Decisions on who requires simultaneous liver-kidney (SLK) transplantation are controversial. United Network for Organ Sharing implemented a “safety net” in 2017 providing prioritization on the kidney ...waitlist for patients with renal failure after liver transplantation. We aimed to compare survival after early kidney after liver transplantation (KALT) and SLK.
We compared SLK, KALT, and liver transplantation alone (LTA) in adult patients who underwent deceased donor (DD) liver transplantation in the US, from 2002 to 2018. Early KALT was defined as 60 to 365 days between liver and subsequent kidney transplantation (reflecting safety net listing criteria). Patients who died within 60 days were excluded to mitigate immortal time bias favoring KALT.
There were 6,774 SLK, 120 KALT at 60 to 365 days, and 11,501 LTA. Early KALT had equivalent survival compared with SLK, both for all KALT (hazard ratio HR 0.58, 95% CI 0.34–1.00, p = 0.05) and for DD KALT only (HR 0.72, 95% CI 0.37–1.38, p = 0.32). Simultaneous liver-kidney transplantation was associated with improved survival compared with LTA (HR 0.82. 95% CI 0.76–0.87, p < 0.01). Early KALT was associated with a greater reduction in mortality compared with LTA, but this was not significant (HR 0.58, 95% CI 0.39–1.00, p = 0.05). There was a lower proportion of early KALT in African Americans relative to SLK transplantations (7% vs 16%, p = 0.04).
Early KALT has equivalent survival compared with SLK transplantation, both for all KALT and for DD KALT only, supporting the promise of the “safety net.” There was a lower proportion of African-American patients undergoing early KALT, indicating the importance of monitoring access to early KALT under the “safety net” policy.
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IMPORTANCE: Ischemic cold storage (ICS) of livers for transplant is associated with serious posttransplant complications and underuse of liver allografts. OBJECTIVE: To determine whether portable ...normothermic machine perfusion preservation of livers obtained from deceased donors using the Organ Care System (OCS) Liver ameliorates early allograft dysfunction (EAD) and ischemic biliary complications (IBCs). DESIGN, SETTING, AND PARTICIPANTS: This multicenter randomized clinical trial (International Randomized Trial to Evaluate the Effectiveness of the Portable Organ Care System Liver for Preserving and Assessing Donor Livers for Transplantation) was conducted between November 2016 and October 2019 at 20 US liver transplant programs. The trial compared outcomes for 300 recipients of livers preserved using either OCS (n = 153) or ICS (n = 147). Participants were actively listed for liver transplant on the United Network of Organ Sharing national waiting list. INTERVENTIONS: Transplants were performed for recipients randomly assigned to receive donor livers preserved by either conventional ICS or the OCS Liver initiated at the donor hospital. MAIN OUTCOMES AND MEASURES: The primary effectiveness end point was incidence of EAD. Secondary end points included OCS Liver ex vivo assessment capability of donor allografts, extent of reperfusion syndrome, incidence of IBC at 6 and 12 months, and overall recipient survival after transplant. The primary safety end point was the number of liver graft–related severe adverse events within 30 days after transplant. RESULTS: Of 293 patients in the per-protocol population, the primary analysis population for effectiveness, 151 were in the OCS Liver group (mean SD age, 57.1 10.3 years; 102 67% men), and 142 were in the ICS group (mean SD age, 58.6 10.0 years; 100 68% men). The primary effectiveness end point was met by a significant decrease in EAD (27 of 150 18% vs 44 of 141 31%; P = .01). The OCS Liver preserved livers had significant reduction in histopathologic evidence of ischemia-reperfusion injury after reperfusion (eg, less moderate to severe lobular inflammation: 9 of 150 6% for OCS Liver vs 18 of 141 13% for ICS; P = .004). The OCS Liver resulted in significantly higher use of livers from donors after cardiac death (28 of 55 51% for the OCS Liver vs 13 of 51 26% for ICS; P = .007). The OCS Liver was also associated with significant reduction in incidence of IBC 6 months (1.3% vs 8.5%; P = .02) and 12 months (2.6% vs 9.9%; P = .02) after transplant. CONCLUSIONS AND RELEVANCE: This multicenter randomized clinical trial provides the first indication, to our knowledge, that normothermic machine perfusion preservation of deceased donor livers reduces both posttransplant EAD and IBC. Use of the OCS Liver also resulted in increased use of livers from donors after cardiac death. Together these findings indicate that OCS Liver preservation is associated with superior posttransplant outcomes and increased donor liver use. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02522871
Deep-sea mining of hydrothermal deposits off the coast of Japan is currently under consideration, and environmental baseline studies of the area are required to understand possible impacts. The aim ...of this study is to clarify population structures of dominant benthic megafaunal species near hydrothermal vent fields in the Okinawa Trough, using a population genetics approach. We examined dominant deep-sea scavenging species including eels, several amphipods, and a decapod and performed population genetic analyses based on the mitochondrial cytochrome c oxidase subunit I region. Several sites were sampled within Okinawa Trough to examine intra-population diversity while two other locations 1400-2400 km away were chosen for inter-population comparisons. For synaphobranchid eels Simenchelys parasitica and Synaphobranchus kaupii, our results showed significant intra-population diversity but no inter-population genetic differentiation, suggesting strong genetic connectivity and/or large population sizes. In addition, single nucleotide polymorphism analysis also confirmed strong genetic connectivity for Simenchelys parasitica. Among scavenging amphipods, we detected seven putative species using molecular phylogenetic analysis. We evaluated population structures of the most abundant species of amphipods and a decapod species (Nematocarcinus lanceopes). Our results provide basic information on the genetic population structures of benthic megafaunal species near hydrothermal vent fields, which can be used to select candidate species for future connectivity analysis with high-resolution genetic markers and aid understanding of the potential population impacts of environmental disturbances.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Background The 2014 Medicaid expansion in participating states increased insurance coverage among people with chronic health conditions, but its implications for access to surgical care remain ...unclear. We investigated how Medicaid expansion influenced the insurance status of candidates for liver transplantation (LT) and transplant center payor mix. Study design Data on LT candidates aged 18 to 64 years, in 2012 to 2013 (pre-expansion) and 2014 to 2015 (post-expansion), were obtained from the United Network for Organ Sharing registry. Change between the 2 periods in the percent of LT candidates using Medicaid was compared between expansion and nonexpansion states. Multivariable logistic regression was used to determine how Medicaid expansion influenced individual LT candidates' likelihood of using Medicaid insurance. Results The study included 33,017 LT candidates, of whom 29,666 had complete data for multivariable analysis. Medicaid enrollment increased by 4% after Medicaid expansion in participating states. One-quarter of the transplant centers in these states experienced ≥10% increase in the proportion of LT candidates using Medicaid insurance. Multivariable analysis confirmed that Medicaid expansion was associated with increased odds of LT candidates using Medicaid insurance (odds ratio 1.49; 95% CI 1.34, 1.66; p < 0.001). However, the absolute number and demographic characteristics of patients listed for LT did not change in Medicaid expansion states during the post-expansion period. Conclusions Candidates for LT became more likely to use Medicaid after the 2014 Medicaid expansion policy came into effect. Enactment of this policy did not appear to increase access to LT or address socioeconomic and demographic disparities in access to the LT wait list.
(2S,3R,4R,5S,6R)-2-(3-(4-Ethoxybenzyl)-4-chlorophenyl)-6-hydroxymethyl-tetrahydro-2H-pyran-3,4,5-triol (dapagliflozin; BMS-512148) is a potent sodium-glucose cotransporter type II inhibitor in ...animals and humans and is currently under development for the treatment of type 2 diabetes. The preclinical characterization of dapagliflozin, to allow compound selection and prediction of pharmacological and dispositional behavior in the clinic, involved Caco-2 cell permeability studies, cytochrome P450 (P450) inhibition and induction studies, P450 reaction phenotyping, metabolite identification in hepatocytes, and pharmacokinetics in rats, dogs, and monkeys. Dapagliflozin was found to have good permeability across Caco-2 cell membranes. It was found to be a substrate for P-glycoprotein (P-gp) but not a significant P-gp inhibitor. Dapagliflozin was not found to be an inhibitor or an inducer of human P450 enzymes. The in vitro metabolic profiles of dapagliflozin after incubation with hepatocytes from mice, rats, dogs, monkeys, and humans were qualitatively similar. Rat hepatocyte incubations showed the highest turnover, and dapagliflozin was most stable in human hepatocytes. Prominent in vitro metabolic pathways observed were glucuronidation, hydroxylation, and O-deethylation. Pharmacokinetic parameters for dapagliflozin in preclinical species revealed a compound with adequate oral exposure, clearance, and elimination half-life, consistent with the potential for single daily dosing in humans. The pharmacokinetics in humans after a single dose of 50 mg of (14)Cdapagliflozin showed good exposure, low clearance, adequate half-life, and no metabolites with significant pharmacological activity or toxicological concern.
In April 2012, the Organ Procurement and Transplantation Network (OPTN) implemented an online explant pathology form for recipients of liver transplantation who received additional wait‐list priority ...for their diagnosis of hepatocellular carcinoma (HCC). The purpose of the form was to standardize the data being reported to the OPTN, which had been required since 2002 but were submitted to the OPTN in a variety of formats via facsimile. From April 2012 to December 2014, over 4500 explant forms were submitted, allowing for detailed analysis of the characteristics of the explanted livers. Data from the explant pathology forms were used to assess agreement with pretransplant imaging. Explant data were also used to assess the risk of recurrence. Of those with T2 priority, 55.7% were found to be stage T2 on explant. Extrahepatic spread (odds ratio OR = 6.8; P < 0.01), poor tumor differentiation (OR = 2.8; P < 0.01), microvascular invasion (OR = 2.6; P < 0.01), macrovascular invasion (OR = 3.2; P < 0.01), and whether the Milan stage based on the number and size of tumors on the explant form was T4 (OR = 2.4; P < 0.01) were the strongest predictors of recurrence. In conclusion, this analysis confirms earlier findings that showed an incomplete agreement between pretransplant imaging and posttransplant pathology in terms of HCC staging, though the number of patients with both no pretransplant treatment and no tumor in the explant was reduced from 20% to <1%. In addition, several factors were identified (eg, tumor burden, age, sex, region, ablative therapy, alpha‐fetoprotein, Milan stage, vascular invasion, satellite lesions, etc.) that were predictive of HCC recurrence, allowing for more targeted surveillance of high‐risk recipients. Continued evaluation of these data will help shape future guidelines or policy recommendations. Liver Transplantation 22 757–764 2016 AASLD.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Japan undertook the first ever tests of deep-sea seafloor massive sulfide (SMS) excavation in 2017 in the Okinawa Trough. This study examines infauna from several nearby stations before and up to 3 ...yr after disturbance. Distance from excavation, current direction, seafloor topography, and modeled and observed deposition were used to classify the level of impact of each station. Metal concentrations were analyzed, as were nanofauna (2-32 µm), meiofauna (32-300 µm), and macrofauna (>300 µm). Elevated Cd, Pb, Hg, Zn, Fe, and Cu were confirmed as indicators of sedimentation from the SMS extraction. Benthic communities appeared altered by the disturbance test, with different size classes showing different levels of response and recovery. Nanofaunal and meiofaunal abundances appeared to take several weeks to show impacts from the disturbance and may have returned to pre-test levels within 1 yr, but changes to nematode community structure persisted longer. In contrast, macrofaunal abundances and diversity appeared to decrease immediately, and possibly remained depressed compared to pre-test levels at impacted sites at least 3 yr later. In addition, meiofaunal nematode:copepod ratio and macrofaunal percent composition of polychaetes, along with several nematode taxa, may serve as useful bioindicators of SMS mining. The small scale of disturbance requires caution when extrapolating to full-scale mining, but these results suggest current direction and topography greatly influence the extent of mining impacts; in addition, several metals may be useful for identifying the mining footprint. Biological results indicate that larger macroinfauna may be less resistant and resilient to mining impacts than smaller meiofauna and impacts from even small-scale mining activities may persist for at least 3 yr.
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