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Background. Ex vivo machine perfusion (MP) has transformed organ preservation, offering significant benefits in liver transplantation (LT), particularly with high-risk donor grafts. However, adoption in the United States has been limited. We aimed to examine early adoption trends, surgeon perceptions, and barriers to implementing MP in the United States after Food and Drug Administration approval of MP platforms. Methods. A 23-question electronic survey was distributed to members of the American Society of Transplant Surgeons between October and November 2022, capturing attitudes and practices related to MP adoption. Responses from 96 surgeons representing 77 LT centers across 11 Organ Procurement and Transplantation Network regions were analyzed. Results. Forty-four respondents (48%) reported having an MP program at their institution. Adoption of MP was significantly more common in high-volume centers and those performing ≥20 donation after circulatory death (DCD) transplants annually (P < 0.001). MP utilization received strong support, with 88% endorsing its use for DCD liver allografts and 82% for donation after brain death allografts. Respondents cited MP’s ability to reduce ischemic cholangiopathy, enable graft repair, and facilitate viability assessment as key benefits. Normothermic MP was preferred for high-risk donor profiles, including DCD grafts, older donors, and steatotic livers, and was associated with an increased willingness to accept medically complex grafts compared with static cold storage. Barriers to MP utilization included program costs, personnel demands, and logistical complexities. Centers with higher proportions of privately insured patients were more likely to adopt MP. Despite these challenges, 84% of respondents expressed interest in future MP adoption. Conclusions. MP enhances graft utilization and outcomes, particularly for complex and high-risk donor livers, but widespread US adoption requires addressing financial and logistical barriers. Future efforts should focus on refining cost-effectiveness analyses, collaboration with organ procurement organizations and device companies, and developing standardized training to optimize MP integration and maximize its clinical impact on LT.

We investigated the prognostic impact of blast counts, TP53 allelic state determinants (number of hits, del(17p), variant allele frequency, complex karyotype),and a novel karyotypic clonal cell fraction (≤50% clonal cells vs >50% clonal cells (termed ‘CK50’)) in 495 individuals with TP53- mutated ( TP53 MUT ) myeloid neoplasms. Outcome examined was 24-month survival (OS24). The cohort (median age 71) included 29% (144/495) myelodysplastic syndromes (MDS)/MDS-acute myeloid leukaemia (AML) (1%–19% blasts) and 71% (351/495) AML (≥20% blasts), with 18% (81/460) having low CK50. Overall, 83% received front-line hypomethylating agents. Higher blast counts (<20% vs ≥20%) were marginally associated with CK50 (p=0.08). In the OS24 analysis, blast count showed a marginal association with OS24 (HR 1.3 (95% CI 1.0 to 1.6); p=0.07), while CK50 predicted significantly inferior outcomes (HR=1.7 (95% CI 1.2 to 2.3); p=0.002). In a multivariable model including all TP53 allelic state determinants, only CK50 and complex karyotype remained relevant for predicting adverse outcomes.

Introduction: Previous findings suggest that sirtuin 6 (SIRT6), a nuclear histone deacetylase, is involved in fundamental processes that regulate aging, which include DNA damage repair and maintenance of genomic stability. It remains unclear, however, whether SIRT6 overexpression can mitigate age-related vascular dysfunction due to multiple mechanisms of posttranslational enzyme inactivation (oxidation, ubiquitination-dependent degradation, etc). We hypothesized that overexpression of SIRT6, will improve both endothelium-dependent relaxation and smooth muscle contractile function and improve molecular mechanisms underlying these functions in healthy aged mice. Methods: We used normocholesterolemic mice that were either wild-type for SIRT6 (WT) or overexpressing one copy of SIRT6 (TG) and studied them at either 3 or 18 months of age. We assessed molecular changes in SIRT6 expression, cellular senescence, and vascular contractile protein expression using qPCR, and aortic rings in isolated organ bath chambers to measure endothelium-dependent relaxation to acetylcholine (ACH), endothelium-independent relaxation to sodium nitroprusside (SNP), and contractile responses to serotonin (5HT) and PGF 2α . Results: As expected, overexpression of SIRT6 in TG mice resulted in ~3-fold mRNA expression increase compared to WT mice in aorta. In line with our previous reports, SIRT6 mRNA levels significantly increased with age in aorta. CDKN2A, a cellular senescence marker, increased with aging in WT mice. Surprisingly, SIRT6 overexpression did not attenuate this increase, with TG mice tending to have higher CDKN2A expression than WT at 18m. ACTA2, a contractile protein marker, had modest reductions with age in WT mice, and surprisingly, overexpression of SIRT6 did not alter ACTA2 levels compared to WT at either time point. Finally, overexpression of SIRT6 did not mitigate age-related changes in vascular relaxation or contractile function. Conclusion: Collectively, these data at the surface level suggest that overexpressing SIRT6 does not protect against conduit vessel dysfunction in aged mice and is associated with paradoxical increases in senescent cell markers. It remains elusive whether there are other molecular modulators of aging that offset or alter the activity of SIRT6 with its genetic overexpression. Therefore, future studies investigating molecular determinants of SIRT6 bioactivity and its tissue/context dependence with aging are warranted.

Background: Levetiracetam administration via intravenous push (IVP) may improve outcomes in status epilepticus (SE) by decreasing time to administration. However, there is a paucity of literature describing the safety of IVP administration of higher loading doses used for early management of SE. Objective: The purpose of this evaluation was to investigate the safety of high-dose IVP levetiracetam. Methods: This was a retrospective, single-arm cohort study conducted at an academic medical center. Patients were included if they received IVP levetiracetam ≥3000 mg. The primary outcome was a composite of clinically significant adverse events (AEs) within 1-hour post-administration of levetiracetam: hypotension, hypertension, bradycardia, tachycardia, arrhythmia, and/or injection site reaction. Results: A total of 140 patients met inclusion criteria, receiving a median levetiracetam dose of 4000 mg (interquartile range [IQR] = 3000, 4500). Seventeen (12.1%) patients experienced a clinically significant AE. The most common clinically significant AE was hypotension (9.2% [10/109]), followed by tachycardia (3.6% [4/112]), arrhythmia (1.8% [2/112]), hypertension (0.9% [1/109]), and injection site reaction (0.7% [1/140]). Eighty percent [8/10] of patients who experienced clinically significant hypotension were on at least 1 medication with potential confounding hemodynamic effects. Conclusion and Relevance: In this retrospective, single-arm analysis, high-dose (≥3000 mg) IVP levetiracetam was relatively well-tolerated but associated with a higher rate of clinically significant hypotension than has been reported in the previous literature, although several confounding factors may have contributed to this outcome. Our findings support the continued use of high-dose IVP levetiracetam with appropriate hemodynamic monitoring; hemodynamic effects should be further explored in future studies.