had at least one grade 3 or worse adverse event. Nineteen of 21 evaluable patients had available tumor tissue, which showed the median PKCι copy number averaged per cell of 3 (range: 2 to 7), and PKCι expression (at least 1+) in all. Conclusions: As prescribed here, auranofin and sirolimus manifested no antineoplastic activity in patients with recurrent high-grade serous ovarian cancer that expressed PKCι.

Variations in liver allocation systems worldwide are presented, with a specific focus on regional differences and their potential impact on outcomes, with the goal of serving as a reference for future policy development. Summaries of liver allocation across multiple European, Scandinavian, and Asian systems, as well as the combined allocation system of Australia plus Canada, the United States, and the systems in Central America, South America, and the Caribbean are reviewed. A comprehensive comparison of how different regions address MELD exceptions, primarily focusing on hepatocellular carcinoma, along with the most common etiologies of liver disease requiring transplantation is presented. In addition, the adoption of living donation and donation after circulatory death is discussed. The study involves contributions from a diverse group of world experts in liver transplantation and may serve as an essential resource to foster international dialogue as countries strive to optimize organ allocation policies, including MELD exceptions.

Abstract Aims The increasing adoption of transcatheter tricuspid valve replacement (TTVR) offers a promising therapeutic option for patients with severe tricuspid regurgitation. However, many of these patients have pre-existing cardiac implantable electronic devices (CIEDs), raising concerns about potential lead-related complications. Despite these concerns, limited data exist on the impact of TTVR on CIED integrity and function. This study aimed to evaluate the impact of TTVR on CIED lead function, including pacing thresholds, sensing, and impedance, in patients undergoing TTVR with the EVOQUE valve system. Methods and results A retrospective observational study was conducted at Mayo Clinic Rochester, including 32 consecutive patients who underwent TTVR with pre-existing CIEDs. A total of 32 patients were included, with a mean age of 79.2 ± 8.4 years; 59% were female. A total of 62.5% had a permanent pacemaker, 12.5% had an implantable cardioverter-defibrillator, 15.6% had a cardiac resynchronization therapy pacemaker, and 9.4% had a cardiac resynchronization therapy defibrillator. Following TTVR, 10 (31%) of patients developed lead function changes during a median device follow-up of 210 days (IQR: 43–307 days). The right ventricular lead was primarily affected, with only one case involving an atrial lead. Neither the Ottawa score nor the anatomical lead position reliably predicted lead abnormality (P = 0.86 and P = 0.53, respectively). R-wave sensing changes were the most common lead change observed, affecting 55% of cases. In 67% of these cases, R-wave sensing alterations occurred as an isolated finding, with no significant change in impedance or thresholds, and were managed conservatively without any need for device reprogramming. Four patients (13%) had findings concerning for a lead insulation breach, in which one (3%) required a lead revision. Among five patients with follow-up exceeding 600 days, two patients exhibited a statistically significant gradual decline in impedance without other lead dysfunction, suggesting potential subclinical lead degradation. Conclusion Transcatheter tricuspid valve replacement with the EVOQUE system in the setting of cardiac device leads is associated with lead function changes in 31%. The majority of lead-related changes were managed conservatively, but 13% of patients had findings concerning for an insulation breach. Future studies should focus on refining implantation techniques and defining optimal strategies for managing device-lead interactions in this population.