Citations

Background: Fontan circulation is characterized by the absence of a subpulmonary ventricle with resultant systemic venous hypertension. Despite exercise intolerance being nearly universal in this population, the determinants of exercise capacity in this population are still poorly understood. Research Question: We investigated the prevalence of peripheral impairment and assessed the contribution of peripheral O 2 extraction versus central hemodynamics to peak O 2 consumption (pVO 2 ) post-Fontan palliation. Methods: This single-center retrospective cross-sectional study compared 52 consecutive adults post-Fontan procedure who underwent exercise catheterization to patients with heart failure with preserved ejection fraction (HFpEF) and non-cardiac dyspnea (NCD) at 1:1 ratio. Several previously reported measures for peripheral O 2 extraction were evaluated in the absence of a golden standard. Correlates of pVO 2 were identified by multivariate linear regression analyses using the backward selection method. Results: Patients with Fontan circulation were younger [age 32 (24;36) years] and tended to have a lower body mass index [26 (23; 29) kg/m 2 ] compared to patients with HFpEF [70 (57; 75) years, p<0.001 and 33 (27; 39) kg/m 2 , p<0.001] and NCD [48 (38; 61) years, p<0.001 and 27 (24; 35) kg/m 2 , p=0.08]. Peak heart rate [108 (85;126) vs 108 (95;125) bpm] and indexed stroke volume [46 (39;54) vs 45 (40;53) ml/m 2 ] were similar in the Fontan and HFpEF groups but lower compared to NCD [126 (108;141) bpm, p<0.001 and 51 (45;59) ml/m 2 , p<0.001]. Peak mean pulmonary artery pressures were highest in HFpEF [45 (41;50) mmHg, p<0.001], followed by Fontan and NCD [26 (22;31) vs 23 (19;25) mmHg, p=0.03]. Median peak O 2 extraction post-Fontan was comparable to HFpEF [12 (10;14) vs 11 (10;13) ml/dl, p=0.17] but higher than in NCD [10 (9;12) ml/dl, p<0.001]. It was <14 ml/dl in 73% compared to 94% and 98% of patients with HFpEF and NCD [p<0.001]. O 2 extraction ratio was <70% in 62% compared to 60% in HFpEF and 96% in NCD [p<0.001]. Correlates of pVO 2 post-Fontan were peak O 2 extraction [β 0.5±0.1 per ml/dl; p<0.001], mean pulmonary artery pressures [β -0.2±0.05 per mmHg; p=0.002], heart rate [β 0.03±0.01 per bpm; p=0.01], and systolic arterial blood pressure [β 0.03±0.01 per mmHg; p=0.02]. Conclusion: Impaired O 2 extraction is prevalent amongst adults post-Fontan. Whether exercise can modulate this important determinant of exercise capacity post-Fontan merits further investigation.

Background: One of the most troublesome complications of acute pericarditis is recurrence. Non-steroidal anti-inflammatory drugs (NSAIDs) and colchicine form the cornerstone treatment, with the addition of steroids in cases of incomplete response. Recent evidence also suggests a role for interleukin-1 (IL-1) antagonists in challenging cases of recurrence. However, with an increasing number of potential therapies, our study aims to examine the relative efficacy of these anti-inflammatory treatments for recurrent pericarditis risk reduction. Methods: We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials in October 2023. We included randomized controlled trials (RCTs) and prospective cohort studies of patients with pericarditis treated with a drug with anti-inflammatory properties compared with those treated with a control. The main outcome evaluated was pericarditis recurrence. Results: A total of 6,831 studies were screened, of which 25 articles were included (14 RCTs and 11 cohort studies) for a total number of patients of 3,561. The mean age across studies was 54.82 years for adults and 9.04 years for children (females = 40.55%). The average follow-up duration was 20.03 months. Bayesian network meta-analysis was performed to calculate risk estimates using a random effects model (Figure 1). Goflikicept, a fusion protein that neutralizes IL-1, showed a significant reduction in recurrent pericarditis rates (OR: 0.00, 95% Credible Limits [Crl]: 0.00-0.08). Similarly, anakinra (OR: 0.01, 95% Crl: 0.00-0.13), rilonacept (OR: 0.02, 95% Crl: 0.00-0.22) and colchicine (OR: 0.35, 95% Crl: 0.19-0.64) were associated with a significant reduction in recurrent pericarditis events. High dose colchicine (OR: 0.70, 95% Crl: 0.13-4.12) was not superior to regular dose colchicine (1 mg vs 0.6 mg twice daily, respectively). Interestingly, there was not enough data to make a meaningful comparison between steroids and control. Conclusion: In our analysis, goflikicept, rilonacept, and anakinra were most effective at reducing recurrent pericarditis rates. However, the evidence is based on a small number of studies. Our analysis also corroborated evidence regarding the efficacy of colchicine in reducing pericarditis recurrence. For a comprehensive analysis of the benefits and harms of anti-inflammatory therapies, larger comparative studies or network meta-analyses of patient-level data are required.

Introduction: Complex congenital heart disease (CHD) patients with atrial arrhythmias have higher rates of morbidity and mortality compared to less complex CHD patients. This study aims to identify echocardiographic predictors of thromboembolism (TE) and major bleeding in patients with Tetralogy of Fallot (ToF) or Pulmonary Atresia with Intact Ventricular Septum (PA-IVS) and atrial fibrillation or flutter (AF). Methods: This cohort study included patients with ToF or PA-IVS who had a diagnosis of AF who underwent a TTE across three sites. Outcomes were incidence rate of major bleeding or TE, calculated using univariable and multivariable cox regression with interaction for anticoagulant choice and fractional area change (FAC). The HAS-BLED score was augmented with major predictors of bleeding, and receiver operator curves compared. Results: We included 300 patients (287 ToF [95.7%], 13 PA-IVS [4.3%]), mean age 45.6 years. Most received warfarin (227 [79.4%]), 40 (13%) used DOACs, and 5 (1.6%) used enoxaparin. TTE predictors of TE included large LVOT diameter ≥3cm (HR 8.92, p=0.002), small LVOT VTI (p=0.014), FAC <30% (HR 7.08, p=0.026) and moderate RV dysfunction (HR 10.75, p=0.026). Predictors of major bleeding included moderate tricuspid regurgitation (HR 2.40, p=0.022), right atrial pressure (1.12, p<0.001), severe RA enlargement (HR 2.30, p=0.048), RV mid diameter (HR 1.06, p=0.005), RV end diastolic area (HR 1.04, p=0.021), RV end systolic area (HR 1.05, p=0.016) elevated RVSP and FAC ≤45% (HR 0.37, p=0.016). Among warfarin users, impaired RV function (FAC ≤45%) was linked to reduced major bleeding events (HR 0.27, p=0.025). There was a nonsignificant trend towards higher bleeding in DOAC users with FAC >45% (HR 3.87, p=0.284), but significantly higher bleeding in DOAC users with FAC ≤45% (HR 12.41, p=0.008) vs. warfarin users with normal RV function (table 1). We developed an augmented HAS-BLED score: the standard score plus one point for moderate-to-severe pulmonic or tricuspid regurgitation and one for FAC ≤45%. This outperformed the standard HAS-BLED in predicting major bleeding (AUC 0.67 augmented vs. 0.57 un-augmented, p=0.008) (figure 1). Conclusion: Echocardiographic evidence of right heart disease is a strong predictor of major bleeding in patients with ToF or PA-IVS. FAC is a useful tool to determine excess major bleeding risk, particularly in DOAC users. Augmenting HAS-BLED with right heart parameters improves diagnostic accuracy.

Abstract Purpose: Mouse models demonstrate a role for RANK and its ligand, RANKL, in osteosarcoma. The primary objective of this single-arm, open-label phase 2 trial was to determine whether denosumab, a RANKL mAb, improved disease control in recurrent osteosarcoma relative to benchmarks derived from historic Children’s Oncology Group clinical trial data. Patients and Methods: Skeletally mature patients ages 11 to 49 years old with measurable disease were eligible for cohort 1, and those with complete surgical resection of all sites of disease were eligible for cohort 2. Patients received denosumab 120 mg subcutaneously every 4 weeks with calcium and vitamin D supplementation. The primary endpoints were RECIST response and remaining event-free for 4 months for cohort 1 and remaining event-free for 12 months for cohort 2. Toxicity, pharmacokinetics, and pharmacodynamic effects were additional endpoints. Results: Fifteen patients in cohort 1 and 38 in cohort 2 were eligible and evaluable for the primary endpoint. One of 15 cohort 1 patients remained event-free at 4 months. There were no objective responses. Ten of 38 cohort 2 patients were event-free at 12 months. The predefined efficacy criteria were not met in either cohort. The most common ≥ grade 3 adverse events were hypocalcemia and hypophosphatemia (8% and 11%, respectively). At steady state, mean serum denosumab trough concentrations were 23.7 to 31 μg/mL in cycles 2 to 7. Serum c-telopeptide and urine n-telopeptide decreased on treatment. Conclusions: Denosumab was well-tolerated with anticipated side effects and pharmacokinetic and pharmacodynamic parameters but had insufficient activity for further development in osteosarcoma.

ABSTRACT Objectives This portion of the Geriatric Emergency Department (GED) Guidelines 2.0 focuses on delirium in the emergency department (ED). Methods A multidisciplinary group applied the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach to assess the certainty of evidence and develop recommendations related to older ED patients with possible delirium. Results The GED Guidelines 2.0 Delirium Work Group derived six evidence‐based recommendations for risk stratification, diagnosis, and brain imaging. To reduce universal screening, the Delirium Risk Score may be used to identify older adults at low risk for delirium, though the evidence certainty is very low. In adults over 65 admitted to ED observation units, Zucchelli's risk assessment tool (threshold ≥ 4) may stratify delirium risk, also with very low certainty. For adults over 75, the REDEEM Score may be used to identify low‐ or high‐risk individuals, again with very low certainty. For diagnosis, 4AT, bCAM, CAM‐ICU, mCAM, AMT‐4, or RASS may be used to rule delirium in or out, based on very low certainty. The Delirium Triage Screen (DTS) may be used to rule out, but not to rule in, delirium, also with very low certainty. For diagnostic imaging, there is very low certainty of evidence to recommend for or against obtaining a head CT as part of the evaluation for older ED patients with delirium. All recommendations are conditional, reflecting very low certainty of evidence due to the lack of high‐quality ED‐based studies and comparative effectiveness research. Conclusion Rigorous ED‐based research is needed to strengthen evidence and guide delirium care for older adults in geriatric emergency medicine.

BACKGROUND: The current study aims to describe outcomes after transcatheter valve replacement in adults with congenital heart disease. METHODS: Retrospective study of adults with congenital heart disease who underwent transcatheter valve replacement and had a 1-year follow-up postintervention at Mayo Clinic (2010–2024). The study period was divided into early (2010–2014), mid (2015–2019), and late (2020–2024) eras. The primary outcome was valve reintervention. The secondary outcomes were all-cause mortality and temporal change in prosthetic valve gradient and clinical indices of disease severity. RESULTS: Overall, 341 patients (age 38±17 years; 175 [51%] men) received 346 prostheses (pulmonary [N=236, 68%], tricuspid [N=75, 22%], aortic [N=22, 8%], and mitral [N=7, 2%]). The prostheses were Sapien (N=181, 52%), Melody (N=142, 41%), and Harmony prostheses (N=23, 7%). The number of transcatheter valve implantations increased from the early era (N=75), mid era (N=109), to the late era (N=162). The 10-year incidence of valve reintervention was 35%, and was similar between Sapien versus Melody prosthesis (41% versus 33%; P =0.11). The 10-year incidence of all-cause mortality was 13%. There was a temporal increase in prosthetic valve Doppler mean gradient (baseline versus 10 years) for pulmonary (12±5 versus 28±11 mmHg; P <0.001), tricuspid (3±1 versus 8±3 mmHg; P <0.001), and aortic prosthesis (13±5 versus 26±12 mmHg; P <0.001). There was a temporal increase in predicted peak oxygen consumption (absolute ∆, 9% [95% CI, 4–13]; P =0.006) and a decrease in NT-proBNP (N-terminal pro-B-type natriuretic peptide) level (absolute ∆, −138 pg/mL [95% CI, −209 to −64]; P <0.001) at 1-year postintervention. CONCLUSIONS: There has been a temporal increase in the number of transcatheter valve implantations over time. Transcatheter valve replacement was associated with clinical improvement across multiple domains. However, there was a significant increase in prosthetic valve gradient within 10 years of follow-up, suggesting limited prosthesis longevity. There is a need for strategies to improve prosthetic valve longevity, which in turn may improve outcomes in this population.

Objective: The specialty of critical care in the United States currently lacks a single, broad, unified database. We conducted a scoping review of existing established national ICU databases, describing national and international patterns of critical care delivery. Data Sources: A systematic literature search was undertaken using MEDLINE, Embase, and Web of Science search engines. Study Selection: Projects describing national critical care delivery (including any subspecialty) published in any language were included. Titles, abstracts, and full-text manuscripts were reviewed in duplicate for inclusion. Data Extraction: National database characteristics were collected, including the number and subspecialty of ICUs, the inaugural year, data entry methodology, the number of episodes of care included, and captured clinical data elements. Data Synthesis: Of 24,003 abstracts screened, 185 manuscripts were eligible for inclusion. Thirty countries were identified as having established national ICU registries: Argentina, Australia/New Zealand, Austria, Belgium, Brazil, Canada, Denmark, Ecuador, Finland, Germany, Iceland, India, Ireland, Italy, Japan, Kenya, Malaysia, Mexico, Nepal, Netherlands, Norway, Pakistan, Paraguay, Spain, Sri Lanka, Sweden, Switzerland, United Kingdom, United States and Uruguay. Data entry commonly incorporates a combination of automated data abstraction from electronic healthcare systems and manual data entry, followed by independent validation. Frequently recorded variables include patient demographics; admission vital signs and laboratory data; comorbidities; admission source and diagnoses; ICU diagnoses, treatments, and complications; illness severity scores; and clinically relevant outcomes including discharge disposition, functional status, lengths of stay, and mortality. Conclusions: Insights and experience gained from the study of mature national ICU registries may be used to guide an equivalent U.S. multidisciplinary program aimed at benchmarking, needs assessment, quality improvement, and research facilitation

Purpose Large aneurysms have a higher rupture risk, yet no available in vivo animal model consistently produces large aneurysms for testing endovascular therapies. Recent research suggests that adding calcium chloride (CaCl 2 ) to elastase yields larger aneurysms in a surgical rabbit model. We evaluated whether this effect translates to an endovascular approach by comparing aneurysm sizes created using elastase alone versus a CaCl 2 –elastase combination. Methods Aneurysms were created in the right common carotid artery of New Zealand rabbits. One group received 1 mL porcine elastase; the other received elastase plus 0.055 g CaCl 2 (0.5 M). After four weeks, patency was confirmed via digital subtraction angiography. Two blinded co-authors measured the neck, width, and height of the aneurysms. Aneurysm volumes were estimated using AngioCalc.com. Statistical analyses were performed using either the Mann–Whitney U -test or t -test based on data distribution. Results Twenty-nine (29) New Zealand rabbits were included in the study: six in the CaCl 2 and elastase groups, 23 in the elastase-alone group. All induced aneurysms remained patent at follow-up. Mean neck size was significantly larger in the CaCl 2 + elastase group than in the elastase-alone group (4.4 ± 1.1 mm vs 3.5 ± 0.95 mm; respectively, p = 0.02). Differences in width (4.1 ± 0.92 mm vs 3.4 ± 0.36 mm; p = 0.06), height (9.0 ± 1.1 mm vs 9.1 ± 2.1 mm; p = 0.46), and volume (83.5 ± 38.35 mm ³ vs 53.0 ± 16.94 mm³; p = 0.11) were not significant between CaCl 2 + elastase and elastase-alone, respectively. Conclusions CaCl 2 modestly increased neck size but did not significantly enlarge overall aneurysm dimensions. Further studies are needed to assess its utility in endovascular aneurysm models.

Case: We present 3 cases of brachial plexus injuries (BPI) secondary to compressive hematomas during extracorporeal membrane oxygenation (ECMO), with follow-up ranging from 18 months to 12 years. Patients exhibited profound upper extremity deficits and underwent variable interventions, including surgical decompression. All demonstrated meaningful neurologic recovery. Conclusion: BPI is a rare but serious complication of ECMO. These cases highlight the importance of early recognition and hematoma evacuation, emphasizing the need for clinical vigilance to optimize neurologic outcomes following hematoma-induced nerve injury.

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.