Photoresponsive arylazopyrazole surfactant/PDADMAC mixtures: reversible control of bulk and interfacial properties.

In many applications of polyelectrolyte/surfactant (P/S) mixtures, it is difficult to fine-tune them after mixing the components without changing the sample composition, e.g. pH or the ionic strength. Here we report on a new approach where we use photoswitchable surfactants to enable drastic changes in both the bulk and interfacial properties. Poly(diallyldimethylammonium chloride) (PDADMAC) mixtures with three alkyl-arylazopyrazole butyl sulfonates (CnAAP) with -H, -butyl and -octyl tails are applied and E/Z photoisomerization of the surfactants is used to cause substantially different hydrophobic interactions between the surfactants and PDADMAC. These remotely controlled changes affect significantly the P/S binding and allows for tuning both the bulk and interfacial properties of PDADMAC/CnAAP mixtures through light irradiation. For that, we have fixed the surfactant concentrations at values where they exhibit pronounced surface tension changes upon E/Z photoisomerization with 365 nm UV light (Z) and 520 nm green (E) light and have varied the PDADMAC concentration. The electrophoretic mobility can be largely tuned by photoisomerisation of CnAAP surfactants and P/S aggregates, which can even exhibit a charge reversal from negative to positive values or vice versa. In addition, low colloidal stability at equimolar concentrations of PDADMAC with CnAAP surfactants in the E configuration lead to the formation of large aggregates in the bulk which can be broken up by irradiation with UV light when the surfactant's alkyl chain is short enough (C0AAP). Vibrational sum-frequency generation (SFG) spectroscopy reveals changes at the interface similar to the bulk, where the charging state at air-water interfaces can be modified with light irradiation. Using SFG spectroscopy, we interrogated the O-H stretching modes of interfacial H2O and provide qualitative information on surface charging that is complemented by neutron reflectometry, from which we resolved the surface excesses of PDADMAC and CnAAP at the air-water interface, independently.

[CHALLENGES IN LIVER TRANSPLANT 2023].

INTRODUCTION: Liver transplantation improves the survival and the quality of life of patients with liver failure and primary liver carcinoma. Candidates for liver transplantation are thoroughly evaluated to rule out infectious and malignant conditions that might deteriorate following the immune suppression so that their cardiovascular and pulmonary function can sustain them through the surgical procedure. Poor nutritional status, sarcopenia and frailty portend a poor prognosis before and after the transplantation. Steatohepatitis (NASH) emerges as the most common indication for liver transplantation due to liver cirrhosis and liver tumors. NASH patients are often elderly and have comorbidities such as cardiovascular disease, renal failure and sarcopenia. Particular effort should be invested to ameliorate these conditions in order to minimize waiting list dropout and to improve the outcome after surgery. The Israeli Ministry of Health is responsible for the regulation of organ transplants in Israel - by law. It organizes the procurement and allocation of organs and supervises all the transplant activity. All the candidates are listed on the national waiting list and the priority is allocated according to the MELD-Na. Transplant candidates who carry EDI cards (expressing their advanced directive of consent to organ donation after death) receive additional points on the waiting list. Acute liver failure, hepatopulmonary syndrome and hepatocellular carcinoma patients are prioritized according to their condition, as their MELD score does not reflect their prognosis. To overcome the continuous shortage of organs new techniques have been adopted such as living donor liver transplantation, better management of marginal livers, be they from brain dead donors or donations after circulatory death. The main challenges after liver transplantation are the metabolic syndrome and its complications, renal failure and malignancy. An aggressive, early preventive approach is highly recommended to promote a healthy lifestyle, optimize medical therapy and screen for malignancy.

Perinatal Outcomes after Liver Transplantation: Is There a Role for Aspirin Treatment?

BACKGROUND: We aimed to describe perinatal outcomes and evaluate aspirin treatment effects in liver-transplanted pregnant women. METHODS: A retrospective study examining perinatal outcomes in liver transplant recipients at a single center (2016-2022). The effect of low-dose aspirin treatment on the risk of developing hypertensive disease in these patients was evaluated. RESULTS: Fourteen deliveries in 11 pregnant liver transplant recipients were identified. Primary liver disease was Wilson's in 50% of pregnancies. The median age was 23 years at transplant and 30 at conception. Tacrolimus was administered in all, steroids in 10 (71.43%), and aspirin (100 mg daily) in 7 (50.0%). Overall, two women (14.28%) developed preeclampsia, and one (7.14%) developed gestational hypertension. Median gestational age at delivery was 37 weeks (31-39 weeks), with six preterm births (between 31-36 weeks) and a median birthweight of 3004 g(range 1450-4100 g). None of those receiving aspirin developed hypertensive disease or suffered excessive bleeding during pregnancy, compared to two (28.57%) with pre-eclampsia in the non-aspirin group. CONCLUSION: Liver-transplanted pregnant women comprise a unique and complex patient population with overall favorable pregnancy outcomes. Based on our single-center experience and due to its safety profile and potential benefit, we recommend low-dose aspirin in all liver transplanted patients during pregnancy for preeclampsia prevention. Further large prospective studies are needed to corroborate our findings.

Effect of Age on Liver Transplantation Recipient Outcomes: Two Centers' Experience.

BACKGROUND: Liver diseases epidemiology has changed with advances in perioperative care. Transplantation at large centers is favorable among older and younger recipients. Local limitations on transplantation for recipients older than 65 years were cancelled in 2014. This study evaluates the effects of age on the transplantation outcome of Israeli patients in the era after removal of the limitations on recipient age. METHODS: This retrospective analysis examined prospective data on patients older than 18 years who underwent liver or liver-kidney transplantation between 2014 and 2019 at 2 transplantation centers. Patients were divided into 4 age groups (group 1: ≤59 years; group 2: 60-64 years; group 3: 65-69 years; and group 4: ≥70 years). Each group's associations of pretransplantation factors with outcome and survival were examined. RESULTS: Two hundred sixty-one recipients underwent 269 transplantations (mean age: 53 ± 12.61 y). There were 181 male (67.8%) and 88 female recipients (67.28%). Overall, 207 patients (79.6%) survived ≥12 months. One-year survival rates were 82.9%, 73.2%, 71.4%, and 93.8% for groups 1 to 4, respectively (not statistically significant; P = .11). One-year graft survival was similar between groups. More patients with chronic obstructive pulmonary disease, diabetes mellitus, or ischemic heart disease tended to survive <12 months. Cardiovascular complication was more common in older groups and affected survival. CONCLUSION: Patient age alone should not be used to deny access to transplantation, which could benefit older nonfrail individuals. However, risk factors such as male sex, chronic obstructive pulmonary disease, ischemic heart disease, diabetes mellitus, and concomitant kidney-liver transplantation should be carefully considered.

Urgent Liver Transplantation for Acute Liver Failure in Pregnant Women: The Optimum Timing for Delivery.

BACKGROUND: The occurrence of acute liver failure (ALF) in pregnant women due to an etiology unrelated to pregnancy (pregALF) that leads to liver transplantation (LT) has rarely been reported. The objective was to report the outcome of pregnant women and fetus and propose a strategy for the timing of delivery and of LT in these patients. METHODS: Five consecutive pregnant patients with ALF were admitted to our center between 1986 and 2018 and underwent an LT. A systematic review of case reports concerning patients with pregALF who underwent LT was extracted from the literature. RESULTS: Three with gestational ages (GA) at admission of 15, 22, and 31 weeks of gestation (WG) were transplanted after delivery (n = 1) or intrauterine demise (n = 2) and 2 with GA of 16 and 23 WG before delivery. One infant survived in each group. Among the 32 cases published previously, 11 (34%) had been transplanted after delivery (median GA:31 [28-33]); 10 of these 11 infants were alive at birth. The other 21 mothers were transplanted before delivery (GA:21 WG [18-22]). The median GA at delivery was 30 WG [27.75-37]. Twelve of 21 infants were alive at birth. One-year survival among the ALF patients in our series and in the literature was 100%. Overall, the perinatal survival rate was low (64.8%). CONCLUSIONS: In pregnant patients presenting with ALF not related to the pregnancy, the LT lifesaving procedure had an excellent outcome. Overall, 65% of the infants were alive at delivery with major mortality in those fetus <22 WG despite continued pregnancy.

The association between chronic liver diseases and preeclampsia.

BACKGROUND: Preeclampsia is a multisystem disorder characterized by an abnormal vascular response to placentation associated with increased systemic vascular resistance. As liver involvement is one of the main clinical features of preeclampsia, we sought to determine if there is an association between chronic liver diseases and preeclampsia. METHODS: A retrospective matched case-control analysis was conducted in a tertiary medical center. Three hundred eleven (311) pregnant women with preexisting chronic liver disease (study group), including viral and autoimmune hepatitis, non-alcoholic fatty liver, Wilson disease, and cirrhosis, were match for age, parity, and number of fetuses to 933 healthy pregnant women (control group). The primary outcome measure was the incidence of preeclampsia in each group. Secondary outcome measures were obstetrical and neonatal complications. Confounders found to be significant on univariate analysis were evaluated using logistic regression models, and odds ratios (OR) and confidence intervals (CI) were calculated. RESULTS: Preeclampsia was diagnosed in 28 women (9.0%) in the study group and 33 women (3.54%) in the control group (p < 0.001). On multivariate analysis adjusted for maternal age, parity, previous preeclampsia, chronic hypertension, gestational diabetes mellitus, pregestational diabetes mellitus, antiphospholipid syndrome, and mode of conception, chronic liver disease was found to be an independent risk factor for preeclampsia (aOR 2.631, 95% CI 1.518-4.561). Although there was no difference in the gestational week at delivery between the groups (38.6 ± 2.13 vs. 38.8 ± 2.17 for study and control group, respectively, p = 0.410), the study group had a lower mean neonatal birthweight (3088 ± 551 vs. 3182 ± 566 g, p = 0.011). There were no between-group differences in the other parameters evaluated. CONCLUSION: In our study, preexisting chronic liver disease was associated with a 2.6-fold increased risk of preeclampsia.

Food processing by-products and wastes as potential dust suppressants at mine sites: Results from unconfined compressive strength testing.

The application of dust suppressants is an effective technique to reduce fugitive emissions, but commercially available products are costly and may harm the environment. By contrast, wastes and by-products from food production and processing can be sustainable alternatives, as they are biodegradable, considered cost-effective and have adhesive properties. The study aimed to investigate the application potential of biogenic wastes and by-products from the food industry to control dust emissions from mine soils. Unconfined compressive strength tests (UCS) were conducted on medium- to coarse-grained sand treated with sixteen biomaterials at two different additive concentrations (2 wt%, 4 wt%). UCS tests showed that rinsing water from jam production (1,366 kPa), corn steep liquor (1,502 kPa), chicory vinasses (1,723 kPa), decantation syrup (2,026 kPa) and palatinose molasses (7,535 kPa) significantly enhanced the mechanical strength of the substrate (11 kPa), indicating a strong potential of these biomaterials as dust suppressants. Such biomaterials that contained biopolymers and not only mono- and disaccharides achieved on average higher UCS values, possibly due to the formation of 3D-network structures. Moreover, the data indicated a low potential for substances with high glucose and fructose content, as they had minor or no impact on soil strength.Implications: The UCS test results indicate that food processing wastes and by-products can be sustainable alternatives to existing dust suppressants. Hence, the present study supports an environmentally friendly and cost-effective dust control of exposed surfaces at mine and mineral processing sites and provides new markets for the food industry's wastes and by-products. Moreover, this research extends our understanding of dust suppressant treatment of soils and contributes to evaluating biogenic food processing wastes and by-products as environmentally benign dust suppressants.

Using population-level incidence of hepatitis C virus and immigration status for data-driven screening policies: a case study in Israel.

BACKGROUND: Most studies estimate hepatitis C virus (HCV) disease prevalence from convenience samples. Consequently, screening policies may not include those at the highest risk for a new diagnosis. METHODS: Clalit Health Services members aged 25-74 as of 31 December 2009 were included in the study. Rates of testing and new diagnoses of HCV were calculated, and potential risk groups were examined. RESULTS: Of the 2 029 501 included members, those aged 45-54 and immigrants had lower rates of testing (12.5% and 15.6%, respectively), higher rates of testing positive (0.8% and 1.1%, respectively), as well as the highest rates of testing positive among tested (6.1% and 6.9%, respectively). DISCUSSION: In this population-level study, groups more likely to test positive for HCV also had lower rates of testing. Policy makers and clinicians worldwide should consider creating screening policies using on population-based data to maximize the ability to detect and treat incident cases.

Randomised clinical trial: A phase 2 double-blind study of namodenoson in non-alcoholic fatty liver disease and steatohepatitis.

BACKGROUND: Namodenoson, an A3 adenosine receptor (A3AR) agonist, improved liver function/pathology in non-alcoholic steatohepatitis (NASH) preclinical models. AIM: To evaluate the efficacy and safety of namodenoson for the treatment of non-alcoholic fatty liver disease (NAFLD) with or without NASH METHODS: This phase 2 study included 60 patients with NAFLD (ALT ≥60 IU/L) who were randomised (1:1:1) to oral namodenoson 12.5 mg b.d. (n = 21), 25 mg b.d. (n = 19), or placebo (n = 20) for 12 weeks (total follow-up: 16 weeks). The main efficacy endpoint involved serum ALT after 12 weeks of treatment. RESULTS: Serum ALT decreased over time with namodenoson in a dose-dependent manner. The difference between change from baseline (CFB) for ALT in the namodenoson 25 mg b.d. arm vs placebo trended towards significance at 12 weeks (P = 0.066). Serum AST levels also decreased with namodenoson in a dose-dependent manner; at 12 weeks, the CFB for 25 mg b.d. vs placebo was significant (P = 0.03). At Week 12, 31.6% in the namodenoson 25 mg b.d. arm and 20.0% in the placebo arm achieved ALT normalisation (P = 0.405). At week 16, the respective rates were 36.8% and 10.0% (P = 0.038). A3AR expression levels were stable over time across study arms. Both doses of namodenoson were well tolerated with no drug-emergent severe adverse events, drug-drug interactions, hepatotoxicity, or deaths. Three adverse events were considered possibly related to study treatment: myalgia (12.5 mg b.d. arm), muscular weakness (25 mg b.d. arm), and headache (25 mg b.d. arm). CONCLUSION: A3AR is a valid target; namodenoson 25 mg b.d. was safe and demonstrated efficacy signals (ClinicalTrials.gov #NCT02927314).

Long-term outcomes of Roux-en-Y gastric bypass or sleeve gastrectomy in patients with cirrhosis; before, during or after liver transplantation: A single center's experience.

BACKGROUND: The increasing prevalence of morbid obesity (MO) results in parallel growth of obesity-associated liver diseases necessitating liver transplantation (LT). OBJECTIVE: To examine the feasibility and safety of Roux-en-Y gastric bypass or sleeve gastrectomy in the setting of LT. METHODS: This retrospective chart review included the data on all the MO candidates before and after LT who underwent bariatric surgery (BS) in our institution between 04/2013-09/2016. The reported outcomes were weight change and early and late postoperative complications (mean follow-up: 43 ± 11.1 months). RESULTS: Eighteen MO peri-LT patients (10 females, 8 males, average age 48 years) were included in the study. Ten had cirrhosis (mean Model of End-stage Liver Disease [MELD] score of 12.5 ± 6.42), three underwent concurrent LT and BS (mean MELD score 23.7 ± 0.58), and five had LT (mean of 56 months from LT). The mean percentage of total and excess weight loss was 31% and 81%, respectively. Six of the eight patients with type 2 diabetes mellitus became normoglycemic after BS. Three patients sustained perioperative complications. Two cirrhotic patients died 1 and 4.5 years after BS with decompensation. CONCLUSIONS: Bariatric surgery appears to effectively address obesity in cirrhotic and LT patients. The surgical risk is higher than that of the regular BS population.

Response guided therapy for reducing duration of direct acting antivirals in chronic hepatitis C infected patients: a Pilot study.

The advent of direct-acting antivirals (DAAs) has transformed the landscape of hepatitis C virus (HCV) management. We aimed to prospectively (real-time) evaluate the feasibility of using a response-guided therapy approach, based on mathematical modeling of early viral kinetics, to reduce the duration of DAAs therapy. Patients were treated with DAAs according to the physicians' preference. HCV was measured at baseline and at day 2 and weeks 1, 2 and 4 after treatment initiation. The primary endpoint was the proportion of patients with sustained-virological response (SVR) at 12 and/or 24 weeks post-treatment. Twenty-nine patients (mean age 54 ± 16, 44% females, 73% with HCV genotype 1), were enrolled and all completed therapy. Treatment duration was shortened in 11 of the 29 patients (38%). SVR was achieved in 28 of the 29 patients (97%). Relapse occurred post treatment in a single case of a non-cirrhotic male with genotype 3, who was treated with sofosbuvir/velpatasvir for 6 weeks. Virus sequencing did not identify baseline or treatment emergent resistance associated substitutions. Real-time mathematical modeling of early HCV kinetics can be utilized for shortening DAAs duration in approximately 40% of patients without compromising treatment efficacy.Clinical trial registration: ClinicalTrials.gov Identifier: NCT03603327.

Post-transplant diabetes mellitus: incidence, predicting factors and outcomes.

PURPOSE: To identify predictors and evaluate outcomes of posttransplant diabetes mellitus (PTDM) and to investigate the effect of treatment modalities on outcomes. METHODS: The database of a tertiary medical center was searched for all adult patients without prior diabetes who underwent lung, liver, or heart transplantation between January 1, 2012 and June 30, 2018. Patients in whom PTDM (defined as HbA1C ≥ 6.5% at least 3 months post transplantation) developed during follow-up (mean 3.32 years) were identified. Risk factors for PTDM, determined by regression analysis and clinical outcomes [all-cause mortality, severe infections, graft loss, and major adverse cardiovascular events (MACE)], were compared between those who developed PTDM and those who did not; in the former, insulin-based therapy was compared with non-insulin regimen. RESULTS: The cohort included 281 transplant recipients: 158 lung, 109 liver, and 14 heart. PTDM was diagnosed in 60 (21.35%) patients at a mean of 11.3 ± 12.89 months post transplantation. The only significant independent risk factor for PTDM was age (HR 1.028, 95% CI = 1.002-1.054, P = 0.0314). PTDM was associated with higher rates of severe infections (HR 2.565, 95% CI = 1.626-4.050, P < 0.0001), MACE (HR 1.856, 95% CI = 1.013-3.401, P = 0.0454) and death (HR 1.840, 95% CI = 1.024-3.304, P = 0.0413). Recipients treated with insulin-based regimens had a higher risk of severe infections (HR 2.579, 95% CI = 1.640-4.055, P < 0.0001), MACE (1.925, 95% CI = 1.074-3.451, P = 0.0278) and death (HR 1.960, 95% CI = 1.071-3.586, P = 0.0291). CONCLUSIONS: PTDM is associated with increased mortality and poor outcomes in lung, liver, and heart transplant recipients. Early identification and aggressive treatment of PTDM and its associated cardiometabolic risk factors may improve outcomes.

Intrahepatic cholestasis of pregnancy as a risk factor for preeclampsia.

PURPOSE: Intrahepatic cholestasis of pregnancy and preeclampsia are two major pregnancy complications. We aimed to investigate the association between intrahepatic cholestasis of pregnancy (ICP) and preeclampsia. METHODS: Single-center retrospective study. Study group included 180 women (162 singletons and 18 twin gestations) who were diagnosed with ICP based on clinical presentation, elevated liver enzymes and bile acids. The reference group included 1618 women (1507 singletons and 111 twin gestations) who delivered during the study period, and were matched according to age, gravidity, parity and singleton or twin gestation. RESULTS: The incidence of ICP was 0.36%. The incidence of preeclampsia was higher in women with ICP compared to reference group (7.78% vs 2.41%, aOR, 3.74 95% CI 12.0-7.02, p < 0.0001), for either without-(3.89% vs 1.61%, aOR 2.83, 95% CI 1.23-6.5, p = 0.145) or with severe features (3.89% vs 0.80%, aOR 5.17 95% CI 2.14-12.50, p = 0.0003). For both singleton and twin pregnancies, overall preeclampsia rates were higher in the ICP group (5.56% vs 2.19%, aOR 2.91 95% CI 1.39-6.07 p = 0.0045; and 27.78% vs 5.41%, aOR 10.9 95% CI 2.16-47.19, p = 0.0033, respectively). Earlier diagnosis of ICP was associated with higher incidence of preeclampsia (31.1 ± 3.8 vs 34.86 ± 6.2 gestational weeks, p = 0.0259). The average time between ICP diagnosis and to the onset of preeclampsia was 29.7 ± 24 days. CONCLUSION: ICP is associated with an increased risk for preeclampsia. We suggest intensified follow-up for preeclampsia in women with ICP, especially among those with early ICP presentation and twins' gestations.

Liver steatosis is a major predictor of poor outcomes in chronic hepatitis C patients with sustained virological response.

Sustained virological response (SVR) results in reduced incidence of hepatocellular carcinoma (HCC) and mortality among chronic hepatitis C (CHC) patients with advanced fibrosis. Since both advanced fibrosis and liver steatosis (LS) may coexist in CHC patients, we evaluated their individual effects on a composite outcome of all-cause mortality and HCC in CHC patients with SVR following direct-acting antivirals (DAA) treatment. We retrospectively evaluated inception cohort of 515 CHC patients who achieved SVR following treatment with DAA, with a mean follow-up of 24 months. Baseline liver fibrosis was assessed by transient elastography, and LS was validated by at least three independent ultrasonographic examinations. 211 of 515 patients (41%) had baseline LS. Patients with LS had a higher cumulative rate of all-cause mortality and HCC at 2 years of follow-up compared to patients without LS (15.75% and 2.79%, respectively, P < 0.001), although they did not have increased incidence of advanced fibrosis or cirrhosis. Consistently, multivariate analysis showed that LS was associated with a significant 7.5-fold increased risk of all-cause mortality and HCC (HR 7.51, 95% C.I 3.61-13.36, P < 0.001) even upon adjustment to components of the metabolic syndrome, whereas advanced fibrosis showed only a trend towards statistical significance (HR 2.32, 95% C.I 0.97-6.59, P = 0.06). In conclusion, LS is a major predictor of all-cause mortality and HCC in patients who achieved SVR following DAA treatment regardless of fibrosis stage. These patients should be rigorously screened for HCC.

High frequency of multiclass HCV resistance-associated mutations in patients failing direct-acting antivirals: real-life data.

BACKGROUND: Direct-acting antiviral (DAA) therapy has dramatically increased sustained virological response rates in HCV-infected patients. However, resistance-associated substitutions (RAS) interfering with NS3- and NS5A-targeted therapy, still emerge. This real-life study analysed the type and frequency of RAS in rare cases of patients failing DAA regimens in 12 clinical centres in Israel. METHODS: Blood samples and clinical data from 49 patients who failed various DAAs were collected. RAS identified in the NS3 and NS5A regions by population (Sanger) and next-generation sequencing (NGS) were compared by treatment regimen and HCV subtypes. RESULTS: The majority (71.4%, 35/49) of patients were infected with the genotype (GT)1b strain, while 12.2% (6/49) carried GT1a and 14.3% GT3a/b (7), GT4a (1) and GT1b/GT3a. RAS were identified in 85.7% (42/49) of failures, of which 90.5% (38/42) were clinically relevant RAS (known to be associated with a specific GT and DAA in patients failing therapy or those with more than twofold change in in vitro replicon assays). The most abundant RAS were 168A/E/Q/G/N/V (32.6%, 16/49) identified in NS3, and 93H/N (61.2%, 30/49), 31I/M/V (34.7%, 17/49) and 30R/H/K (12.2%, 6/49), identified in NS5A. Significantly more clinically relevant RAS were identified in NS5A (82.2%, 37/45) than in NS3 (35.7%, 10/28; P<0.01). While RAS were identified in all GT1a, GT3b and GT4a failures (100%, 10/10), only 71.8% (28/39) of GT1b or GT3a failures had RAS (P=0.09). In four cases, NGS identified additional clinically relevant RAS and in one patient, NGS deciphered coexistence of GT3a and GT1b infections. CONCLUSIONS: Our findings, together with additional real-life data, will contribute to the optimization of retreatment in DAA failure, when cost-related and suboptimal regimens must be employed.

Lusutrombopag for the Treatment of Thrombocytopenia in Patients With Chronic Liver Disease Undergoing Invasive Procedures (L-PLUS 2).

Thrombocytopenia may be associated with increased bleeding risk impacting timing and outcome of invasive procedures in patients with chronic liver disease (CLD). Lusutrombopag, a small-molecule, thrombopoietin (TPO) receptor agonist, was evaluated as a treatment to raise platelet counts (PCs) in patients with thrombocytopenia and CLD undergoing invasive procedures. L-PLUS 2 was a global, phase 3, randomized, double-blind, placebo-controlled study. Adults with CLD and baseline PCs < 50 × 109 /L were randomized to receive once-daily lusutrombopag 3 mg or placebo ≤ 7 days before an invasive procedure scheduled 2-7 days after the last dose. The primary endpoint was avoidance of preprocedure platelet transfusion and avoidance of rescue therapy for bleeding. A key secondary endpoint was number of days PCs were ≥ 50 × 109 /L throughout the study. Safety analysis was performed on patients who received at least one dose of study drug. This study occurred between June 15, 2015, and April 19, 2017, with a total of 215 randomized patients (lusutrombopag, 108; placebo, 107); 64.8% (70/108) of patients in the lusutrombopag group versus 29.0% (31/107) in the placebo group met the primary endpoint (P < 0.0001; difference of proportion 95% confidence interval [CI], 36.7 [24.9, 48.5]). The median duration of PCs ≥ 50 × 109 /L was 19.2 days with lusutrombopag (without platelet transfusion) compared with 0.0 in the placebo group (with platelet transfusion) (P = 0.0001). Most adverse events were mild or moderate in severity, and rates were similar in the lusutrombopag and placebo groups (47.7% and 48.6%, respectively). Conclusion: Lusutrombopag was superior to placebo for reducing the need for platelet transfusions and achieved durable PC response in patients with thrombocytopenia and CLD undergoing invasive procedures, with a safety profile similar to placebo.

The Pattern of Elevated Liver Function Tests in Nonalcoholic Fatty Liver Disease Predicts Fibrosis Stage and Metabolic-Associated Comorbidities.

BACKGROUND: Patients with nonalcoholic fatty liver disease (NAFLD) and with abnormal liver function tests (LFTs) most commonly present with elevated hepatocellular enzymes (H pattern), but a subset of patients is found to have elevated cholestatic enzymes (C pattern) or a mixed (M) pattern. AIMS AND METHODS: To determine whether the epidemiologic background and comorbidities, as well as the degree of liver fibrosis, differ between NAFLD patients with different patterns of elevated LFTs by retrospectively analyzing data of 106 patients with a biopsy-proven diagnosis of NAFLD. The pattern of elevated LFTs was determined by adopting the "R-Ratio" formula commonly used for drug-induced liver injury. RESULTS: Advanced fibrosis (F > 2) was found in 15 out of 48 (31.3%) patients with a C pattern of elevated LFTs as compared to 2 out of 44 (4.5%) in M patients and 2 out of 11 (18.2%) in H patients (p = 0.004). Group C patients are older and also had a higher prevalence of diabetes, a higher mean hemoglobin A1c, and a higher prevalence of hypertension, as well as a trend for a higher prevalence of hypertriglyceridemia. CONCLUSIONS: Using a simple formula incorporating routine LFTs can help to categorize NAFLD patients as low or high risk for advanced fibrosis stage and metabolic-associated comorbidities.

Liver steatosis is a strong predictor of mortality and cancer in chronic hepatitis B regardless of viral load.

Liver steatosis may occur concomitantly in patients with chronic hepatitis B infection (CHB) and is implicated in increased morbidity and mortality. Hepatitis B virus (HBV) viral load is a marker for disease progression and long-term outcomes in CHB. We investigated the association between liver steatosis and HBV viral load and their individual effects on all-cause mortality and the development of cancer in patients with CHB and liver steatosis. METHODS: This retrospective study included 524 treatment-naïve patients with CHB, with a mean follow-up of 6 years. Liver biopsy was available for 170 patients and liver steatosis was validated by at least 3 ultrasonographic examinations. RESULTS: A total of 241/524 (46%) patients with CHB had liver steatosis, with a strong correlation between the degree of liver steatosis as assessed by ultrasonography or by liver biopsy (r = 0.9, p < 0.001). Although liver steatosis was not significantly associated with advanced fibrosis, a multivariate analysis showed that liver steatosis was associated with a 4-fold increased risk of all-cause mortality and cancer (hazard ratio 4.35; 95% CI 1.69-8.99; p < 0.001), irrespective of other major metabolic factors. However, baseline HBV viral load was not significantly associated with this composite outcome (hazard ratio 1.65; p = 0.29). In addition, liver steatosis was inversely associated with HBV viral load. CONCLUSION: Patients with CHB and liver steatosis have an increased risk of all-cause mortality and cancer development compared to patients with CHB without liver steatosis, regardless of their baseline HBV viral load. Although tending to have a lower baseline viral load, patients with CHB and liver steatosis should be closely monitored irrespective of viral load. LAY SUMMARY: Patients with chronic hepatitis B infection (CHB) may have liver steatosis at the same time. Here we show that in patients with CHB, liver steatosis is significantly associated with all-cause mortality and cancer, irrespective of other major metabolic factors, and the effect of liver steatosis on mortality and cancer is stronger than the effect of hepatitis B viral load on these outcomes. Thus, patients with CHB and liver steatosis should be closely monitored, irrespective of their viral load.