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Background and Aims: Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established., Approach and Results: In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm 2 /m 2 (95% CI: 1.3-7.4 cm 2 /m 2 , p =0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p =0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms., Conclusions: LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc.)

Lean individuals with nonalcoholic fatty liver disease (NAFLD) represent a subset of patients with a distinct risk factor profile. We assessed the association between body mass index (BMI) on waitlist and postliver transplantation (LT) outcomes among these patients. We retrospectively analyzed the United Network for Organ Sharing data, including adult patients with NAFLD listed for LT between February 27, 2002, and June 30, 2020. We first used competing risk analyses to estimate the association of BMI with waitlist removal due to death or clinical deterioration. We then conducted Kaplan-Meier estimates and Cox regression models to determine the impact of weight change during the waiting list on all-cause mortality and graft failure after LT. Patients with normal weight (BMI 18.5-24.9 kg/m 2 ) suffered higher waitlist removal (adjusted subdistribution hazard ratio 1.26, 95% confidence interval [CI] 1.10-1.43; p = 0.001) compared with patients with obesity class I (BMI 30-34.9 kg/m 2 ). Those who remained at normal weight had higher all-cause mortality (adjusted hazard ratio [aHR] 1.61, 95% CI 1.32-1.96; p  <0.001) and graft failure (aHR 1.57, 95% CI 1.32-1.88; p  <0.001) than patients with stable obesity. Among patients with normal weight, those with the greatest weight increase (BMI gain ≥3 kg/m 2 ) had lower all-cause mortality (aHR 0.55, 95% CI 0.33-0.93; p = 0.03) and graft failure (aHR 0.49, 95% CI 0.30-0.81; p = 0.01) compared with patients with stable weight (BMI change ≤1 kg/m 2 ). Patients with NAFLD with normal weight have increased waitlist removal and those who remained at normal weight during the waitlist period have worse posttransplantation outcomes. Identifying and addressing factors influencing apparent healthy weight prior to LT are crucial to mitigate poor outcomes., (Copyright © 2023 American Association for the Study of Liver Diseases.)

Individuals on immunosuppressive (IS) therapy have increased mortality from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, and delayed viral clearance may lead to new viral variants. IS therapy reduces antibody responses following coronavirus disease 2019 (COVID-19) messenger RNA (mRNA) vaccination; however, a comprehensive assessment of vaccine immunogenicity is lacking. Here we show that IS therapy reduced neutralizing, binding, and nonneutralizing antibody functions in addition to CD4 and CD8 T-cell interferon-γ responses following COVID-19 mRNA vaccination compared to immunocompetent individuals. Moreover, IS therapy reduced cross-reactivity against SARS-CoV-2 variants. These data suggest that the standard COVID-19 mRNA vaccine regimens will likely not provide optimal protection in immunocompromised individuals., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Survival following liver transplant (LT) is influenced by a variety of factors, including donor risk factors and recipient disease burden and co-morbidities. It is difficult to separate these effects from those of socioeconomic factors, such as income or insurance. The United Network for Organ Sharing (UNOS) created equitable access policies, such as Share 35, to ensure that organs are distributed to individuals with greatest medical need; however, the effect of Share 35 on disparities in post-LT survival is not clear. This study aimed to (1) characterize associations between post-transplant survival and race and ethnicity, income, insurance, and citizenship status, when adjusted for other clinical and demographic factors that may influence survival, and (2) determine if the direction of associations changed after Share 35., Methods: A retrospective, cohort study of adult LT recipients ( n  = 83,254) from the UNOS database from 2005 to 2019 was conducted. Kaplan-Meier survival graphs and stepwise multivariate cox-regression analyses were performed to characterize the effects of socioeconomic status on post-LT survival, adjusted for recipient and donor characteristics, across the time period and after Share 35., Findings: Male sex (HR: 0.93 (95% CI: 0.90-0.96)), private insurance (0.91 (0.88-0.94)), income (0.82 (0.79-0.85)), U.S. citizenship, and Asian (0.81 (0.75-0.88)) or Hispanic (0.82 (0.79-0.86)) race and ethnicity were associated with higher post-transplant survival, after adjustment for clinical and demographic factors (Table 3). These associations were found across the entire time period studied and many persisted after the implementation of Share 35 in 2013 (Table 3; male sex (0.84 (0.79-0.90)), private insurance (0.94 (0.89-1.00)), income (0.82 (0.77-0.89)), and Asian (0.87 (0.73-1.02)) or Hispanic (0.88 (0.81-0.96)) race and ethnicity)., Interpretation: Recipients' socioeconomic factors at time of transplant may impact long-term post-transplant survival, and a single policy may not significantly alter these structural health inequalities., Funding: None., Competing Interests: Alan Bonder has the following disclosures: Scientific Advisory Boards: Intercept, Primary Investigator for trials for Gilead and CARA; Royalties or Licenses: UptoDate, Dynamed; Work with AASLD Editorial Board for Clinical Liver Disease; Expert testimony for Expert Review Inc. Zachary P. Fricker has the following disclosures: AASLD Foundation, payments made to institution in support of research, and Mallinckrodt Pharmaceuticals, payments made to institution in support of clinical trials. The other authors do not have conflicts of interests relevant to this work., (© 2021 The Authors.)

Background and Aims: The nature and outcomes of infection among patients with cirrhosis in safety-net hospitals are not well described. We aimed to characterize the rate of and risk factors for infection, both present on admission and nosocomial, in this unique population. We hypothesized that infections would be associated with adverse outcomes such as short-term mortality., Methods: We used descriptive statistics to characterize infections within a retrospective cohort characterized previously. We used multivariable logistic regression models to assess potential risk factors for infection and associations with key outcomes such as short-term mortality and length of stay., Results: The study cohort of 1112 patients included 33% women with a mean age of 56 ± 10 years. Infections were common (20%), with respiratory and urinary tract infections the most frequent. We did not observe a difference in the incidence of infection on admission based on patient demographic factors such as race/ethnicity or estimated household income. Infections on admission were associated with greater short-term mortality (12% vs 4% in-hospital and 14% vs 7% 30-day), longer length of stay (6 vs 3 days), intensive care unit admission (28% vs 18%), and acute-on-chronic liver failure (10% vs 2%) (p < 0.01 for all). Nosocomial infections were relatively uncommon (4%), but more frequent among patients admitted to the intensive care unit. Antibiotic resistance was common (38%), but not associated with negative outcomes., Conclusion: We did not identify demographic risk factors for infection, but did confirm its morbid effect among patients with cirrhosis in safety-net hospitals.

Goals: To determine whether diabetic patients with hepatitis C virus (HCV) treated with direct-acting antiviral agents have improved diabetes, accounting for change in both hemoglobin A1c (HbA1c) and diabetes medications, and whether any improvement was sustained., Background: HCV infection is associated with an increased risk of diabetes, with improvement in glycemic control after eradication. There remains uncertainty about the durability and magnitude of this effect., Study: HbA1c and diabetes medications were recorded at 6-month intervals for 1.5 years pretreatment and posttreatment for 122 patients. Subjects were classified as having improved diabetes if there was a decrease in HbA1c≥0.5% with no increase in diabetes medications or a decrease in diabetes medications with a stable HbA1c., Results: HbA1c at the nearest time point before treatment was 8.4%±1.9%, compared with 7.8%±1.7% after treatment, a mean difference of 0.6% [95% CI (0.2, 0.9), P<0.01]. A linear mixed effects model incorporating each subject's repeated measurements over time also demonstrated a reduction after treatment of 0.5% [95% CI, (0.3, 0.8), P<0.001]. Accounting for both HbA1c and diabetes medications, 42 of 122 (34%) had an improvement in diabetes after HCV treatment, and 20 of 28 (71%) of these subjects sustained improvement at 1.5 years follow-up. Prescription of insulin was associated with improved diabetes., Conclusions: Treatment of HCV with direct-acting antiviral agents was associated with improved diabetes in a significant portion of patients with an average reduction in HbA1c of clinically significant magnitude. Among responders, this effect was sustained over 1.5 years of follow-up.

Objectives: Acute kidney injury (AKI) is a common complication in hospitalized patients with cirrhosis which contributes to morbidity and mortality. Improved prediction of AKI in this population is needed for prevention and early intervention. We developed a model to identify hospitalized patients at risk for AKI., Methods: Admission data from a prospective cohort of hospitalized patients with cirrhosis without AKI on admission (n = 397) was used for derivation. AKI development in the first week of admission was captured. Independent predictors of AKI on multivariate logistic regression were used to develop the prediction model. External validation was performed on a separate multicenter cohort (n = 308)., Results: In the derivation cohort, the mean age was 57 years, the Model for End-Stage Liver Disease score was 17, and 59 patients (15%) developed AKI after a median of 4 days. Admission creatinine (OR: 2.38 per 1 mg/dL increase [95% CI: 1.47-3.85]), international normalized ratio (OR: 1.92 per 1 unit increase [95% CI: 1.92-3.10]), and white blood cell count (OR: 1.09 per 1 × 10/L increase [95% CI: 1.04-1.15]) were independently associated with AKI. These variables were used to develop a prediction model (area underneath the receiver operator curve: 0.77 [95% CI: 0.70-0.83]). In the validation cohort (mean age of 53 years, Model for End-Stage Liver Disease score of 16, and AKI development of 13%), the area underneath the receiver operator curve for the model was 0.70 (95% CI: 0.61-0.78)., Discussion: A model consisting of admission creatinine, international normalized ratio, and white blood cell count can identify patients with cirrhosis at risk for in-hospital AKI development. On further validation, our model can be used to apply novel interventions to reduce the incidence of AKI among patients with cirrhosis who are hospitalized.

Background & Aims: Nonalcoholic fatty liver disease is an inflammatory condition that results in progressive liver disease. It is unknown if individuals with hepatic steatosis, but not known to have liver disease, have higher serum concentrations of markers of systemic inflammation and oxidative stress., Methods: We collected data from 2482 participants from the Framingham Heart Study (mean age, 51 ± 11 y; 51% women) who underwent computed tomography and measurement of 14 serum markers of systemic inflammation. Heavy alcohol users were excluded. The liver:phantom ratio (a continuous parameter of liver attenuation relative to a calibration phantom) was used to identify individuals with radiographic evidence of liver fat. Primary covariates included age, sex, smoking, alcohol, aspirin use, hypertension, dyslipidemia, diabetes, and cardiovascular disease. Body mass index and visceral fat were secondary covariates. We used multivariable linear regression models to assess the association between liver fat and systemic inflammatory markers., Results: In multivariable-adjusted models, liver fat was associated with the following inflammatory markers: high-sensitivity C-reactive protein (P < .001), urinary isoprostanes (P < .001), interleukin 6 (P < .001), intercellular adhesion molecule 1 (P < .001), and P-selectin (P = .002). Additional adjustment for body mass index or visceral fat attenuated the results slightly, although all associations remained statistically significant (P for all ≤ .01)., Conclusions: In a community-based cohort, individuals with hepatic steatosis without known liver disease had higher mean serum concentrations of systemic markers of inflammation. Studies are needed to determine whether treatment of hepatic steatosis reduces systemic inflammation., (Copyright © 2019 AGA Institute. Published by Elsevier Inc. All rights reserved.)

End-stage liver disease (ESLD) is associated with a high degree of morbidity and mortality as well as symptom burden. Despite this, the rate of consultation with palliative care (PC) providers remains low, and invasive procedures near the end of life are commonplace. Studies show that involvement of PC providers improves patient satisfaction, and evidence from other chronic diseases demonstrates reduced costs of care and potentially increased survival. Better integration of PC is imperative but hindered by patient and provider misconceptions about its role in the care of patients with ESLD, specifically among candidates for liver transplantation. Additionally, reimbursement barriers and lack of provider knowledge may contribute to PC underutilization. In this review, we discuss the benefits of PC in ESLD, the variability of its delivery, and key stakeholders' perceptions about its use. Additionally, we identify barriers to more widespread PC adoption and highlight areas for future research., (Copyright © 2019 by the American Association for the Study of Liver Diseases.)

Background: Safety-net hospitals provide care for racially/ethnically diverse and disadvantaged urban populations. Their hospitalized patients with cirrhosis are relatively understudied and may be vulnerable to poor outcomes and racial/ethnic disparities., Aims: To examine the outcomes of patients with cirrhosis hospitalized at regionally diverse safety-net hospitals and the impact of race/ethnicity., Methods: A study of patients with cirrhosis hospitalized at 4 safety-net hospitals in 2012 was conducted. Demographic, clinical factors, and outcomes were compared between centers and racial/ethnic groups. Study endpoints included mortality and 30-day readmission., Results: In 2012, 733 of 1,212 patients with cirrhosis were hospitalized for liver-related indications (median age 55 years, 65% male). The cohort was racially diverse (43% White, 25% black, 22% Hispanic, 3% Asian) with cirrhosis related to alcohol and viral hepatitis in 635 (87%) patients. Patients were hospitalized mainly for ascites (35%), hepatic encephalopathy (20%) and gastrointestinal bleeding (GIB) (17%). Fifty-four (7%) patients died during hospitalization and 145 (21%) survivors were readmitted within 30 days. Mortality rates ranged from 4 to 15% by center (p = .007) and from 3 to 10% by race/ethnicity (p = .03), but 30-day readmission rates were similar. Mortality was associated with Model for End-stage Liver Disease (MELD), acute-on-chronic liver failure, hepatocellular carcinoma, sodium and white blood cell count. Thirty-day readmission was associated with MELD and Charlson Comorbidity Index >4, with lower risk for GIB. We did not observe geographic or racial/ethnic differences in hospital outcomes in the risk-adjusted analysis., Conclusions: Hospital mortality and 30-day readmission in patients with cirrhosis at safety-net hospitals are associated with disease severity and comorbidities, with lower readmissions in patients admitted for GIB. Despite geographic and racial/ethnic differences in hospital mortality, these factors were not independently associated with mortality., Competing Interests: The authors have declared that no competing interests exist.

Primary sclerosing cholangitis is a rare, chronic cholestatic liver disease characterized by progressive idiopathic stricturing of the biliary system, typically leading to cirrhosis, end-stage liver disease, and colonic or hepatobiliary malignancy. Its presentation is often that of asymptomatic alkaline phosphatase elevation. When symptoms are present, they typically include fatigue, pruritus, or jaundice. The diagnosis can be confirmed via cholangiography, either magnetic resonance cholangiography (MRCP) or endoscopic retrograde cholangiography if the former is inconclusive. The clinical course is marked by progressive liver disease leading to cirrhosis with its attendant complications of portal hypertension, often including recurrent episodes of cholangitis. Greater elevation in alkaline phosphatase or liver stiffness is associated with worse clinical outcomes. Management includes endoscopic treatment of symptomatic biliary strictures and evaluation of dominant strictures as no adequate medical treatment is available. Multiple medical therapies are under evaluation. Ultimately, liver transplantation may be necessary for management of decompensated cirrhosis or disabling symptoms. There is also a markedly increased risk of cancer, notably including cholangiocarcinoma and gallbladder and colorectal cancers (particularly in patients with colitis). Cancer screening can be done with semi-annual liver imaging (MRCP or ultrasound) and colonoscopy every 1-2 years in those with colitis.

Background: Treatment of hepatitis C virus (HCV) with direct-acting antiviral (DAA) regimens has resulted in high rates of sustained virologic response (SVR). Treatment of vulnerable populations may be improved by incorporating an on-site intensive specialty pharmacy (ON-ISP)., Aims: To describe outcomes of HCV treatment at a safety-net hospital and proportion of subjects achieving SVR for those using the ON-ISP compared to an off-site pharmacy (OFF-SP)., Methods: A retrospective cohort study of 219 subjects treated for HCV with DAA at Boston Medical Center was conducted. Subject characteristics, virologic response, and pharmacy services used were recorded. We used multivariable logistic regression to test the association between ON-ISP and SVR after adjusting for covariates., Results: SVR occurred in 71% of subjects by intention-to-treat (73% among ON-ISP users vs 57% among OFF-SP users) and 95% completing treatment per-protocol (96% among ON-ISP users vs 87% among OFF-SP users). Adjustment for age, sex, ethnicity, insurance, fibrosis, prior treatment, and MELD revealed an increased likelihood of SVR among users of ON-ISP: OR 6.0 (95% CI 1.18-31.0). No significant difference in treatment delay or adverse events was seen among users of either pharmacy type., Conclusions: HCV treatment with DAA was well tolerated, but the rate of SVR was low (71%) compared to trials. This was due to loss to follow-up, as the per-protocol rate of SVR was much higher (95%). Use of ON-ISP was associated with an increase in SVR and may be valuable for improving care for vulnerable populations.

Greater loss in structural integrity of the ipsilesional corticospinal tract (CST) is associated with poorer motor outcome in patients with hemiparetic stroke. Animal models of stroke have demonstrated that structural remodeling of white matter in the ipsilesional and contralesional hemispheres is associated with improved motor recovery. Accordingly, motor recovery in patients with stroke may relate to the relative strength of CST degeneration and remodeling. This study examined the relationship between microstructural status of brain white matter tracts, indexed by the fractional anisotropy (FA) metric derived from diffusion tensor imaging (DTI) data, and motor skill of the stroke-affected hand in patients with chronic stroke. Voxelwise analysis revealed that motor skill significantly and positively correlated with FA of the ipsilesional and contralesional CST in the patients. Additional voxelwise analyses showed that patients with poorer motor skill had reduced FA of bilateral CST compared to normal control subjects, whereas patients with better motor skill had elevated FA of bilateral CST compared to controls. These findings were confirmed using a DTI-tractography method applied to the CST in both hemispheres. The results of this study suggest that the level of motor skill recovery achieved in patients with hemiparetic stroke relates to microstructural status of the CST in both the ipsilesional and contralesional hemispheres, which may reflect the net effect of degeneration and remodeling of bilateral CST.

A unique, air-based system has been developed and implemented for rapid and accurate determination of pressure drop versus flow rate characteristics of generic catheter lumens; dimensionless scaling parameters can be effectively used to express these characteristics in units of blood flow used in the clinical setting. Theoretical models are compared with experimental data. For flow and geometric parameters of practical importance, the pronounced effect of developing flow in the lumen must be accounted for in calculation of the pressure drop along the lumen. That is, the theory of classical Poiseuille flow substantially underpredicts the pressure drop. Moreover, a side hole can induce significant, and in some cases large, values of pressure drop, even when the area of the hole exceeds the cross-sectional area of the lumen.