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Abstract Background Bicuspid aortic valve(BAV) disease carries a cumulative lifetime morbidity >80%. This morbidity includes surgery for aortic valve dysfunction, aortic dilatation, infective endocarditis, and aortic dissection. This study assessed surgical intervention patterns for BAV-related morbidity and long-term survival of these patients in a community-based cohort versus a tertiary referral cohort. Methods The tertiary-referral cohort included all patients with BAV-related surgeries across Mayo Clinic sites (Arizona, Florida, and Minnesota), from January 1990 to May 2024. The community-based cohort included all patients with BAV-related surgeries in Olmsted County, Minnesota, from January 1980 to May 2024. The tertiary-referral cohort comprised 2529 BAV patients of which 991(39%) [mean age 53±15 years, 76% males] underwent aortic valve surgery(AVR), aorta surgery, or a combination thereof, while the community-based cohort included 652 BAV patients of whom 262(40%) [mean age 43±20 year, 70% males] had the mentioned interventions. Cumulative survival was calculated by Kaplan-Meier method compared to the U.S population. Statistical significance was evaluated using one-sample log rank statistics. Results In the tertiary-referral cohort, 530/991(54%) patients underwent isolated AVR, 62/991(6%) had isolated aortic surgery, and 399(40%) underwent combined procedures. In the community-based cohort, 179/262(68%) patients underwent isolated AVR, 30/262(11%) underwent isolated aortic surgery, and 53(21%) had combined surgeries. In the tertiary-referral cohort, 940 patients underwent AVR; 57% for aortic stenosis(AS), 29% for aortic regurgitation(AR), 13% for mixed valvular disease, and 1% for endocarditis. In comparison, in the community-based cohort, 236 patients underwent AVR for AS in 71%, AR 20%, mixed valvular disease 7%, and endocarditis 2%. In the tertiary-referral cohort, 459 patients underwent aortic surgery; 21% for the root, 69% for the ascending aorta, 1% for the arch, <1% for aortic dissection, and 8% for coarctation repair. In comparison, 105 patients from the community-based cohort underwent aortic surgery; 33% for the root, 44% for the ascending aorta, 1% for the arch, 4% for aortic dissection and 18% coarctation repair. Compared to age- and sex-matched U.S. population, the relative risk for all cause death in the tertiary-referral cohort was 0.89 [95% CI: 0.70-1.11, p=0.35], whereas in the community-based cohort was 1.06 [95% CI: 0.85-1.32, p=0.57](Figure1). Conclusion Surgical intervention patterns were similar for community and tertiary BAV cohorts, with most patients undergoing isolated AVR or AVR plus aortic surgery, and isolated aortic surgery being uncommon. AVR indications were driven by AS, followed by AR and mixed valvular disease. Aortic surgery indications were driven by ascending aorta dilatation, followed by root dilatation and coarctation. Survival in both cohorts was similar to the U.S. general population.

Abstract Background/Introduction Tricuspid valve regurgitation (TR) is a common valvular disease associated with increased mortality. There is a need for tools to assess the interaction between the pulmonary artery (PA) circulation and the right ventricle (RV) in patients with TR and to investigate their association with outcomes. Various echo parameters have emerged that assess RV-PA coupling, including the ratio of TAPSE to RV systolic pressure (RVSP) and the PA pulsatility index (PAPi). The effective PA elastance (PA Ea) is a composite measure of RV afterload that refers to the measure of the pulmonary vascular load that the RV must overcome to eject blood into the PA. PA Ea is simple to estimate by echo and found to be an independent haemodynamic risk measure in various left heart and pulmonary hypertension (PH) diseases. Whether PA Ea discriminates risk in unselected patients with significant TR and how it compares to other measures of RV-PA coupling is untested. Purpose To ascertain the prognostic value of PA Ea in patients with TR. Methods In consecutive patients with a first diagnosis of ≥ moderate TR (regardless of aetiology), we compared all-cause mortality at five years based on the PA Ea (defined as the RVSP/stroke volume as measured by transthoracic echocardiography). As stroke volume was measured by Doppler at the left ventricular (LV) outflow tract, patients with > moderate aortic valve regurgitation were excluded. The Tricuspid Regurgitation Impact on Outcomes (TRIO) score was calculated as previously described. PA Ea was separated into 4 groups for comparison based on the separation of quartiles of PA Ea rounded to one decimal place. Results In the 13,608 patients studied, PA Ea could be calculated in 12,682 patients (94.4%). The median PA Ea was 0.68 mmHg/mL (IQR 0.50, 0.92). Increasing levels of PA Ea were associated with clinical comorbidities including heart failure, liver and kidney disease and clinical markers of risk such as the TRIO score. Increasing levels of PA Ea were also associated with larger RVs, worse RV systolic function, higher NT-pro BNP levels, and greater degrees of right heart failure (Table). Each quartile of PA Ea was associated with a significant increase in all-cause mortality (Figure). After adjusting for age and sex, PA Ea was associated with higher risk of death (HR 2.41 (2.28-2.56); p<.0001). While worsening degrees of PA Ea correlated with both declining levels of TAPSE/PASP and PAPi (Table), PA Ea was independently predictive of outcome in a combined model: PA Ea HR 1.65 (1.51-1.80, Chi-squ 120, p<.0001); PAPi HR 0.84 (0.80-0.89, Chi-squ 48, p<.0001) and TAPSE/PASP HR 0.32 (017-0.60, Chi-squ 12, p=.0004). Conclusion(s) In patients with significant TR, PA Ea is highly feasible and higher PA Ea is progressively associated with RV dysfunction, right heart failure, and worse survival. Incorporating PA Ea into the routine echo assessment may help stratify disease severity in patients with significant TR. Table Assoc. of PA Ea with mortality in TR

Abstract Purpose: Data on clear-cell renal cell carcinoma (ccRCC) xenografts defined the seleno-L-methionine (SLM) dose and the plasma selenium concentrations associated with the enhancement of hypoxia-inducible factor-1α/2α degradation, stabilization of tumor vasculature, enhanced drug delivery, and efficacy of axitinib. The data provided the rationale for the development of this phase I clinical trial of SLM and axitinib in advanced or metastatic relapsed ccRCC. Patients and Methods: Patients were ≥18 years with histologically and radiologically confirmed advanced or metastatic ccRCC who had received at least one prior systemic therapy, which could include axitinib (last dose ≥6 months prior to enrollment). Escalating dose levels of SLM (2,500, 3,000, and 4,000 μg) were administered orally twice daily for 14 days and then once daily concurrently with axitinib 5 mg twice daily using a 3 + 3 design in phase I. Patients were treated at the 4,000 μg dose level in the expansion cohort to obtain preliminary estimates of efficacy. Results: No dose-limiting toxicities occurred at the 4,000 μg SLM dose level. Among the 27 patients treated with 4,000 μg of SLM, the overall response rate was 55.6%, median duration of response was 18.4 months, median progression-free survival was 14.8 months, and median overall survival was 19.6 months. Preliminary results have shown that plasma selenium concentrations, inhibition of TGF-β1, and stabilization of tumor vasculature by SLM are time dependent. Conclusions: SLM (4,000 μg) in sequential combination with axitinib is well tolerated with encouraging efficacy.

Background: Acute ischemic stroke (AIS) from distal medium vessel occlusion (DMVO) presents unique treatment challenges. Mechanical thrombectomy (MT) is emerging as a viable option for these patients, yet the role of pre-stroke aspirin treatment is unclear. This study evaluates the impact of pre-stroke low-dose aspirin on outcomes in DMVO patients undergoing MT. Methods: We conducted a multinational, multicenter, propensity score-weighted analysis within the Multicenter Analysis of primary Distal medium vessel occlusions: effect of Mechanical Thrombectomy (MAD-MT) registry. Patients with AIS due to DMVO, treated with MT, were included. We compared outcomes between patients on pre-stroke low-dose aspirin (75–100 mg) and those not on antiplatelet therapy. The primary outcome was functional independence at 90 days (modified Rankin Scale (mRS), 0–2). Secondary outcomes included excellent functional outcome at 90 days (mRS, 0–1), mortality, and day 1 post-MT National Institutes of Health Stroke Scale (NIHSS) score. Safety outcomes focused on hemorrhagic complications, including symptomatic intracerebral hemorrhage (sICH). Results: Among 1354 patients, 150 were on pre-stroke low-dose aspirin. After applying inverse probability of treatment weighting (IPTW), aspirin use was associated with significantly better functional outcomes (mRS, 0–2: odds ratio (OR) = 1.89, 95% confidence interval (CI) = 1.14 to 3.12) and lower 90-day mortality (OR = 0.56, 95% CI = 0.32 to 1.00). The aspirin group had lower NIHSS scores on day 1 (β = −1.5, 95% CI = −2.8 to −0.27). The sICH rate was not significantly different between the groups (OR = 0.92, 95% CI = 0.60 to 1.43). Conclusions: Pre-stroke low-dose aspirin was associated with improved functional outcomes and reduced mortality in patients with DMVO undergoing MT, without a significant increase in sICH. These findings suggest that low-dose aspirin may be safe and associated with more frequent excellent outcomes for this patient population. Further prospective studies are needed to validate these results and assess long-term outcomes.

Background: It has been demonstrated that an athlete’s psychological readiness contributes to one’s ability to successfully return to sport (RTS) after anterior cruciate ligament (ACL) reconstruction. However, the effect of graft choice on psychological readiness is not yet understood. Purpose/Hypothesis: The purpose of this study was to evaluate the association between graft choice and an athlete’s psychological readiness to RTS. It was hypothesized that similar ACL-Return to Sport after Injury (ACL-RSI) scores would be achieved among patients who underwent ACL reconstruction with quadriceps autograft (QA), hamstring tendon autograft (HA), and bone–patellar tendon–bone (BTB) autograft. Study Design: Cohort study; Level of evidence, 3. Methods: Patients who underwent primary ACL reconstruction at a single institution between January 2017 and December 2018 were placed into separate cohorts depending on graft type (HA, BTB, or QA; n = 30 patients in each group), and the ACL-RSI, International Knee Documentation Committee subjective form, and Lysholm scores were compared between the different graft cohorts at 6 months postoperatively, at RTS, and at 2 years postoperatively. Also, the rate of patients who achieved an ACL-RSI score of ≥65 (predictive of return to preinjury sport at 2 years postoperatively) was calculated, as was the RTS rate and time. Results: The QA group demonstrated significantly higher ACL-RSI scores than both the HA and BTB groups at 6 months postoperatively ( P < .0001) and RTS ( P = .011). The QA group also had a higher rate of achieving ≥65 on ACL-RSI than the other groups at 6 months postoperatively ( P = .002) and RTS ( P = .024). There was no significant difference in the RTS rate between the 3 groups, although the QA group demonstrated a significantly quicker return (QA, 8.1 months; BTB, 9.6 months; HA, 10.5 months; P < .001). Conclusion: Athletes undergoing primary ACL reconstruction with QA achieved a higher mean ACL-RSI score and more often achieved a score of ≥65 at the 6-month and RTS time points compared with the HA and BTB groups. QA may afford an advantage over other grafts in terms of improved psychological readiness to RTS.

Background: Randomized controlled trials (RCTs) evaluating the efficacy of platelet-rich plasma (PRP) for the management of lateral epicondylitis (LE) have been characterized by substantial variability in reported outcomes. The source of this heterogeneity is uncertain. Purpose: To determine the effect of estimated platelet concentration on the efficacy of PRP for the management of LE. Study Design: Systematic review and meta-analysis; Level of evidence, 2. Methods: All RCTs evaluating the efficacy of PRP in managing LE were identified. RCTs were classified according to whether the study documented a platelet concentration factor of PRP representing a greater than 3-fold increase over whole blood or a supraphysiological platelet dose (high-dose vs low-dose PRP). The primary outcome was the mean difference (MD) in the visual analog scale (VAS) score at latest follow-up. Random-effects and mixed-effects meta-analyses were performed, and meta-regression was used to evaluate whether differences in outcomes after treatment with PRP could be explained by differences in the concentration of PRP used. Results: Overall, 13 RCTs with a total of 791 patients were included in this analysis, with 5 that utilized low-dose PRP and 8 that used high-dose PRP. Meta-analysis of VAS scores reported by studies that used high-dose PRP resulted in an MD of −1.31 (95% CI, −1.87 to −0.75) in favor of PRP over all alternative treatment strategies ( P < .001). Meta-analysis of VAS scores reported by studies that used low-dose PRP resulted in an MD of 0.08 (95% CI, −0.51 to 0.68), suggesting no difference in the effect between PRP and all alternative treatment strategies ( P = .79). The platelet concentration factor of PRP used in each RCT was found to be strongly predictive of the VAS score at final follow-up in meta-regression ( P < .001), with 58.5% of the heterogeneity in the outcomes of PRP between studies explained by the platelet concentration factor alone. Conclusion: The platelet concentration of PRP may play a significant role in the outcomes of patients with LE. A direct linear relationship was observed between the platelet concentration factor of PRP used and the magnitude of patient-reported symptom relief after the management of LE with PRP. Clinicians should ensure a supraphysiological platelet concentration when preparing PRP for the management of LE.

Hemorrhagic complications associated with regional anesthesia are extremely rare. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine’s Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy reviews the published evidence since 2018 and provides guidance to help avoid this potentially catastrophic complication. The fifth edition of the American Society of Regional Anesthesia and Pain Medicine’s Evidence-Based Guidelines on regional anesthesia in the patient receiving antithrombotic or thrombolytic therapy uses similar methodology as previous editions but is reorganized and significantly condensed. Therefore, the clinicians are encouraged to review the earlier texts for more detailed descriptions of methods, clinical trials, case series and pharmacology. It is impossible to perform large, randomized controlled trials evaluating a complication this rare; therefore, where the evidence is limited, the authors continue to maintain an ‘antihemorrhagic’ approach focused on patient safety and have proposed conservative times for the interruption of therapy prior to neural blockade. In previous versions, the anticoagulant doses were described as prophylactic and therapeutic. In this version, we will be using ‘low dose’ and ‘high dose,’ which will allow us to be consistent with other published guidelines and more accurately describe the dose in the setting of specific patient characteristics and indications. For example, the same ‘high’ dose may be used in one patient as a treatment for deep venous thrombosis (DVT) and in another patient as prophylaxis for recurrent DVT. Due to the increasing ability to obtain drug-specific assays, we have included suggestions for when ordering these tests may be helpful and guide practice. Like previous editions, at the end of each recommendation the authors have clearly noted how the recommendation has changed from previous editions.

Objectives: Many individuals with dementia with Lewy bodies (DLB) die of disease-related complications, but predicting the end of life can be challenging. We identified a phenotype associated with approaching end of life. Methods: We present 4 exemplar cases where individuals with DLB experienced refractory psychosis before death. We reviewed codebooks and quotes from 3 studies regarding end-of-life experiences in DLB to identify experiences that aligned with this phenotype. Results: In addition to the 4 cases, family caregivers in prior studies described prominent worsening of psychosis before death in some individuals with DLB. The worsening often occurred several months before death and was sometimes associated with rapid deterioration. Worsening psychosis was the prominent symptom and was not initially accompanied by cognitive or physical decline. In many cases, the refractory psychosis resulted in inpatient psychiatric hospitalization or residential care, but these scenarios were challenging because of the individual’s behavior. Conclusion: Refractory psychosis in DLB, particularly out of proportion to other symptoms, may be a signal of approaching the end of life. More research is needed to understand this phenomenon and to develop effective and safe treatments for psychosis in DLB.

Importance Normothermic machine perfusion (NMP) has been shown to reduce peritransplant complications. Despite increasing NMP use in liver transplant (LT), there is a scarcity of real-world clinical experience data. Objective To compare LT outcomes between donation after brain death (DBD) and donation after circulatory death (DCD) allografts preserved with NMP or static cold storage (SCS). Design, Setting, and Participants This single-center, retrospective observational cohort study included all consecutive adult LTs performed between January 2019 and December 2023 at the Mayo Clinic in Arizona. Data analysis was performed between February 2024 and June 2024. Outcomes of DBD-SCS, DBD-NMP, DCD-SCS, and DCD-NMP transplants were compared. Exposure DBD and DCD livers preserved on NMP or SCS. Main Outcomes and Measures The primary outcomes were early allograft dysfunction (EAD), intraoperative transfusion, and post-LT hospital resource use, including length of stay (LOS) and readmissions. Secondary outcomes included acute kidney injury (AKI) and 1-year graft and patient survival. Results A total of 1086 LTs were included in the following 4 groups: DBD-SCS (n = 480), DBD-NMP (n = 63), DCD-SCS (n = 264), and DCD-NMP (n = 279). Among LT recipients, median (IQR) age was 60.0 years (52.0-66.0); 399 LT recipients (36.7%) were female. DCD-NMP had the lowest EAD rate (17.5%), followed by DCD-SCS (50.0%), DBD-NMP (36.8%), and DBD-SCS (27.3%) ( P &amp;lt; .001). DCD-NMP had the lowest intraoperative transfusion requirement compared to all other groups. Hospital and intensive care unit (ICU) LOS were shortest in DCD-NMP (median [IQR] hospital LOS, 5.0 days [4.0-7.0]; P = .01; median [IQR] ICU LOS, 1.5 days [1.2-3.1]; P = .01). One-year cumulative readmission probability was 86% lower for DCD-NMP vs DCD-SCS (95% CI, 0.09-0.22; P &amp;lt; .001) and 53% lower for DBD-NMP vs DBD-SCS (95% CI, 0.26-0.87; P &amp;lt; .001). AKI events were lower in DCD-NMP (31.1%) vs DCD-SCS (47.4%) ( P = .001). Compared to SCS, the NMP group had a 78% overall reduction in graft failure (hazard ratio [HR], 0.22; 95% CI, 0.10-0.49; P &amp;lt; .001). For those receiving DCD allografts, the risk reduction was even more pronounced, with an 87% decrease in graft failure (HR, 0.13; 95% CI, 0.05-0.33; P &amp;lt; .001). NMP was significantly protective from patient mortality vs SCS (HR, 0.31; 95% CI, 0.12-0.80; P = .02). Conclusions and Relevance In this observational high-volume cohort study, NMP significantly improved LT clinical outcomes and reduced hospital resource use, especially in DCD allografts. NMP may enhance access to LT by addressing the challenges historically linked with DCD liver use.

Summary LINE-1 retrotransposons, comprising 17% of the genome, drive cancer instability through hypomethylation. The Detection of long Interspersed nuclear element Altered Methylation ON plasma DNA (DIAMOND) assay, targeting LINE-1 hypomethylation with bisulfite sequencing of cell-free DNA, achieved AUCs of 88% to 100% across six cancer types, surpassing mutation-based diagnostics and suggesting utility in early cancer detection and management. See related article by Michel et al., p. 1275