Effects of Subnormothermic Regulated Hepatic Reperfusion on Mitochondrial and Transcriptomic Profiles in a Porcine Model.

OBJECTIVE: We sought to investigate the biological effects of pre-reperfusion treatments of the liver after warm and cold ischemic injuries in a porcine donation after circulatory death model. SUMMARY OF BACKGROUND DATA: Donation after circulatory death represents a severe form of liver ischemia and reperfusion injury that has a profound impact on graft function after liver transplantation. METHODS: Twenty donor pig livers underwent 60 minutes of in situ warm ischemia after circulatory arrest and 120 minutes of cold static preservation prior to simulated transplantation using an ex vivo perfusion machine. Four reperfusion treatments were compared: Control-Normothermic (N), Control- Subnormothermic (S), regulated hepatic reperfusion (RHR)-N, and RHR-S (n = 5 each). The biochemical, metabolic, and transcriptomic profiles, as well as mitochondrial function were analyzed. RESULTS: Compared to the other groups, RHR-S treated group showed significantly lower post-reperfusion aspartate aminotransferase levels in the reperfusion effluent and histologic findings of hepatocyte viability and lesser degree of congestion and necrosis. RHR-S resulted in a significantly higher mitochondrial respiratory control index and calcium retention capacity. Transcriptomic profile analysis showed that treatment with RHR-S activated cell survival and viability, cellular homeostasis as well as other biological functions involved in tissue repair such as cytoskeleton or cytoplasm organization, cell migration, transcription, and microtubule dynamics. Furthermore, RHR-S inhibited organismal death, morbidity and mortality, necrosis, and apoptosis. CONCLUSION: Subnormothermic RHR mitigates IRI and preserves hepatic mitochondrial function after warm and cold hepatic ischemia. This organ resuscitative therapy may also trigger the activation of protective genes against IRI. Sub- normothermic RHR has potential applicability to clinical liver transplantation.

Approaches to Address the Anemia Challenge.

Anemia is a multifactorial condition; approaches to address it must recognize that the causal factors represent an ecology consisting of internal (biology, genetics, and health) and external (social/behavioral/demographic and physical) environments. In this paper, we present an approach for selecting interventions, followed by a description of key issues related to the multiple available interventions for prevention and reduction of anemia. We address interventions for anemia using the following 2 main categories: 1) those that address nutrients alone, and, 2) those that address nonnutritional causes of anemia. The emphasis will be on interventions of public health relevance, but we also consider the clinical context. We also focus on interventions at different stages of the life course, with a particular focus on women of reproductive age and preschool-age children, and present evidence on various factors to consider when selecting an intervention-inflammation, genetic mutations, nutrient delivery, bioavailability, and safety. Each section on an intervention domain concludes with a brief discussion of key research areas.

Fluorescein clearance kinetics in blood and bile indicates hepatic ischemia-reperfusion injury in rats.

Quantitative measurement of the degree of hepatic ischemia-reperfusion injury (IRI) is crucial for developing therapeutic strategies for its treatment. We hypothesized that clearance of fluorescent dye through bile metabolism may reflect the degree of hepatic IRI. In this study, we investigated sodium fluorescein clearance kinetics in blood and bile for quantifying the degree of hepatic IRI. Warm ischemia times (WITs) of 0, 30, or 60 min followed by 1 h or 4 h of reperfusion, were applied to the median and lateral lobes of the liver in Sprague-Dawley rats. Subsequently, 2 mg/kg of sodium fluorescein was injected intravenously, and blood and bile samples were collected over 60 min to measure fluorescence intensities. The bile-to-plasma fluorescence ratios demonstrated an inverse correlation with WIT and were distinctly lower in the 60-min WIT group than in the control or 30-min WIT groups. Bile-to-plasma fluorescence ratios displayed superior discriminability for short versus long WITs when measured 1 h after reperfusion versus 4 h. We conclude that the bile-to-blood ratio of fluorescence after sodium fluorescein injection has the potential to enable the quantification of hepatic IRI severity.NEW & NOTEWORTHY Previous attempts to use fluorophore clearance to test liver function have relied on a single source of data. However, the kinetics of substrate processing via bile metabolism include decreasing levels in blood and increasing levels in bile. Thus, we analyzed data from blood and bile to better reflect fluorescein clearance kinetics.

Higher Extrusion Temperature Induces Greater Formation of Less Digestible Type V and Retrograded Starch in Iron-Fortified Rice Grains But Does Not Affect Iron Bioavailability: Stable Isotope Studies in Young Women.

BACKGROUND: Hot extrusion is widely used to produce iron-fortified rice, but heating may increase resistant starch and thereby decrease iron bioavailability. Cold-extruded iron-fortified rice may have higher bioavailability but has higher iron losses during cooking. Thus, warm extrusion could have nutritional benefits, but this has not been tested. Whether the addition of citric acid (CA) and trisodium citrate (TSC) counteracts any detrimental effect of high-extrusion temperature on iron bioavailability is unclear. OBJECTIVES: Our aim was to assess the effects of varying processing temperatures on the starch microstructure of extruded iron-fortified rice and resulting iron solubility and iron bioavailability. METHODS: We produced extruded iron-fortified rice grains at cold, warm, and hot temperatures (40°C, 70°C, and 90°C), with and without CA/TSC at a molar ratio of iron to CA/TSC of 1:0.3:5.5. We characterized starch microstructure using small- and wide-angle X-ray scattering and differential scanning calorimetry, assessed color over 6 mo, and measured in vitro iron solubility. In standardized rice and vegetable test meals consumed by young women (n = 22; mean age: 23 y; geometric mean plasma ferritin: 29.3 µg/L), we measured iron absorption from the fortified rice grains intrinsically labeled with 57ferric pyrophosphate (57FePP), compared with ferrous sulfate (58FeSO4) solution added extrinsically to the meals. RESULTS: Warm and hot extrusion altered starch morphology from native type A to type V and increased retrograded starch. However, extrusion temperature did not significantly affect iron solubility or iron bioavailability. The geometric mean fractional iron absorption of iron from fortified rice extruded with CA/TSC (8.2%; 95% CI: 7.9%, 11.0%) was more than twice that from extruded rice without CA/TSC (3.0%; 95% CI: 2.7%, 3.4%; P < 0.001). CONCLUSIONS: Higher extrusion temperatures did not affect iron bioavailability from extruded rice in young women, but co-extrusion of CA/TSC with FePP sharply increased iron absorption independently from extrusion temperature. This trial is registered at www.clinicaltrials.gov as NCT03703726.

Liver Transplantation Outcomes in a U.S. Multicenter Cohort of 789 Patients With Hepatocellular Carcinoma Presenting Beyond Milan Criteria.

BACKGROUND AND AIMS: The Organ Procurement and Transplantation Network recently approved liver transplant (LT) prioritization for patients with hepatocellular carcinoma (HCC) beyond Milan Criteria (MC) who are down-staged (DS) with locoregional therapy (LRT). We evaluated post-LT outcomes, predictors of down-staging, and the impact of LRT in patients with beyond-MC HCC from the U.S. Multicenter HCC Transplant Consortium (20 centers, 2002-2013). APPROACH AND RESULTS: Clinicopathologic characteristics, overall survival (OS), recurrence-free survival (RFS), and HCC recurrence (HCC-R) were compared between patients within MC (n = 3,570) and beyond MC (n = 789) who were down-staged (DS, n = 465), treated with LRT and not down-staged (LRT-NoDS, n = 242), or untreated (NoLRT-NoDS, n = 82). Five-year post-LT OS and RFS was higher in MC (71.3% and 68.2%) compared with DS (64.3% and 59.5%) and was lowest in NoDS (n = 324; 60.2% and 53.8%; overall P < 0.001). DS patients had superior RFS (60% vs. 54%, P = 0.043) and lower 5-year HCC-R (18% vs. 32%, P < 0.001) compared with NoDS, with further stratification by maximum radiologic tumor diameter (5-year HCC-R of 15.5% in DS/<5 cm and 39.1% in NoDS/>5 cm, P < 0.001). Multivariate predictors of down-staging included alpha-fetoprotein response to LRT, pathologic tumor number and size, and wait time >12 months. LRT-NoDS had greater HCC-R compared with NoLRT-NoDS (34.1% vs. 26.1%, P < 0.001), even after controlling for clinicopathologic variables (hazard ratio [HR] = 2.33, P < 0.001) and inverse probability of treatment-weighted propensity matching (HR = 1.82, P < 0.001). CONCLUSIONS: In LT recipients with HCC presenting beyond MC, successful down-staging is predicted by wait time, alpha-fetoprotein response to LRT, and tumor burden and results in excellent post-LT outcomes, justifying expansion of LT criteria. In LRT-NoDS patients, higher HCC-R compared with NoLRT-NoDS cannot be explained by clinicopathologic differences, suggesting a potentially aggravating role of LRT in patients with poor tumor biology that warrants further investigation.

A novel escalation from veno-venous bypass to veno-venous ECMO during orthotopic liver transplantation. A case report.

We describe the challenging perioperative course of a 55-year-old patient with hepatic failure requiring liver transplantation (LT). Different modalities of the extracorporeal device were successfully used, ranging from veno-veno bypass to partial and full veno-veno extracorporeal membrane oxygenation (ECMO) in order to optimize preload, reduce bleeding from the collateral circulation, optimize acid base balance and/or improve oxygenation. The case highlights the potential use of the device as a rescue method in challenging cases. Furthermore this is the first documented case that extracorporeal CO2 removal (ECCO2R) is used to optimize the biochemistry profile intraoperatively during a LT. The patient was weaned off the device at the end of the case and has been discharged home.

Pathologic Response to Pretransplant Locoregional Therapy is Predictive of Patient Outcome After Liver Transplantation for Hepatocellular Carcinoma: Analysis From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: The aim of the study was to determine the rate, predictors, and impact of complete pathologic response (cPR) to pretransplant locoregional therapy (LRT) in a large, multicenter cohort of hepatocellular carcinoma (HCC) patients undergoing liver transplantation (LT). BACKGROUND: LRT is used to mitigate waitlist dropout for patients with HCC awaiting LT. Degree of tumor necrosis found on explant has been associated with recurrence and overall survival, but has not been evaluated in a large, multicenter study. METHODS: Comparisons were made among patients receiving pre-LT LRT with (n = 802) and without (n = 2637) cPR from the United States Multicenter HCC Transplant Consortium (UMHTC), and multivariable predictors of cPR were identified using logistic regression. RESULTS: Of 3439 patients, 802 (23%) had cPR on explant. Compared with patients without cPR, cPR patients were younger; had lower Model for End-stage Liver Disease (MELD) scores, AFP levels, and neutrophil-lymphocyte ratios (NLR); were more likely to have tumors within Milan criteria and fewer LRT treatments; and had significantly lower 1-, 3-, and 5-year incidence of post-LT recurrence (1.3%, 3.5%, and 5.2% vs 6.2%, 13.5%, and 16.4%; P < 0.001) and superior overall survival (92%, 84%, and 75% vs 90%, 78%, and 68%; P < 0.001). Multivariable predictors of cPR included age, sex, liver disease diagnosis, MELD, AFP, NLR, radiographic Milan status, and number of LRT treatments (C-statistic 0.67). CONCLUSIONS: For LT recipients with HCC receiving pretransplant LRT, achieving cPR portends significantly lower posttransplant recurrence and superior survival. Factors predicting cPR are identified, which may help prioritize patients and guide LRT strategies to optimize posttransplant cancer outcomes.

Transperineal prostate biopsy with cognitive magnetic resonance imaging/biplanar ultrasound fusion: description of technique and early results.

OBJECTIVE: To describe our technique and early results performing transperineal prostate biopsy using cognitive magnetic resonance imaging (MRI)/biplanar ultrasound fusion. Key components of this technique include use of the PrecisionPoint Transperineal Access System (Perineologic, Cumberland, MD) and simultaneous transrectal ultrasound guidance in the axial and sagittal planes. PATIENTS AND METHODS: In total, 95 patients (38 studied retrospectively and 57 studied prospectively) underwent a transperineal MRI-targeted prostate biopsy using the technique detailed in this manuscript. All biopsies were performed by a single urologist (MAG). Data were collected with respect to cancer detection rates, tolerability, and complications. The subset of patients who were studied prospectively was assessed for complications by telephone interviews performed at 4-6 days and 25-31 days following the prostate biopsy. RESULTS: Between February 2018 and June 2019, 95 men underwent a transperineal prostate biopsy using MRI/biplanar ultrasound fusion guidance. Patients had a total of 124 PI-RADS 3-5 lesions that were targeted for biopsy. In total, 108 (87.1%) lesions were found to harbor prostate cancer of any grade. Grade group ≥ 2 prostate cancer was found in 81 (65.3%) of targeted lesions. The detection rates for grade group ≥ 1 and grade group ≥ 2 prostate cancer rose with increasing PI-RADS score. In 65 (68.4%) cases, the patient's highest grade prostate cancer was found within an MRI target. Additionally, 12 of 55 (21.8%) patients who were found to have no or grade group 1 prostate cancer on systematic biopsy were upgraded to grade group ≥ 2 prostate cancer with MRI targeting. Only 1 (1.1%) patient received periprocedural antibiotics and no patient experienced an infectious complication. Self-limited hematuria and hematospermia were commonly reported following the procedure (75.4% and 40.4%, respectively) and only 1 (1.1%) patient developed urinary retention. CONCLUSIONS: We demonstrate the safety and feasibility of performing transperineal prostate biopsy using cognitive MRI/biplanar ultrasound fusion guidance. The described technique affords the safety benefits of the transperineal approach as well as obviates the need for a formal fusion platform. Additionally, this method can conveniently be performed under local anesthesia with acceptable tolerability.

Human Leukocyte Antigen Class I Antibodies and Response to Platelet Transfusion in Patients Undergoing Liver Transplantation.

BACKGROUND: Patients undergoing liver transplantation (LT) frequently receive platelet transfusion (PLT) to minimize their risk of hemorrhage. Alloimmunization to platelets may lead to refractoriness to PLT. Data on the implications of platelet alloimmunization in patients undergoing LT remain limited. We examined the effect of human leukocyte antigen class I (HLA-I) antibodies on PLT refractoriness and short-term outcomes after LT. METHODS: Peritransplant clinical and PLT factors were reviewed for all adult liver or simultaneous liver-kidney transplantations from 2012 to 2017. Sensitized patients (SE) with pretransplant HLA-I calculated panel-reactive antibody ≥20% were compared with unsensitized patients (US) with calculated panel-reactive antibody <20%. The mean follow-up was 21.4 mo. RESULTS: Alloimmunization was observed in 39% of the study cohort. SE (n = 28) received 272 PLTs, and US (n = 44) received 246 PLTs. History of pregnancy was higher among SE than US (P < 0.01); otherwise, both groups had similar clinical characteristics. SE had higher rates of PLT refractoriness (66% versus 47%; P < 0.01) than US. The mean platelet corrected count increment was lower among SE compared with US up to 100 min after PLT (P < 0.05). Alloimmunization and simultaneous liver-kidney transplantation independently predicted refractoriness on multivariate logistic regression (P < 0.05). Early allograft rejection and patient survival rates were comparable for both groups. CONCLUSIONS: LT patients experienced high rates of HLA-I alloimmunization and PLT refractoriness. SE had higher rates of refractoriness and lower mean corrected count increment after transfusion compared with US. Our study suggests that further research to evaluate the utility of HLA-matched PLTs in HLA-I alloimmunized LT patients is warranted.

Downstaging Locally Advanced Cholangiocarcinoma Pre-Liver Transplantation: A Prospective Pilot Study.

BACKGROUND: Orthotopic liver transplantation (OLT) after neoadjuvant therapy (NT) in well-selected patients with unresectable hilar cholangiocarcinoma (CCA) achieves excellent recurrence-free survival. Current criteria for NT-OLT exclude patients with locally advanced hilar and intrahepatic CCA from potential cure. We sought to evaluate the efficacy of NT in downstaging locally advanced CCA, and examine outcomes after OLT. METHODS: Among 24 patients referred for unresectable hilar and intrahepatic CCA from January 2013 through August 2017, 18 met center-specific inclusion criteria for the NT-OLT treatment protocol: hilar tumor size ≤3.5 cm or intrahepatic ≤8 cm, and regional lymphadenopathy but without distant metastasis. Median follow-up was 22.1 mo from diagnosis. RESULTS: Of 18 patients who initiated NT, 11 were removed from the protocol due to tumor progression (n = 6) or uncontrolled infection and failure-to-thrive (n = 5). Median NT duration tended to be shorter for patients progressing to dropout than for those surviving to OLT (5.5 versus 13.5 mo, P = 0.109). Among five patients who received OLT, 1-y post-OLT patient survival was 80%: three survive recurrence-free (14.5-29.2 mo post-OLT); one developed an isolated tumor recurrence in a single portacaval lymph node at 12 mo post-OLT; and one experienced non-tumor-related death. All dropout patients died at a median of 14.4 mo after diagnosis. CONCLUSIONS: This is the first prospective study to show successful NT downstaging of unresectable locally advanced hilar and intrahepatic CCA before OLT. NT-OLT for select patients with locally advanced hilar and intrahepatic CCA achieved acceptable short-term recurrence-free survival.

Effects of Hepatic Ischemia-Reperfusion Injuries and NRF2 on Transcriptional Activities of Bile Transporters in Rats.

BACKGROUND: The effect of hepatic ischemia-reperfusion injury (IRI) on bile transporter (BT) gene expression is unknown. We hypothesized that abnormal expression of BTs during hepatic IRI is dependent on nuclear factor erythroid 2-related factor 2 (NRF2), which contributes to the cholestasis after reperfusion. METHODS: Sham surgery and short (60 min) or long (90 min) periods of warm ischemia time (WIT) with or without reperfusion for 24 h were applied to wild-type Sprague-Dawley rats and Nrf2 knockout rats (n = 5 per group). At each stage of IRI, the serum levels of aminotransferase, total bilirubin, and bile acids were measured. In addition, hepatic tissue was sampled to determine the histologic score of IRI (Suzuki score), measure adenosine triphosphate (ATP), and identify the quantitative real-time polymerase chain reactions of BTs (Oatp1, Ntcp, Mrp2, Bsep, and Mrp3). RESULTS: In short periods of WIT, BT expression increased during the ischemia stage and returned to the baseline after reperfusion. However, in long periods of WIT, BT expression did not increase after ischemia and decreased further after reperfusion. Short WIT did not increase BT expression in Nrf2 knockout animals. The level of BT expression was correlated with the Suzuki score, the serum levels of aminotransferase, bilirubin, and bile acids, and tissue ATP level. Stepwise multiple regression analysis derived equations to predict the Suzuki score (R2 = 76.8, P < 0.001), serum total bilirubin (R2 = 61.2, P < 0.001), and tissue ATP (R2 = 61.1, P < 0.001). CONCLUSIONS: Short WIT induces the transcriptional activities of BT, whereas long WIT depresses them, and the effect was blunted by Nrf2 knockout status. BT expression can be considered a surrogate marker for hepatic IRI.

Imaging of prostate cancer with positron emission tomography.

Prostate cancer is most commonly imaged through a combination of magnetic resonance imaging, x-ray computed tomography, and 99mTc-methylene diphosphonate bone scan. These conventional imaging modalities, however, suffer from limited sensitivity and specificity for the detection of disease. This can lead to disease understaging and the improper selection of treatment. To address this problem, a variety of novel radiotracers for positron emission tomography (PET) imaging have been developed. This includes agents that accumulate on the basis of alterations in cellular metabolism (eg, 11C-choline and 18F-FACBC) as well as those that bind to specific proteins (eg, 68Ga-PSMA-11, 18F-DCFPyL, 68Ga-RM2, and 18F-DHT). In this review, we examine the performance characteristics of these new PET radiotracers for imaging prostate cancer and discuss ways in which PET imaging can offer more precise clinical information to patients and providers.

Combining food-based dietary recommendations using Optifood with zinc-fortified water potentially improves nutrient adequacy among 4- to 6-year-old children in Kisumu West district, Kenya.

Children in developing countries often face multiple micronutrient deficiencies. Introduction of zinc-fortified water can increase zinc intake, but additional recommendations are required to address overall diet nutrient adequacy. We developed and tested food-based recommendations (FBRs) that included zinc-fortified water for children aged between 4 and 6 years from rural Kenya to achieve the best possible nutrient adequacy. Dietary intakes of 60 children aged 4-6 years, from Kisumu West district, Kenya, were assessed using a quantitative multipass 24-hr recall. Linear programming model parameters were derived, including a list of foods consumed, median serving sizes, and distribution of frequency of consumption. By using the Optifood linear programming tool, we developed FBRs for diets including zinc-fortified water. FBRs with nutrient levels achieving ≥70% recommended nutrient intake (RNI) of the World Health Organization/Food and Agriculture Organization of the United Nations RNI for most of the 12 considered nutrients were selected as the final recommendations for the children. With no FBRs and no zinc-fortified water, percent RNI coverage range was between 40% and 76% for zinc, improving to 66-101% after introduction of zinc-fortified water. The final set of FBRs achieved nutrient adequacy for all nutrients except for vitamin A (25% RNI) and folate (68% RNI). Introduction of zinc-fortified water combined with FBRs will likely improve the nutrient adequacy of diets consumed by children in Kenya but needs to be complemented with alternative interventions to ensure dietary adequacy.

Modified Associating Liver Partition and Portal Vein Ligation for Staged Hepatectomy for Hepatoblastoma in a Small Infant: How Far Can We Push the Envelope?

: For patients with hepatoblastoma, a timely and complete resection of the tumor is critical to the patient's tumor recurrence-free survival. Associating liver partition and portal vein ligation for staged hepatectomy (ALPPS), a 2-stage hepatectomy procedure, has revolutionized the surgical management of large hepatic tumors with insufficient future liver remnant (FLR) at presentation. Although existing data support the utility of ALPPS in adults with primary and metastatic hepatobiliary malignancy, the literature in children is scarce. To our knowledge, this is the first report showing clinical applicability and safety of the modified ALPPS procedure in a small infant (54 days old) with hepatoblastoma who presented with insufficient FLR. Our report suggests the modified ALPPS could potentially expand the surgical treatment alternative for small infants with large hepatoblastoma.

Impact of Pretransplant Bridging Locoregional Therapy for Patients With Hepatocellular Carcinoma Within Milan Criteria Undergoing Liver Transplantation: Analysis of 3601 Patients From the US Multicenter HCC Transplant Consortium.

OBJECTIVE: To evaluate the effect of pretransplant bridging locoregional therapy (LRT) on hepatocellular carcinoma (HCC) recurrence and survival after liver transplantation (LT) in patients meeting Milan criteria (MC). SUMMARY BACKGROUND DATA: Pre-LT LRT mitigates tumor progression and waitlist dropout in HCC patients within MC, but data on its impact on post-LT recurrence and survival remain limited. METHODS: Recurrence-free survival and post-LT recurrence were compared among 3601 MC patients with and without bridging LRT utilizing competing risk Cox regression in consecutive patients from 20 US centers (2002-2013). RESULTS: Compared with 747 LT recipients not receiving LRT, 2854 receiving LRT had similar 1, 3, and 5-year recurrence-free survival (89%, 77%, 68% vs 85%, 75%, 68%; P = 0.490) and 5-year post-LT recurrence (11.2% vs 10.1%; P = 0.474). Increasing LRT number [3 LRTs: hazard ratio (HR) 2.1, P < 0.001; 4+ LRTs: HR 2.5, P < 0.001), and unfavorable waitlist alphafetoprotein trend significantly predicted post-LT recurrence, whereas LRT modality did not. Treated patients achieving complete pathologic response (cPR) had superior 5-year RFS (72%) and lower post-LT recurrence (HR 0.52, P < 0.001) compared with both untreated patients (69%; P = 0.010; HR 1.0) and treated patients not achieving cPR (67%; P = 0.010; HR 1.31, P = 0.039), who demonstrated increased recurrence compared with untreated patients in multivariate analysis controlling for pretransplant and pathologic factors (HR 1.32, P = 0.044). CONCLUSIONS: Bridging LRT in HCC patients within MC does not improve post-LT survival or HCC recurrence in the majority of patients who fail to achieve cPR. The need for increasing LRT treatments and lack of alphafetoprotein response to LRT independently predict post-LT recurrence, serving as a surrogate for underlying tumor biology which can be utilized for prioritization of HCC LT candidates.

Biliary reconstructive techniques and associated anatomic variants in adult living donor liver transplantations: The adult-to-adult living donor liver transplantation cohort study experience.

Living donor liver transplantation (LDLT) is a technically demanding endeavor, requiring command of the complex anatomy of partial liver grafts. We examined the influence of anatomic variation and reconstruction techniques on surgical outcomes and graft survival in the 9-center Adult-to-Adult Living Donor Liver Transplantation Cohort Study (A2ALL). Data from 272 adult LDLT recipients (2011-2015) included details on anatomic characteristics and types of intraoperative biliary reconstruction. Associations were tested between reconstruction technique and complications, which included first biliary complication (BC; leak, stricture, or biloma) and first vascular complication (VC; hepatic artery thrombosis [HAT] or portal vein thrombosis [PVT]). Time to patient death, graft failure, and complications were estimated using Kaplan-Meier curves and tested with log-rank tests. Median posttransplant follow-up was 1.2 years. Associations were found between the type of biliary reconstruction and the incidence of VC (P = 0.03) and BC (P = 0.05). Recipients with Roux-en-Y hepaticojejunostomy had the highest probability of VC. Recipients with biliary reconstruction involving the use of high biliary radicals on the recipient duct had the highest likelihood of developing BC (56% by 1 year) compared with duct-to-duct (42% by 1 year). In conclusion, the varied surgical approaches in the A2ALL centers offer a novel opportunity to compare disparate LDLT approaches. The choice to use higher biliary radicals on the recipient duct for reconstruction was associated with more BC, possibly secondary to devascularization and ischemia. The use of Roux-en-Y biliary reconstruction was associated with VCs (HAT and PVT). These results can be used to guide biliary reconstruction decisions in the setting of anatomic variants and inform further improvements in LDLT reconstructions. Ultimately, this information may contribute to a lower incidence of technical complications after LDLT. Liver Transplantation 23 1519-1530 2017 AASLD.

In Rwandese Women with Low Iron Status, Iron Absorption from Low-Phytic Acid Beans and Biofortified Beans Is Comparable, but Low-Phytic Acid Beans Cause Adverse Gastrointestinal Symptoms.

BACKGROUND: Phytic acid (PA) is a major inhibitor of iron bioavailability from beans, and high PA concentrations might limit the positive effect of biofortified beans (BBs) on iron status. Low-phytic acid (lpa) bean varieties could increase iron bioavailability. OBJECTIVE: We set out to test whether lpa beans provide more bioavailable iron than a BB variety when served as part of a composite meal in a bean-consuming population with low iron status. METHODS: Dietary iron absorption from lpa, iron-biofortified, and control beans (CBs) (regular iron and PA concentrations) was compared in 25 nonpregnant young women with low iron status with the use of a multiple-meal crossover design. Iron absorption was measured with stable iron isotopes. RESULTS: PA concentration in lpa beans was ∼10% of BBs and CBs, and iron concentration in BBs was ∼2- and 1.5-fold compared with CBs and lpa beans, respectively. Fractional iron absorption from lpa beans [8.6% (95% CI: 4.8%, 15.5%)], BBs [7.3% (95% CI: 4.0%, 13.4%)], and CBs [8.0% (95% CI: 4.4%, 14.6%)] did not significantly differ. The total amount of iron absorbed from lpa beans and BBs was 421 µg (95% CI: 234, 756 µg) and 431 µg (95% CI: 237, 786 µg), respectively, and did not significantly differ, but was >50% higher (P < 0.005) than from CBs (278 µg; 95% CI: 150, 499 µg). In our trial, the lpa beans were hard to cook, and their consumption caused transient adverse digestive side effects in ∼95% of participants. Gel electrophoresis analysis showed phytohemagglutinin L (PHA-L) residues in cooked lpa beans. CONCLUSION: BBs and lpa beans provided more bioavailable iron than control beans and could reduce dietary iron deficiency. Digestive side effects of lpa beans were likely caused by PHA-L, but it is unclear to what extent the associated digestive problems reduced iron bioavailability. This trial was registered at clinicaltrials.gov as NCT02215278.

Pathologic sequelae of allosensitization in liver transplantation.

The long-term impact of allosensitization between ABO compatible donor/recipient pairs in liver transplantation is unclear. Accumulating clinical evidence suggests that donor-specific antibody formation may lead to antibody-mediated rejection and is causally linked to pathologic injury, graft loss, and death. Although this immune-mediated graft dysfunction is increasingly being associated with poor outcomes, the specific pathologic sequelae are not defined. Herein, we examine the relationship between allosensitization, antibody-mediated rejection, and subsequent graft pathology.

Signaling through hepatocellular A2B adenosine receptors dampens ischemia and reperfusion injury of the liver.

Ischemia and reperfusion significantly contributes to the morbidity and mortality of liver surgery and transplantation. Based on studies showing a critical role for adenosine signaling in mediating tissue adaptation during hypoxia, we hypothesized that signaling events through adenosine receptors (ADORA1, ADORA2A, ADORA2B, or ADORA3) attenuates hepatic ischemia and reperfusion injury. Initial screening studies of human liver biopsies obtained during hepatic transplantation demonstrated a selective and robust induction of ADORA2B transcript and protein following ischemia and reperfusion. Subsequent exposure of gene-targeted mice for each individual adenosine receptor to liver ischemia and reperfusion revealed a selective role for the Adora2b in liver protection. Moreover, treatment of wild-type mice with an Adora2b-selective antagonist resulted in enhanced liver injury, whereas Adora2b-agonist treatment was associated with attenuated hepatic injury in wild-type, but not in Adora2b(-/-) mice. Subsequent studies in mice with Adora2b deletion in different tissues--including vascular endothelia, myeloid cells, and hepatocytes--revealed a surprising role for hepatocellular-specific Adora2b signaling in attenuating nuclear factor NF-κB activation and thereby mediating liver protection from ischemia and reperfusion injury. These studies provide a unique role for hepatocellular-specific Adora2b signaling in liver protection during ischemia and reperfusion injury.