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Yueming Cao,1 Catherine Mezzacappa,1,2 Ariel Jaffe,1,2 Mario Strazzabosco,1,2 Tamar H Taddei1,2 1Department of Internal Medicine, Yale School of Medicine, New Haven, CT, USA; 2Department of Internal Medicine Digestive Disease Section, Yale School of Medicine, New Haven, CT, USACorrespondence: Tamar H Taddei, Department of Internal Medicine, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA, Tel +1 203-785-7312, Fax +1 203-785-7273, Email tamar.taddei@yale.eduBackground: Hepatocellular carcinoma (HCC) is a heterogeneous disease that typically arises in the setting of chronic liver disease, making treatment selection complex. Multidisciplinary liver tumor boards (MDLTB) have been shown to improve outcomes in patients with HCC. However, in many cases, patients evaluated by MDLTBs ultimately do not receive the board’s recommended treatment.Purpose: This study aims to assess adherence to MDLTB recommendations for the treatment of HCC, the reasons for non-adherence, and the survival of Barcelona Clinic Liver Cancer (BCLC) Stage A patients treated with curative treatment compared to palliative locoregional therapy.Patients and Methods: A single-site, retrospective cohort study was conducted of all patients with treatment-naïve HCC who were evaluated by an MDLTB at a tertiary care center in Connecticut between 2013 and 2016, of which 225 patients met inclusion criteria. Investigators conducted a chart review and recorded adherence to the MDLTB’s recommendations, and in cases of discordance, evaluated and recorded the underlying cause; investigators assessed MDLTB recommendations’ compliance with BCLC guidelines. Survival data was accrued through February 1st of 2022 and analyzed via Kaplan–Meier analysis and multivariate Cox regression.Results: Treatment adherent to MDLTB recommendations occurred in 85.3% of patients (n=192). The majority of non-adherence occurred in the management of BCLC Stage A disease. In cases where adherence was possible but the recommendation was not followed, most discrepancies were whether to treat with curative or palliative intent (20/24), with almost all discrepancies occurring in patients (19/20) with BCLC Stage A disease. For patients with Stage A unifocal HCC, those who received curative therapy lived significantly longer than patients who received palliative locoregional therapy (5.55 years vs 4.26 years, p=0.037).Conclusion: Most forms of non-adherence to MDLTB recommendations were unavoidable; however, treatment discordance in the management of patients with BCLC Stage A unifocal disease may present an opportunity for clinically significant quality improvement.Keywords: compliance, multidisciplinary liver tumor board, HCC, treatment guidelines

In this paper, we consider the inverse problem of state estimation of nuclear power fields in a power plant from a limited number of observations of the neutron flux. For this, we use the Parametrized Background Data Weak approach. The method combines the observations with a parametrized PDE model for the behavior of the neutron flux. Since, in general, even the most sophisticated models cannot perfectly capture reality, an inevitable model error is made. We investigate the impact of the model error in the power reconstruction when we use a diffusion model for the neutron flux, and assume that the true physics are governed by a neutron transport model.

We present a parameterized-background data-weak (PBDW) approach [Y Maday, AT Patera, JD Penn, M Yano, Int J Numer Meth Eng, 102(5), 933–965] to the steady-state variational data assimilation (DA) problem for systems modeled by partial differential equations (PDEs) and characterized by multiple interconnected components, with emphasis on vascular flows. We focus on the problem of reconstructing the state of the system in one specific component, based on local measurements. The PBDW approach does not require the solution of any PDE model at prediction stage (projection-by-data) and, as such, enables local state estimates on single components, as long as good background and update spaces for the estimation can be constructed. We discuss the application of PBDW to a two-dimensional steady Navier-Stokes problem for a family of parameterized geometries, and investigate instead the effects of enforcing no-slip boundary conditions and incompressibility constraints on the background and update spaces to enhance the state estimation. Furthermore, we show an actionable strategy to train local reduced-order bases (ROBs) for the background space that can later be used for DA tasks.

We present a model-order-reduction approach to simulation-based classification, with particular application to structural health monitoring. The approach exploits (1) synthetic results obtained by repeated solution of a parametrized mathematical model for different values of the parameters, (2) machine-learning algorithms to generate a classifier that monitors the damage state of the system, and (3) a reduced basis method to reduce the computational burden associated with the model evaluations. Furthermore, we propose a mathematical formulation which integrates the partial differential equation model within the classification framework and clarifies the influence of model error on classification performance. We illustrate our approach and we demonstrate its effectiveness through the vehicle of a particular physical companion experiment, a harmonically excited microtruss. [ABSTRACT FROM AUTHOR]

There is some debate regarding the differing levels of plasma homocysteine, vitamin B12 and serum folate between healthy controls (HC), mild cognitive impairment (MCI), and Alzheimer's disease (AD). As part of the Australian Imaging Biomarker Lifestyle (AIBL) study of aging cohort, consisting of 1,112 participants (768 HC, 133 MCI patients, and 211 AD patients), plasma homocysteine, vitamin B12, and serum and red cell folate were measured at baseline to investigate their levels, their inter-associations, and their relationships with cognition. The results of this cross-sectional study showed that homocysteine levels were increased in female AD patients compared to female HC subjects (+16%, p-value < 0.001), but not in males. Red cell folate, but not serum folate, was decreased in AD patients compared to HC (-10%, p-value = 0.004). Composite z-scores of short- and long-term episodic memory, total episodic memory, and global cognition all showed significant negative correlations with homocysteine, in all clinical categories. Increasing red cell folate had a U-shaped association with homocysteine, so that high red cell folate levels were associated with worse long-term episodic memory, total episodic memory, and global cognition. These findings underscore the association of plasma homocysteine with cognitive deterioration, although not unique to AD, and identified an unexpected abnormality of red cell folate. [ABSTRACT FROM AUTHOR]

Competing Interests: The authors have no conflict of interests related to this publication., (© 2024 Authors.)

Background & Aims: Treatment of alcohol use disorder (AUD) improves survival in patients with alcohol-related cirrhosis. However, medications for alcohol use disorder (MAUD) are underutilized in this population, partially due to concerns regarding drug-induced liver injury (DILI). Our aim was to evaluate the safety of naltrexone in patients with cirrhosis., Methods: This was a retrospective study of patients with cirrhosis who were prescribed naltrexone using the VOCAL (Veterans Outcomes and Costs Associated with Liver Disease) database. Patients with new initiation of naltrexone after diagnosis of cirrhosis who had liver enzymes checked within a 3-month time frame were included. A chart review was performed on patients who developed alanine aminotransferase or alkaline phosphatase elevations to more than 2× or 5× the upper limit of normal, respectively. The RUCAM (Roussel Uclaf causality assessment method) was used to determine if DILI occurred., Results: A total of 3,285 patients with cirrhosis were initiated on naltrexone, of whom 2,940 had laboratory testing during the high-risk DILI period. Only 2% of patients had liver enzyme elevations, and among those, 30 (48%) were classified as "DILI excluded" and 32 (52%) were classified as "DILI unlikely". No patients were classified as possible, probable, or highly probable DILI. No deaths or new decompensations were attributed to naltrexone., Conclusions: Naltrexone in patients with cirrhosis was not associated with development of DILI using RUCAM scoring. Naltrexone appears to be safe in patients with compensated and decompensated cirrhosis., Impact and Implications: Naltrexone is an effective medication for treating alcohol use disorder but is underutilized in patients with underlying liver disease due to historical concerns regarding hepatotoxicity. This retrospective study shows no drug-induced liver injury in a large cohort of patients with cirrhosis with new initiation of naltrexone. This study may encourage providers to prescribe naltrexone to patients with existing liver disease with ongoing alcohol use disorder.

Background: Alterations to DNA methylation have been identified in both hepatocellular carcinoma (HCC) tumor and circulating DNA from affected individuals. These markers have potential utility in HCC screening. Adherence to HCC screening is poor and acceptable HCC screening tests are needed., Methods: A feasibility study was performed on a subset of case patients and control subjects from a prior study of risk factors for HCC. Case patients (n=12) included adults aged 47-85 years with a first diagnosis of HCC between 2011 and 2016 and without viral hepatitis. Control subjects (n=12) were matched on age, sex, and state of residence. Participants provided saliva samples for DNA genotyping. Log fold change in salivary DNA methylation at 1359 CpG sites representing 25 candidate genes previously associated with HCC was compared across case patients and control subjects., Results: The quantity of DNA ranged from 9.65 to 257.79 μg. The purity of DNA isolates was good, with mean OD260/280 ratio of 1.78 (SD: 0.14). Of 25 candidate genes, 16 had at ≥1 CpG site with detectable differences in methylation across HCC case patients and control subjects. Sites differentially methylated in HCC case patients included genes encoding tumor suppressors (PRDM2, RUNX3, p15/16, and RASSF1/5), regulators of cell cycle progression (DAPK1 and TP73), and DNA repair (MGMT and GSTP1). No associations met the significance threshold 3.7 × 10-5 required for multiple comparisons., Conclusions: Salivary DNA may be a feasible alternative to blood samples in the era of novel DNA-based screening tests for HCC. The ease of saliva-based testing supports further investigation of its potential., (© 2024 The Author(s).)

Background & Aims: There is growing acceptance that principles of palliative care should be integrated into the management of serious illnesses affecting the liver, such as acute-on-chronic liver failure (ACLF). However, rates, patterns, and predictors of specialty palliative care consultation among patients with ACLF have not been well-described., Methods: We performed a retrospective cohort study of patients hospitalized with ACLF between 1/1/2008 and 12/31/2018 using the VOCAL cohort. Patients were followed until 6/2021. We used mixed-effects regression analyses to identify significant patient and facility factors associated with palliative care consultation. We examined timing of consultation, the influence of ACLF characteristics, and facility-level variation on receipt of palliative care consultation., Results: We identified 21,987 patients hospitalized with ACLF, of whom 30.5% received specialty palliative care consultation. Higher ACLF grade (ACLF-2 [odds ratio (OR) 1.82, 95% CI 1.67-1.99], ACLF-3 [OR 3.06, 95% CI 2.76-3.40]), prior specialty palliative care consultation (OR 2.62, 95% CI 2.36-2.91), and hepatocellular carcinoma (OR 2.10, 95% CI 1.89-2.33) were associated with consultation. Consultation occurred latest and closest to the time of death for patients with ACLF-3 compared to ACLF-1 and ACLF-2. Significant facility-level variation in consultation persisted among patients with ACLF-3, despite adjusting for multiple patient and facility factors., Conclusion: In this large cohort of hospitalized patients with ACLF, specialty palliative care consultation was rare, more common in patients with higher grade ACLF, and tended to occur closer to the time of death for the sickest patients. Greater attention should be placed on earlier integration of palliative care during acute hospitalizations in patients with ACLF., Impact and Implications: Though palliative care consultation is recommended for patients with acute-on-chronic liver failure, there is no data demonstrating how often this occurs during hospitalizations, on a population level. We found that consultation occurs in only 30.5% of patients and occurs later for patients with grade 3 acute-on-chronic liver failure. Our data should provoke clinicians to urgently consider quality improvement efforts to integrate palliative care into the management of these seriously ill patients., Competing Interests: The authors of this manuscript have no conflicts of interest to disclose. Please refer to the accompanying ICMJE disclosure forms for further details.

We sought to determine the influence of background liver biopsies on hepatocellular carcinoma (HCC) management. The pathology database at a large university hospital was searched between 2013 and 2018 for all instances of when a separate biopsy of the nontumoral liver was performed within 6 months of an HCC biopsy. Patients were evaluated for baseline demographic and clinical characteristics, treatment proposed prior to biopsy, and impact of biopsy results on management. Among the 104 identified cases of paired liver biopsies, 22% were women; the median age was 64 years; and most were of earlier HCC stages at diagnosis (Barcelona Clinic Liver Cancer stages 0-A: 70%). Four patients among 10 in whom cirrhosis status was clinically unclear were confirmed to have cirrhosis on biopsy, and 4 patients did not have cirrhosis despite clinical suspicion. Treatment was altered by the background parenchymal findings for 5 patients (5%): management was less aggressive for 4 patients and more aggressive for 1 patient. A background liver biopsy can significantly impact the management of a small subset of HCC patients, especially those with early disease, and should be considered concurrently with the biopsy of the mass., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Background: Medications for alcohol use disorder (MAUD) are highly effective in achieving and maintaining abstinence in patients with alcohol use disorder (AUD). Our aim was to evaluate the effect of MAUD on all-cause mortality in patients with alcohol-associated cirrhosis and active alcohol use., Methods: This was a retrospective cohort study of patients with alcohol-associated cirrhosis and high-risk alcohol use disorder in the Veterans Outcomes and Costs Associated with Liver Disease (VOCAL) database. Propensity score matching for exposure to MAUD (acamprosate or naltrexone) within a year after cirrhosis diagnosis was performed to account for potential confounders, and the association between MAUD and all-cause mortality was subsequently evaluated using Cox regression analysis., Results: A total of 9131 patients were included, of whom 886 (9.7%) were exposed to MAUD (naltrexone: 520, acamprosate: 307, both medications: 59). The duration of MAUD exposure was >3 months in 345 patients (39%). The strongest positive predictor of MAUD prescription was an inpatient diagnosis code for AUD, followed by a concurrent diagnosis of depression; the strongest negative predictor was a history of cirrhosis decompensation. After propensity score matching (866 patients in each group) with excellent covariate balance (absolute standardized mean differences <0.1), MAUD exposure was associated with improved survival, with an HR of 0.80 relative to no MAUD exposure (95% CI: 0.67-0.97, p = 0.024)., Conclusion: MAUD are underutilized in patients with alcohol-associated cirrhosis with high-risk alcohol use behavior but are associated with improved survival after adjustment for confounders such as the severity of liver disease, age, and engagement in the healthcare system., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Association for the Study of Liver Diseases.)

Background & Aims: Acute-on-chronic liver failure (ACLF) carries a high short-term mortality for patients with cirrhosis. Prior literature suggests that statin exposure may reduce the likelihood of ACLF events. However, it is unclear if statin exposure is associated with ACLF-related mortality. This study sought to determine the association between statin use and short-term mortality among patients hospitalised with ACLF., Methods: This was a retrospective cohort study of Veterans Health Administration (VHA) patients diagnosed with cirrhosis between 2008 and 2021 and hospitalised with high-grade (2 or 3) ACLF. Patients were stratified into those with and without continuous statin exposure for at least 90 days prior to hospitalisation. Multivariable logistic regression models were created to determine the adjusted association between statin exposure and 28-day and 90-day mortality. Categorical statin dose exposure, converted to simvastatin equivalents, was also explored., Results: A total of 11,731 patients with cirrhosis hospitalised with Grade 2 or 3 ACLF were included in the analytic cohort, 26% of whom had statin exposure. In adjusted logistic regression models, statin use was associated with 18% lower odds of ACLF-related 28-day mortality (odds ratio [OR] 0.82, 95% CI 0.73-0.93, p  = 0.001) and 24% lower odds of 90-day mortality (OR 0.76, 95% CI 0.68-0.86, p <0.001). Increasing statin dose exposure was also associated with further reductions in 90-day mortality ( e.g. OR 0.81, 95% CI 0.70-0.93 for 10-40 mg vs. 0 mg and OR 0.72, 95% CI 0.60-0.87 for 80 mg vs. 0 mg, p <0.001)., Conclusions: In this large, retrospective cohort study, statin exposure before high-grade ACLF hospitalisation was associated with reduced odds of 28-day and 90-day mortality in patients with cirrhosis. A statin dose-dependent reduction in 90-day ACLF-related mortality was also observed., Impact and Implications: Statins have been identified as a class of medications with potential beneficial effects for patients with cirrhosis. In this large, retrospective cohort study of patients with cirrhosis who seek care at the Veterans Health Administration, statin use was associated with a decrease in short term (28-day and 90-day) mortality as a result of acute-on-chronic liver failure. Future prospective studies are needed to further clarify the relative safety and efficacy of statin therapy in reducing morbidity and mortality associated with acute-on-chronic liver failure in patients with cirrhosis., Competing Interests: The authors have no additional disclosures or conflicts as relevant to this manuscript. Please refer to the accompanying ICMJE disclosure forms for further details., (© 2023 The Author(s).)

Novel corona virus disease (COVID-19) is an ongoing pandemic that has spread across the globe. The virus primarily infects type-2 pneumocytes in alveoli and causes lung disease, with severity ranging from mild pneumonia to acute respiratory distress syndrome. The virus also invades gastrointestinal epithelial cells, hepatocytes, and biliary epithelial cells. Derangement of liver function tests is noted in about one third of patients and appears to correlate with more severe disease. There are multiple mechanisms by which the virus can cause liver injury; immune-mediated inflammation and direct viral cytotoxicity are believed to be the predominant mechanisms. Liver injury appears to be transient, usually recovering with resolution of illness. Limited available studies and experience from prior corona virus pandemics seem to suggest that immunosuppressed patients have similar outcomes compared to non-immunosuppressed patients. Age and comorbid conditions seem to influence outcome, irrespective of immune status. Additionally, patients with preexisting comorbid conditions are more prone to acquire infection and should strictly adhere to travel and social distancing advisories. Telemedicine should be utilized to provide uninterrupted care for patients with liver disease, and clinic or hospital visits should be advised only in sick patients with advanced liver disease. In conclusion, liver dysfunction is not uncommon in COVID-19, it generally improves with resolution of disease, and patients with chronic liver disease (CLD) need continued follow up, uninterrupted by the ongoing pandemic, preferably in virtual clinic settings., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tgh.amegroups.com/article/view/10.21037/tgh-20-243/coif). The authors have no conflicts of interest to declare., (2022 Translational Gastroenterology and Hepatology. All rights reserved.)