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Hepatitis B virus (HBV) is a small double-stranded DNA virus that chronically infects 296 million people. Over half of its compact genome encodes proteins in two overlapping reading frames, and during evolution, multiple selective pressures can act on shared nucleotides. This study combines an RNA-based HBV cell culture system with deep mutational scanning (DMS) to uncouple cis- and trans-acting sequence requirements in the HBV genome. The results support a leaky ribosome scanning model for polymerase translation, provide a fitness map of the HBV polymerase at single-nucleotide resolution, and identify conserved prolines adjacent to the HBV polymerase termination codon that stall ribosomes. Further experiments indicated that stalled ribosomes tether the nascent polymerase to its template RNA, ensuring cis-preferential RNA packaging and reverse transcription of the HBV genome., Competing Interests: Declaration of interests Y.Y., W.M.S., and C.M.R. filed a patent application, US 62/741,032, with Rockefeller University on September 19, 2019, entitled “RNA-Based Methods to Launch Hepatitis B Virus Infection.” Patent pending. C.M.R. is a shareholder and member of the scientific advisory board at VIR Biotechnology., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Imaging-based assessment of sarcopenia is a well-validated prognostic tool for patients with chronic liver disease. However, little is known about its value in patients with primary sclerosing cholangitis (PSC). This cross-sectional study aimed to investigate the predictive value of the cross-sectional imaging-based skeletal muscle index (SMI) for transplant-free survival (TFS) in patients with PSC., Methods: A total of 95 patients with PSC who underwent abdominal cross-sectional imaging between 2008 and 2022 were included in this retrospective study. SMI was measured at the third lumbar vertebra level (L3-SMI). The cut-off values to define sarcopenia were < 50 cm²/m² in male patients and < 39 cm²/m² in female patients. The primary outcome of this study was TFS, which was defined as survival without liver transplantation or death from any cause., Results: Our study indicates that L3-SMI sarcopenia impairs TFS in patients with PSC (5-year TFS: 33.9% vs. 83.3%, p = 0.001, log-rank test). L3-SMI sarcopenia was independently associated with reduced TFS via multivariate Cox regression analysis (HR = 2.749; p = 0.028). Body mass index reduction > 10% at 12 months, which is used as MELD standard exception (SE) criterion in Eurotransplant (in Germany only until September 2023), was not significantly associated with TFS in the multivariate Cox regression analysis (HR = 1.417; p = 0.330). Substitution of BMI reduction with L3-SMI in the German SE criteria improved the predictive accuracy of TFS compared to the established SE criteria (multivariable Cox regression analysis: HR = 4.007, p < 0.001 vs. HR = 1.691, p = 0.141)., Conclusion: Imaging-based diagnosis of sarcopenia via L3-SMI is associated with a low TFS in patients with PSC and may provide additional benefits as a prognostic factor in patient selection for liver transplantation., (© 2024. The Author(s).)

Background and Aims: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an established procedure to treat portal hypertension. Impact of administration of aspirin on transplant-free survival after TIPS remains unknown., Methods: A multicenter retrospective analysis including patients with TIPS implantation between 2011 and 2018 at three tertiary German Liver Centers was performed. N = 583 patients were included. Survival analysis was performed in a matched cohort after propensity score matching. Patients were grouped according to whether aspirin was (PSM-aspirin-cohort) or was not (PSM-no-aspirin-cohort) administered after TIPS. Primary endpoint of the study was transplant-free survival at 12 months after TIPS., Results: Aspirin improved transplant-free survival 12 months after TIPS with 90.7% transplant-free survival compared to 80.0% (p = 0.001) after PSM. Separated by TIPS indication, aspirin did improve transplant-free survival in patients with refractory ascites significantly (89.6% vs. 70.6% transplant-free survival, p < 0.001), while no significant effect was observed in patients with refractory variceal bleeding (91.1% vs. 92.2% transplant-free survival, p = 0.797)., Conclusion: This retrospective multicenter study provides first data indicating a beneficial effect of aspirin on transplant-free survival after TIPS implantation in patients with refractory ascites., (© 2022. The Author(s).)

Surgery has become well established for patients with colorectal and neuroendocrine liver metastases. However, the value of this procedure in non-colorectal and non-neuroendocrine metastases (NCRNNELMs) remains unclear. We analyzed the outcomes of patients that underwent liver surgery for NCRNNELMs and for colorectal liver metastases (CRLMs) between 2012 and 2017 at our institution. Prognostic factors of overall and recurrence-free survival were analyzed, and a comparison of survival between two groups was performed. Seventy-three patients (30 NCRNNELM and 43 CRLM) were included in this study. Although the mean age, extrahepatic metastases, and rate of reoperation were significantly different between the groups, recurrence-free survival was comparable. The 5-year overall survival rates were 38% for NCRNNELM and 55% for CRLM. In univariate analysis, a patient age of ≥60 years, endodermal origin of the primary tumor, and major complications were negative prognostic factors. Resection for NCRNNELM showed comparable results to resection for CRLM. Age, the embryological origin of the primary tumor, and the number of metastases might be the criteria for patient selection.

Prophylactic donor lymphocyte infusions (DLI) are part of the sequential FLAMSA-reduced intensity conditioning (RIC) regimen to cure high risk myeloid neoplasia with allogeneic hematopoietic stem cell transplantation (HSCT). Although DLI themselves carry significant risks, their prophylactic use has not been analyzed in a time-dependent manner. One hundred and fourteen patients underwent FLAMSA-RIC HSCT between 2013 and 2020. Next to Kaplan-Meier estimation of overall, disease-free, and graft-versus-host relapse-free survival (OS, DFS, GRFS), cumulative incidences of relapse and death in remission were calculated in a competing risk model. Additionally, the contribution of prophylactic and preemptive DLI as time-dependent covariates was assessed using a time-varying model toward DFS (Simon-Makuch method, Mantel-Byar test). At 2 years, OS was 45.2% [95% CI 36.7-55.7%], DFS 31.8% [95% CI 24-42.2%] and GRFS 11.3 [95% CI 6.5-19.8]. Neither prophylactic nor preemptive DLI showed a significant influence on DFS when considered time-dependent covariates (Mantel-Byar, p = .3). This was further corroborated in competing risk analysis with DLI as time-dependent covariates. Both prophylactic and preemptive DLI miss significance in their impact on survival within a high-risk cohort in a time-varying model. Controlled trials to address the impact of postgrafting immunotherapy approaches are needed., (© 2021 The Authors. European Journal of Haematology published by John Wiley & Sons Ltd.)

Background: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an established procedure to treat portal hypertension with hepatic encephalopathy (HE) as a common complication. There is lack of evidence concerning HE prophylaxis after TIPS., Methods: N = 233 patients receiving TIPS between 2011 and 2018 at a German tertiary care center were included. Of them, 21% (n = 49) had a history of HE. The follow-up period was 12 months. The risk factors of post-TIPS HE were analyzed via multivariate analysis. The efficacy of prophylactic medication regimens was studied. The results show that 35.6% (n = 83) received no medication ( NM ), 36.5% (n = 85) received lactulose monoprophylaxis ( LM ), 2.6% (n = 6) rifaximin monoprophylaxis ( RM ) and 25.3% (n = 59) lactulose and rifaximin ( LR ) of which 64.4% received l-ornithin-l-aspartate ( LOLA ) additionally ( LR + LOLA ) and 36.6% did not ( LRonly )., Results: Multivariate analysis revealed higher age ( p = 0.003) and HE episodes prior to TIPS ( p = 0.004) as risk factors for HE after TIPS. LM has no prophylactic effect. LR prevents HE recurrence at 1, 3 and 12 months after TIPS ( p = 0.003, p = 0.003, p = 0.006) but does not prevent HE in patients with no history of HE ( p = 0.234, p = 0.483, p = 0.121). LR prevents HE recurrence compared with LM/NM (25.0% vs. 64.7%, p = 0.007) within 12 months after TIPS, whereas de novo occurrence is unaffected ( p = 0.098). The additional administration of LOLA to LR has no benefit ( LRonly : 25.0%, LR + LOLA : 29.7%, p = 0.780)., Conclusions: Higher age and previous HE are risk factors post-TIPS HE. In patients with HE prior to TIPS, effective prophylaxis of HE is feasible via combination of lactulose and rifaximin with no additional benefit from LOLA .

Transjugular intrahepatic portosystemic shunt (TIPS) is the most effective measure to treat complications of portal hypertension. However, liver function may deteriorate after TIPS. Predictors of liver function and outcome after TIPS are therefore important for management of TIPS patients. The study aimed to evaluate the impact of liver volume on transplant-free survival (TFS) after TIPS, as well as the evolution of liver volume and its relationship with liver function after TIPS. A retrospective analysis of all consecutive patients who underwent TIPS in a tertiary care university liver center between 2012 and 2017 ( n = 216) was performed; n = 72 patients with complete prior and follow-up (FU) computed tomography (CT) imaging studies were included in the study. Volumetry of the liver was performed by a semi-automatic 9-lobe image segmentation algorithm at baseline and FU (FU 1: 90-180 d; FU 2: 180-365 d; FU 3: 365-545 d; FU 4: 545-730 d; FU 5: >730 d). Output variables were total liver volume (TLV, cm 3 ), left liver volume (LLV, cm 3 ), right liver volume (RLV, cm 3 ) and TLV/body weight ratio. CT derived liver volumes were correlated with liver function tests, portosystemic pressure gradient (PPG) measurements and survival. To assess predictors of liver volume change over time we fitted linear mixed models. Kaplan-Meier analysis was performed and validated by matched pair analysis followed by Cox regression to determine independent prognostic factors for survival. The median TLV at baseline was 1507.5 cm 3 (773.7-3686.0 cm 3 ). Livers with higher baseline liver volumes and larger TLV/weight ratios retained their volume after an initial loss while smaller livers continuously lost volume after TIPS. At the first follow-up period (90-180 d post-TIPS) lower liver volumes and TLV/weight ratios were associated with higher bilirubin levels. Within the final multivariable model containing time (days since TIPS), baseline INR and baseline TLV, the average loss of liver volume was 0.74 mL per day after TIPS. Twelve-month overall transplant-free survival was 89% and median overall TFS was 33 months. The median TFS for a baseline TLV/body weight ratio > 20 was significantly higher compared with ≤20 (40.0 vs. 27.0 months, p = 0.010) while there were no differences regarding the indication for TIPS or etiology of liver disease in the matched pair analysis. Lower TLV/weight ratios before TIPS were associated with shorter TFS and should therefore be critically considered when selecting patients for TIPS. In addition, this study provides first evidence of an effect of TIPS on subsequent liver volume change and associated liver function.

Background & Aims: Transjugular intrahepatic portosystemic shunt (TIPS) implantation is an effective and safe treatment for complications of portal hypertension. Survival prediction is important in these patients as they constitute a high-risk population. Therefore, the aim of our study was to develop an alternative prognostic model for accurate survival prediction after planned TIPS implantation., Methods: A total of 1,871 patients with de novo TIPS implantation for ascites or secondary prophylaxis of variceal bleeding were recruited retrospectively. The study cohort was divided into a training set (80% of study patients; n = 1,496) and a validation set (20% of study patients; n = 375). Further, patients with early (preemptive) TIPS implantation due to variceal bleeding were included as another validation cohort (n = 290). Medical data and overall survival (OS) were assessed. A Cox regression model was used to create an alternative prediction model, which includes significant prognostic factors., Results: Age, bilirubin, albumin and creatinine were the most important prognostic factors. These parameters were included in a new score named the Freiburg index of post-TIPS survival (FIPS). The FIPS score was able to identify high-risk patients with a significantly reduced median survival of 5.0 (3.1-6.9) months after TIPS implantation in the training set. These results were confirmed in the validation set (median survival of 3.1 [0.9-5.3] months). The FIPS score showed better prognostic discrimination compared to the Child-Pugh, MELD, MELD-Na score and the bilirubin-platelet model. However, the FIPS score showed insufficient prognostic discrimination in patients with early TIPS implantation., Conclusions: The FIPS score is superior to established scoring systems for the identification of high-risk patients with a worse prognosis following elective TIPS implantation., Lay Summary: Implantation of a transjugular intrahepatic portosystemic shunt (TIPS) is a safe and effective treatment for patients with cirrhosis and clinically significant portal hypertension. However, risk stratification is a major challenge in these patients as currently available scoring systems have major drawbacks. Age, bilirubin, albumin and creatinine were included in a new risk score which was named the Freiburg index of post-TIPS survival (FIPS). The FIPS score can identify patients at high risk and may guide clinical decision making., Competing Interests: Conflict of interest JT: Grants: Gore, Consultant: Martins Pharma, Ironwood, Gore, Alexion, BMS, Grifols, Sequana Medicals, Versantis, Sponsored lectures (National or International): Gilead, Gore, Alexion, BMS, Grifols, Sequana Medicals, Norgine, Intercept. DB: Consultant: Bayer Healthcare, Boston Scientific, Shionogi. Lectures: Falk Foundation. LS: Lectures: Falk Foundation. RK: Consultant: Boston Scientific, Bristol-Myers Squibb, Guerbet, Roche, and SIRTEX. Lectures: BTG, Guerbet, Ipsen, SIRTEX, MSD Sharp & Dohme. MS: Consultant: Bayer Healthcare, L.W.Gore Lectures: Falk Foundation. Please refer to the accompanying ICMJE disclosure forms for further details., (Copyright © 2021 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.)

Introduction:  In the management of patients with decompensated liver cirrhosis, transjugular intrahepatic portosystemic shunt (TIPS) insertion is well-established but common recommendations in the follow up management are inconsistent. Doppler sonography is commonly used for detection for TIPS dysfunction whilst data on the impact of elective invasive examinations are scarce., Aim:  The aim of this retrospective analysis is to evaluate potential benefits of elective invasive examinations in the follow up management of patients after TIPS insertion METHODS:  Data of all patients receiving TIPS at the university hospitals of Muenster and Bonn between 2013 and 2018 (n = 534) were collected. The impact of performance of elective invasive examinations at 12 months after TIPS insertion on the occurrence of liver related events (LREs) and frequency of TIPS revisions within 24 months after TIPS insertion was analyzed., Results:  No significant differences were found concerning occurrence of liver related events after 24 months depending on whether an elective invasive examination was performed. Occurrence of hepatic encephalopathy, relapse of initial indication for TIPS, as well as death or liver transplantation all did not differ. These findings were verified by a subgroup analysis including only patients who did not experience a LRE or TIPS revision within the first 12 months after TIPS procedure., Conclusion:  The analyzed data suggest no evidence for a beneficial impact due to implementation of an elective invasive examination program after TIPS insertion. Invasive examinations should remain reserved to patients with suspected TIPS dysfunction., Competing Interests: The authors declare that they have no conflict of interest., (Thieme. All rights reserved.)

Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons., Competing Interests: The authors have declared that no competing interests exist.

BACKGROUND Direct-acting antivirals (DAAs) represent a new hallmark in antiviral therapy of hepatitis C virus (HCV). DAAs have been shown to be safe and effective after liver transplantation (LT), but there is little information about their use in peritransplant settings. Former intravenous drug users represent an increasing group seeking HCV treatment. This case report demonstrates the successful peritransplant antiviral treatment of a former intravenous drug user who had been treated in a methadone maintenance program. CASE REPORT The patient was diagnosed with Child B cirrhosis for the first time in 2009. He had a Model for End-stage Liver Disease (MELD) score of 21 and started antiviral therapy with sofosbuvir (SOF) and daclatasvir (DCV) in March 2014. Due to hepatic decompensation, he received a LT in April 2014. Immunosuppression was performed with tacrolimus (TAC) and mycophenolate-mofetil (MMF), and boosted with prednisolone in the initial stage. Four weeks after his LT, the patient presented with an acute renal injury. The patient was discharged one week later after sufficient hydration, discontinuation of non-steroidal anti-phlogistics therapy, and adjustments to his immunosuppressive regimen. At the beginning of his therapy, the number of RNA copies was 13,000 IU/mL. He received 24 weeks of anti-HCV treatment with SOF and DCV; the antiviral treatment was successful and his LT was well tolerated.  CONCLUSIONS Treatment of HCV is feasible in a peritransplant setting. The antiviral regimen we used did not seem to have any relevant interactions with the patient's immunosuppressive regimens. Still, the peritransplant setting is a very demanding environment for anti-HCV therapy, and further studies are needed.

Hepatitis C virus (HCV) was discovered 26 years ago. For decades, interferon-based therapy has been the mainstay of treatment for HCV. Recently, several direct-acting antivirals (DAAs) have been approved for treatment of HCV-infected patients and to help combat the virus. These drugs have revolutionized the management of HCV as all-oral regimens with favorable side effect profiles and superior rates of sustained virological response. Emerging real-world data are demonstrating results comparable to registration trials for DAA agents. Suddenly, the potential for eradicating HCV is on the horizon.

Background: Therapy for HCV-infected patients after orthotopic liver transplantation (OLT) is based on interferon (IFN) as the gold standard, but sustained virologic response (SVR) and safety profiles of the IFN-based therapies are very unsatisfactory. The aim of this continuing analysis is evaluation of the impact of an IFN-free sofosbuvir (SOF)-based therapy in HCV-infected liver transplant recipients., Material and Methods: Post-OLT patients with a proven recurrence of HCV were treated with SOF and ribavirin (RBV) for 24 weeks (n=10). Laboratory parameters and FibroScan® are continuously evaluated at weeks 0, 12, 24, and 36. A retrospectively analyzed HCV patient cohort who received antiviral therapy with pegylated INF and RBV± telaprevir (TLV) were used as a control group., Results: All patients who finished their treatment with SOF/RBV at least 12 weeks ago showed an SVR. The SOF-based therapy showed a significantly higher rate of rapid virologic response (RVR) and sustained virologic response (SVR) compared to the IFN-based therapies (RVR: p=0.007; SVR: p=0.009). According to temporary data on FibroScan® analysis, regression of fibrosis was observed in 8 patients treated with SOF/RBV. No premature termination of SOF became necessary., Conclusions: In this small group of patients, the preliminary results indicate that a regression of fibrosis is achievable within 24 weeks of therapy with SOF after OLT. SOF seems to be effective and safe in the treatment of OLT patients infected with HCV and will likely improve patient and transplant survival.

Study Objective: We identify the incidence, nature, and consequences of medication errors among acutely ill and injured children receiving care in a sample of rural emergency departments (EDs)., Methods: Two pediatric pharmacists applied a medication error data collection instrument to the medical records of all critically ill children (highest triage category) treated in 4 northern California rural EDs between January 2000 and June 2003. Physician-related medication errors were defined as those involving wrong dose, wrong or inappropriate medication for condition, wrong route, or wrong dosage form. Wrong dose was determined by preset criteria, with doses above or below 10% to 25% of correct dose considered errors, depending on class of medication. Medication errors were classified into categories A through I under 3 broader categories, including errors having the potential to cause harm (A), errors that cause no harm (B to D), and errors that cause harm to the patient (E to I)., Results: Complete data were available from 177 (97.3%) of the 182 patients identified as having been triaged in the highest category during the study period. A total of 84 medication errors were identified among 69 patients, resulting in a medication error incidence of 39.0%. Twenty-four physician-related medication errors were identified among 21 patients, resulting in a physician-related medication error incidence of 11.9%. Among the 69 patients with medication errors, 11 had errors categorized as having the potential to cause harm (15.9%), and 58 had errors categorized as causing no harm (85.5%)., Conclusion: We found a high incidence of medication errors and physician-related medication errors among the acutely ill and injured children presenting to rural EDs in northern California. None of the medication errors identified caused harm to the patients included in this study.

Five children received nevirapine, a nonnucleoside reverse transcriptase inhibitor used as part of a triple-drug regimen to treat human immunodeficiency virus infection. They all developed resistance mutations to the agent within 4-10 months. They differed in compliance with drug therapy and development of specific mutations. Whether these mutations predict clinical resistance has yet to be determined.