Terlipressin plus albumin was associated with greater improvement in renal function vs albumin alone in patients with cirrhosis and HRS-1. Patients had similar rates of HRS reversal with terlipressin as they did with albumin. ClinicalTrials.gov no: NCT01143246.
Severe alcoholic hepatitis (sAH) is associated with a poor prognosis. There is no proven effective treatment for sAH, which is why early transplantation has been increasingly discussed. Hepatoblastoma‐derived C3A cells express anti‐inflammatory proteins and growth factors and were tested in an extracorporeal cellular therapy (ELAD) study to establish their effect on survival for subjects with sAH. Adults with sAH, bilirubin ≥8 mg/dL, Maddrey's discriminant function ≥ 32, and Model for End‐Stage Liver Disease (MELD) score ≤ 35 were randomized to receive standard of care (SOC) only or 3‐5 days of continuous ELAD treatment plus SOC. After a minimum follow‐up of 91 days, overall survival (OS) was assessed by using a Kaplan‐Meier survival analysis. A total of 203 subjects were enrolled (96 ELAD and 107 SOC) at 40 sites worldwide. Comparison of baseline characteristics showed no significant differences between groups and within subgroups. There was no significant difference in serious adverse events between the 2 groups. In an analysis of the intent‐to‐treat population, there was no difference in OS (51.0% versus 49.5%). The study failed its primary and secondary end point in a population with sAH and with a MELD ranging from 18 to 35 and no upper age limit. In the prespecified analysis of subjects with MELD < 28 (n = 120), ELAD was associated with a trend toward higher OS at 91 days (68.6% versus 53.6%; P = .08). Regression analysis identified high creatinine and international normalized ratio, but not bilirubin, as the MELD components predicting negative outcomes with ELAD. A new trial investigating a potential benefit of ELAD in younger subjects with sufficient renal function and less severe coagulopathy has been initiated. Liver Transplantation 24 380–393 2018 AASLD.
Pre-transplant evaluation for orthotopic liver transplantation (OLT) commonly includes a cardiac evaluation using dobutamine stress echocardiography (DSE). We performed a quantitative systematic review assessing DSE's use in detecting coronary artery disease (CAD) and predicting perioperative and long term cardiac events in patients undergoing OLT. Published studies in pubmed were accessed using keyword searches and bibliographic review. Included studies evaluated the use of DSE in patients undergoing OLT, including its accuracy for detection of CAD, and in predicting perioperative and long term cardiac prognosis for both hard (myocardial infarction, cardiac death, cardiac arrest, and asystole) and soft cardiac events (all other events that were cardiovascular in nature). We calculated DSE's sensitivity, specificity, negative predictive value (NPV), and positive predictive value (PPV) in the above areas. We identified 7 studies, including a total of 580 patients, which included 4 accuracy studies (n = 110 patients), 4 perioperative studies, and 3 long term studies. Accuracy for CAD included a sensitivity of 0.32, specificity of 0.78, PPV of 0.37, and NPV of 0.75. Accuracy for prediction of perioperative hard and soft cardiac events was a sensitivity of 0.20 and 0, specificity of 0.99 and 0.99, PPV of 0.33 and 0, and NPV of 0.98 and 0.89, respectively. For long term hard and soft cardiac events, sensitivity was 0.5 and 0, specificity 0.99 and 0.98, PPV 0.33 and 0, and NPV 0.99 and 0.96, respectively. DSE has a limited accuracy for the detection of CAD in candidates for OLT. However, among those patients selected for OLT, the negative predictive value of DSE for both perioperative and long term cardiac events is high.
The family of p21-activated kinases (PAKs) has been shown to contain a domain that can independently bind to the Ras-like proteins Cdc42Hs and Rac. We have expressed a 72 amino acid recombinant form of this p21-binding domain (PBD) from mPAK-3 in Escherichia Coli for use in structure-function studies. The protein can be purified on a nickel affinity resin due to a hexa-His tag that is incorporated onto the amino terminus of the domain. PBD binds to Cdc42Hs in a guanine nucleotide-dependent manner as demonstrated by a novel fluorescence assay that takes advantage of the spectroscopic properties of N-methylanthraniloyl (Mant)-guanine nucleotides. Ionic strength has little effect on the affinity of PBD for Cdc42Hs, but alkaline pH values tend to weaken the interaction. We have shown that the inhibition of the GTPase activity of Cdc42Hs, as well as a previously undescribed inhibition of guanine nucleotide dissociation, is mediated by the PBD portion of the mPAK-3 molecule. These findings suggest that PBD binding alters the geometry of the guanine nucleotide binding site on Cdc42Hs, perhaps as an outcome of the target/effector molecule binding in close proximity to the nucleotide domain. We therefore tested if mutations in the effector region of Cdc42Hs (32-40), which in Ras are very close to the guanine nucleotide binding site, had any effect on PBD binding. Changing tyrosine 32 to lysine (Y32K) resulted in a small (5-fold) inhibition of PBD binding, but the very conservative mutation D38E yielded at least a 50-fold decrease in affinity. Finally, the catalytic domain of the GTPase activating protein, Cdc42-GAP, was shown to inhibit PBD binding in a competitive manner, indicating that this target molecule and the negative regulator (GAP) bind to overlapping sites on the Cdc42Hs molecule.
Hepatitis C virus (HCV) recurrence after liver transplantation (LT) is associated with worse outcomes. The combination of ledipasvir (LDV) and sofosbuvir (SOF) has been approved for HCV treatment after LT, but there are limited data on the effectiveness and safety of LDV/SOF in the "real-world" setting. This multicenter study is the largest report to date on the effectiveness and safety of LDV/SOF in the post-LT setting. A total of 204 patients (72% male, 68% Caucasian, 66% genotype [GT] 1a, 21% METAVIR F3-F4, 49% treatment-experienced) were treated with LDV/SOF. The mean duration from LT to treatment initiation was 4.8 years. The overall sustained virological response rate 12 weeks after completion of therapy (SVR12) was 96%. Patients treated with 8 or 12 weeks of LDV/SOF without RBV experienced an SVR12 rate of 100% and 96%, respectively. Calcineurin inhibitors were used in 89% of patients, and 32% of patients underwent adjustment in immunosuppression during treatment. One episode of mild rejection, responsive to an increase in immunosuppression dosage, was observed. There was no graft loss attributed to HCV treatment. Four deaths occurred unrelated to HCV treatment, and no significant serious adverse events were documented. In conclusion, SOF and LDV with or without RBV for 8, 12, or 24 weeks in post-LT patients was effective and safe with a high SVR12 rate across a spectrum of GTs and stages of fibrosis. Liver Transplantation 22 1536-1543 2016 AASLD.
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