Background: The epidemic of drug overdose deaths in the United States has led to an increase in organ donors. Objective: To characterize donors who died of overdose and to analyze outcomes among transplant recipients. Design: Prospective observational cohort study. Setting: Scientific Registry of Transplant Recipients, 1 January 2000 to 1 September 2017. Participants: 138 565 deceased donors; 337 934 transplant recipients at 297 transplant centers. Measurements: The primary exposure was donor mechanism of death (overdose-death donor [ODD], trauma-death donor [TDD], or medical-death donor [MDD]). Patient and graft survival and organ discard (organ recovered but not transplanted) were compared using propensity score-weighted standardized risk differences (sRDs). Results: A total of 7313 ODDs and 19 897 ODD transplants (10 347 kidneys, 5707 livers, 2471 hearts, and 1372 lungs) were identified. Overdose-death donors accounted for 1.1% of donors in 2000 and 13.4% in 2017. They were more likely to be white (85.1%), aged 21 to 40 years (66.3%), infected with hepatitis C virus (HCV) (18.3%), and increased-infectious risk donors (IRDs) (56.4%). Standardized 5-year patient survival was similar for ODD organ recipients compared with TDD organ recipients (sRDs ranged from 3.1% lower to 3.9% higher survival) and MDD organ recipients (sRDs ranged from 2.1% to 5.2% higher survival). Standardized 5-year graft survival was similar between ODD and TDD grafts (little difference for kidneys and lungs, marginally lower [sRD, −3.2%] for livers, and marginally higher [sRD, 1.9%] for hearts). Kidney discard was higher for ODDs than TDDs (sRD, 5.2%) or MDDs (sRD, 1.5%); standardization for HCV and IRD status attenuated this difference. Limitation: Inability to distinguish between opioid and nonopioid overdoses. Conclusion: In the United States, transplantation with ODD organs has increased dramatically, with noninferior outcomes in transplant recipients. Concerns about IRD behaviors and hepatitis C among donors lead to excess discard that should be minimized given the current organ shortage.

Helicases often achieve functional specificity through utilization of unique structural features incorporated into an otherwise conserved core. The archaeal Rad3 (xeroderma pigmentosum group D protein (XPD)) helicase is a prototypical member of the Rad3 family, distinct from other related (superfamily II) SF2 enzymes because of a unique insertion containing an iron-sulfur (FeS) cluster. This insertion may represent an auxiliary domain responsible for modifying helicase activity or for conferring specificity for selected DNA repair intermediates. The importance of the FeS cluster for the fine-tuning of Rad3-DNA interactions is illustrated by several clinically relevant point mutations in the FeS domain of human Bach1 (FancJ) and XPD helicases that result in distinct disease phenotypes. Here we analyzed the substrate specificity of the Rad3 (XPD) helicase from Ferroplasma acidarmanus (FacRad3) and probed the importance of the FeS cluster for Rad3-DNA interactions. We found that the FeS cluster stabilizes secondary structure of the auxiliary domain important for coupling of single-stranded (ss) DNA-dependent ATP hydrolysis to ssDNA translocation. Additionally, we observed specific quenching of the Cy5 fluorescent dye when the FeS cluster of a bound helicase is positioned in close proximity to a Cy5 fluorophore incorporated into the DNA molecule. Taking advantage of this Cy5 quenching, we developed an equilibrium assay for analysis of the Rad3 interactions with various DNA substrates. We determined that the FeS cluster-containing domain recognizes the ssDNA-doublestranded DNA junction and positions the helicase in an orientation consistent with duplex unwinding. Although it interacts specifically with the junction, the enzyme binds tightly to ssDNA, and the single-stranded regions of the substrate are the major contributors to the energetics of FacRad3-substrate interactions.The function of many multisubunit DNA repair complexes requires activity of DNA helicases, which are ubiquitous, highly diverse molecular motors that convert the chemical energy of ATP binding and hydrolysis into mechanical work of unidirectional translocation along the DNA lattice (reviewed in Refs. 1, 2). Unidirectional translocation of a helicase may be coupled to other thermodynamically unfavorable processes, including separation of the nucleic acid duplexes and disassembly of protein-nucleic acid complexes. Coupling of ATP hydrolysis to translocation is achieved through the set of so-called "helicase signature motifs" that define the motor core of the enzyme (3, 4). The motor cores of numerous helicases are structurally and mechanistically similar, yet these enzymes display remarkable functional diversity (for review see Ref. 4). It has become clear in recent years that such diversity may be achieved in trans through utilization of specific processivity factors or in cis by incorporating additional structural features that direct interaction with nucleic acids, duplex destabilization, and strand separation activities.The Rad3 (XPD) 2 helica...

Frailty and markers of inflammation were associated with increased waitlist mortality risk, but only markers of inflammation significantly improved ESRD risk prediction. These findings help clarify the accelerated aging physiology of ESRD and highlight easy-to-measure markers of increased waitlist mortality risk.

The impact of donor quality on post-kidney transplant (KT) survival may vary by candidate condition. Characterizing this variation would increase access to KT without sacrificing outcomes. We developed a tool to estimate post-KT survival for combinations of donor quality and candidate condition. We studied deceased donor KT recipients (n = 120 818) and waitlisted candidates (n = 376 272) between 2005 and 2016 by using the Scientific Registry of Transplant Recipients. Donor quality and candidate condition were measured by using the Kidney Donor Profile Index (KDPI) and the Estimated Post Transplant Survival (EPTS) score. We estimated 5-year post-KT survival based on combinations of KDPI and EPTS score using random forest algorithms and waitlist survival by EPTS score using Weibull regressions. Survival benefit was defined as absolute reduction in mortality risk with KT. For candidates with an EPTS score of 80, 5-year waitlist survival was 47.6%, and 5-year post-KT survival was 78.9% after receiving kidneys with a KDPI of 20 and was 70.7% after receiving kidneys with a KDPI of 80. The impact of KDPI on survival benefit varied greatly by EPTS score. For candidates with low EPTS scores (eg, <40), the KDPI had limited impact on survival benefit. For candidates with middle or high EPTS scores (eg, >40), survival benefit decreased with higher KDPI but was still substantial even with a KDPI of 100 (>16 percentage points). Our prediction tool (www.transplantmodels.com/kdpi-epts) can support individualized decision-making on kidney offers in clinical practice.