Improving adenine and dual base editors through introduction of TadA-8e and Rad51DBD.

Base editors, including dual base editors, are innovative techniques for efficient base conversions in genomic DNA. However, the low efficiency of A-to-G base conversion at positions proximal to the protospacer adjacent motif (PAM) and the A/C simultaneous conversion of the dual base editor hinder their broad applications. In this study, through fusion of ABE8e with Rad51 DNA-binding domain, we generate a hyperactive ABE (hyABE) which offers improved A-to-G editing efficiency at the region (A10-A15) proximal to the PAM, with 1.2- to 7-fold improvement compared to ABE8e. Similarly, we develop optimized dual base editors (eA&C-BEmax and hyA&C-BEmax) with markedly improved simultaneous A/C conversion efficiency (1.2-fold and 1.5-fold improvement, respectively) compared to A&C-BEmax in human cells. Moreover, these optimized base editors catalyze efficiently nucleotide conversions in zebrafish embryos to mirror human syndrome or in human cells to potentially treat genetic diseases, indicating their great potential in broad applications for disease modeling and gene therapy.

Core implementation strategies for improving cirrhosis care in the Veterans Health Administration.

BACKGROUND AND AIMS: The Veterans Health Administration (VHA) provides care for more than 80,000 veterans with cirrhosis. This longitudinal, multimethod evaluation of a cirrhosis care quality improvement program aimed to (1) identify implementation strategies associated with evidence-based, guideline-concordant cirrhosis care over time, and (2) use qualitative interviews to operationalize strategies for a manualized intervention. APPROACH AND RESULTS: VHA providers were surveyed annually about the use of 73 implementation strategies to improve cirrhosis care in fiscal years 2018 (FY18) and 2019 (FY19). Implementation strategies linked to guideline-concordant cirrhosis care were identified using bivariate statistics and comparative configurational methods. Semistructured interviews were conducted with 12 facilities in the highest quartile of cirrhosis care to specify the successful implementation strategies and their mechanisms of change. A total of 106 VHA facilities (82%) responded at least once over the 2-year period (FY18, n = 63; FY19, n = 100). Facilities reported using a median of 12 (interquartile range [IQR] 20) implementation strategies in FY18 and 10 (IQR 19) in FY19. Of the 73 strategies, 35 (48%) were positively correlated with provision of evidence-based cirrhosis care. Configurational analysis identified multiple strategy pathways directly linked to more guideline-concordant cirrhosis care. Across both methods, a subset of eight strategies was determined to be core to cirrhosis care improvement and specified using qualitative interviews. CONCLUSIONS: In a national cirrhosis care improvement initiative, a multimethod approach identified a core subset of successful implementation strategy combinations. This process of empirically identifying and specifying implementation strategies may be applicable to other implementation challenges in hepatology.

Mapping the road to elimination: a 5-year evaluation of implementation strategies associated with hepatitis C treatment in the veterans health administration.

BACKGROUND: While few countries and healthcare systems are on track to meet the World Health Organization's hepatitis C virus (HCV) elimination goals, the US Veterans Health Administration (VHA) has been a leader in these efforts. We aimed to determine which implementation strategies were associated with successful national viral elimination implementation within the VHA. METHODS: We conducted a five-year, longitudinal cohort study of the VHA Hepatic Innovation Team (HIT) Collaborative between October 2015 and September 2019. Participants from 130 VHA medical centers treating HCV were sent annual electronic surveys about their use of 73 implementation strategies, organized into nine clusters as described by the Expert Recommendations for Implementing Change taxonomy. Descriptive and nonparametric analyses assessed strategy use over time, strategy attribution to the HIT, and strategy associations with site HCV treatment volume and rate of adoption, following the Theory of Diffusion of Innovations. RESULTS: Between 58 and 109 medical centers provided responses in each year, including 127 (98%) responding at least once, and 54 (42%) responding in all four implementation years. A median of 13-27 strategies were endorsed per year, and 8-36 individual strategies were significantly associated with treatment volume per year. Data warehousing, tailoring, and patient-facing strategies were most commonly endorsed. One strategy-"identify early adopters to learn from their experiences"-was significantly associated with HCV treatment volume in each year. Peak implementation year was associated with revising professional roles, providing local technical assistance, using data warehousing (i.e., dashboard population management), and identifying and preparing champions. Many of the strategies were driven by a national learning collaborative, which was instrumental in successful HCV elimination. CONCLUSIONS: VHA's tremendous success in rapidly treating nearly all Veterans with HCV can provide a roadmap for other HCV elimination initiatives.

Iodoacetic Acid, a Water Disinfection Byproduct, Disrupts Hypothalamic, and Pituitary Reproductive Regulatory Factors and Induces Toxicity in the Female Pituitary.

Iodoacetic acid (IAA) is a water disinfection byproduct (DBP) formed by reactions between oxidizing disinfectants and iodide. In vitro studies have indicated that IAA is one of the most cyto- and genotoxic DBPs. In humans, DBPs have been epidemiologically associated with reproductive dysfunction. In mouse ovarian culture, IAA exposure significantly inhibits antral follicle growth and reduces estradiol production. Despite this evidence, little is known about the effects of IAA on the other components of the reproductive axis: the hypothalamus and pituitary. We tested the hypothesis that IAA disrupts expression of key neuroendocrine factors and directly induces cell damage in the mouse pituitary. We exposed adult female mice to IAA in drinking water in vivo and found 0.5 and 10 mg/l IAA concentrations lead to significantly increased mRNA levels of kisspeptin (Kiss1) in the arcuate nucleus although not affecting Kiss1 in the anteroventral periventricular nucleus. Both 10 mg/l IAA exposure in vivo and 20 µM IAA in vitro reduced follicle stimulating hormone (FSHß)-positive cell number and Fshb mRNA expression. IAA did not alter luteinizing hormone (LHß) expression in vivo although exposure to 20 µM IAA decreased expression of Lhb and glycoprotein hormones, alpha subunit (Cga) mRNA in vitro. IAA also had toxic effects in the pituitary, inducing DNA damage and P21/Cdkn1a expression in vitro (20 µM IAA) and DNA damage and Cdkn1a expression in vivo (500 mg/l). These data implicate IAA as a hypothalamic-pituitary-gonadal axis toxicant and suggest the pituitary is directly affected by IAA exposure.

The Hepatic Innovation Team Collaborative: A Successful Population-Based Approach to Hepatocellular Carcinoma Surveillance.

After implementing a successful hepatitis C elimination program, the Veterans Health Administration's (VHA) Hepatic Innovation Team (HIT) Collaborative pivoted to focus on improving cirrhosis care. This national program developed teams of providers across the country and engaged them in using systems redesign methods and population health approaches to improve care. The HIT Collaborative developed an Advanced Liver Disease (ALD) Dashboard to identify Veterans with cirrhosis who were due for surveillance for hepatocellular carcinoma (HCC) and other liver care, promoted the use of an HCC Clinical Reminder in the electronic health record, and provided training and networking opportunities. This evaluation aimed to describe the VHA's approach to improving cirrhosis care and identify the facility factors and HIT activities associated with HCC surveillance rates, using a quasi-experimental design. Across all VHA facilities, as the HIT focused on cirrhosis between 2018-2019, HCC surveillance rates increased from 46% (IQR 37-53%) to 51% (IQR 42-60%, p < 0.001). The median HCC surveillance rate was 57% in facilities with high ALD Dashboard utilization compared with 45% in facilities with lower utilization (p < 0.001) and 58% in facilities using the HCC Clinical Reminder compared with 47% in facilities not using this tool (p < 0.001) in FY19. Increased use of the ALD Dashboard and adoption of the HCC Clinical Reminder were independently, significantly associated with HCC surveillance rates in multivariate models, controlling for other facility characteristics. In conclusion, the VHA's HIT Collaborative is a national healthcare initiative associated with significant improvement in HCC surveillance rates.

Smartphone sensing of social interactions in people with and without schizophrenia.

Social impairment is a cardinal feature of schizophrenia spectrum disorders (SZ). Smaller social network size, diminished social skills, and loneliness are highly prevalent. Existing, gold-standard assessments of social impairment in SZ often rely on self-reported information that depends on retrospective recall and detailed accounts of complex social behaviors. This is particularly problematic in people with SZ given characteristic cognitive impairments and reduced insight. Ecological Momentary Assessment (EMA; repeated self-reports completed in the context of daily life) allows for the measurement of social behavior as it occurs in vivo, yet still relies on participant input. Momentary characterization of behavior using smartphone sensors (e.g., GPS, microphone) may also provide ecologically valid indicators of social functioning. In the current study we tested associations between both active (e.g., EMA-reported number of interactions) and passive (GPS-based mobility, conversations captured by microphone) smartphone-based measures of social activity and measures of social functioning and loneliness to examine the promise of such measures for understanding social impairment in SZ. Our results indicate that passive markers of mobility were more consistently associated with EMA measures of social behavior in controls than in people with SZ. Furthermore, dispositional loneliness showed associations with mobility metrics in both groups, while general social functioning was less related to these metrics. Finally, interactions detected in the ambient audio were more tied to social functioning in SZ than in controls. Findings speak to the promise of smartphone-based digital phenotyping as an approach to understanding objective markers of social activity in people with and without schizophrenia.

Getting to implementation: a protocol for a Hybrid III stepped wedge cluster randomized evaluation of using data-driven implementation strategies to improve cirrhosis care for Veterans.

BACKGROUND: Cirrhosis is a rapidly increasing cause of global mortality. To improve cirrhosis care, the Veterans Health Administration (VHA) developed the Hepatic Innovation Team (HIT) Collaborative to support VA Medical Centers (VAMCs) to deliver evidence-based cirrhosis care. This randomized HIT program evaluation aims to develop and assess a novel approach for choosing and applying implementation strategies to improve the quality of cirrhosis care. METHODS: Evaluation aims are to (1) empirically determine which combinations of implementation strategies are associated with successful implementation of evidence-based practices (EBPs) for Veterans with cirrhosis, (2) manualize these "data-driven" implementation strategies, and (3) assess the effectiveness of data-driven implementation strategies in increasing cirrhosis EBP uptake. Aim 1 will include an online survey of all VAMCs' use of 73 implementations strategies to improve cirrhosis care, as defined by the Expert Recommendations for Implementing Change taxonomy. Traditional statistical as well as configurational comparative methods will both be employed to determine which combinations of implementation strategies are associated with site-level adherence to EBPs for cirrhosis. In aim 2, semi-structured interviews with high-performing VAMCs will be conducted to operationalize successful implementation strategies for cirrhosis care. These data will be used to inform the creation of a step-by-step guide to tailoring and applying the implementation strategies identified in aim 1. In aim 3, this manualized implementation intervention will be assessed using a hybrid type III stepped-wedge cluster randomized design. This evaluation will be conducted in 12 VAMCs, with four VAMCs crossing from control to intervention every 6 months, in order to assess the effectiveness of using data-driven implementation strategies to improve guideline-concordant cirrhosis care. DISCUSSION: Successful completion of this innovative evaluation will establish the feasibility of using early evaluation data to inform a manualized, user-friendly implementation intervention for VAMCs with opportunities to improve care. This evaluation will provide implementation support tools that can be applied to enhance the implementation of other evidence-based practices. TRIAL REGISTRATION: This project was registered at ClinicalTrials.Gov ( NCT04178096 ) on 4/29/20.

Characterizing patient-reported outcomes in veterans with cirrhosis.

BACKGROUND AND AIMS: The Veterans Health Administration (VA) cares for over 80,000 Veterans with cirrhosis annually. Given the importance of understanding patient reported outcomes in this complex population, we aimed to assess the associations between attitudes towards care, disease knowledge, and health related quality of life (HRQoL) in a national sample. METHODS: In this cross-sectional study, we mailed paper surveys to a random sample of Veterans with cirrhosis, oversampling those with decompensated disease. Surveys included the Veterans RAND 12-Item Health Survey (measuring HRQoL) and questions about demographics, characteristics of care, satisfaction with care ("attitudes towards care"), and symptoms of cirrhosis. Those who reported being "unsure" about whether they had decompensation events were defined as "unsure about cirrhosis symptoms" ("disease knowledge"). We used multivariable regression models to assess the factors associated with HRQoL. RESULTS: Of 1374 surveys, 551 (40%) completed surveys were included for analysis. Most Veterans (63%) were "satisfied" or "very satisfied" with VA liver care. Patients often self-reported being unsure about whether they had experienced hepatic decompensation events (34%). Overall average physical (PCS) and mental (MCS) component scores of HRQoL were 30±11 and 41±12. In multivariable regression models, hepatic decompensation (PCS:ß = -3.8, MCS:ß = -2.2), medical comorbidities (ß = --2.0, ß = -1.7), and being unsure about cirrhosis symptoms (ß = -1.9, ß = -3.3) were associated with worse HRQoL, while age (ß = 0.1, ß = 0.2) and satisfaction with care (ß = 0.6; ß = 1.6) were associated with significantly better HRQoL. CONCLUSIONS: Hepatic decompensation, lower satisfaction with care, and being unsure about cirrhosis symptoms were associated with reduced QOL scores in this national cohort.

Strategy Configurations Directly Linked to Higher Hepatitis C Virus Treatment Starts: An Applied Use of Configurational Comparative Methods.

BACKGROUND: The Department of Veterans Affairs (VA) cares for more patients with hepatitis C virus (HCV) than any other US health care system. We tracked the implementation strategies that VA sites used to implement highly effective new treatments for HCV with the aim of uncovering how combinations of implementation strategies influenced the uptake of the HCV treatment innovation. We applied Configurational Comparative Methods (CCMs) to uncover causal dependencies and identify difference-making strategy configurations, and to distinguish higher from lower HCV treating sites. METHODS: We surveyed providers to assess VA sites' use of 73 implementation strategies to promote HCV treatment in the fiscal year 2015. CCMs were used to identify strategy configurations that uniquely distinguished higher HCV from lower HCV treating sites. RESULTS: From the 73 possible implementation strategies, CCMs identified 5 distinct strategy configurations, or "solution paths." These were comprised of 10 individual strategies that collectively explained 80% of the sites with higher HCV treatment starts with 100% consistency. Using any one of the following 5 solution paths was sufficient to produce higher treatment starts: (1) technical assistance; (2) engaging in a learning collaborative AND designating leaders; (3) site visits AND outreach to patients to promote uptake and adherence; (4) developing resource sharing agreements AND an implementation blueprint; OR (5) creating new clinical teams AND sharing quality improvement knowledge with other sites AND engaging patients. There was equifinality in that the presence of any one of the 5 solution paths was sufficient for higher treatment starts. CONCLUSIONS: Five strategy configurations distinguished higher HCV from lower HCV treating sites with 100% consistency. CCMs represent a methodological advancement that can help inform high-yield implementation strategy selection and increase the efficiency and effectiveness of future implementation efforts.

How did that interaction make you feel? The relationship between quality of everyday social experiences and emotion in people with and without schizophrenia.

People with schizophrenia report positive emotion during social interactions in ecological momentary assessment (EMA) studies; however, few of these studies examine the qualities of social interactions (e.g., intimacy) that may affect emotion experience. In the current EMA study, people with (n = 20) and without schizophrenia (n = 15) answered questions about the quality of their social interactions, including their emotion experiences. We also explored the relationship between EMA-reported social experiences and trait loneliness, negative symptoms, and social functioning. People with and without schizophrenia did not differ in EMA-reported proportion of time spent with others, extent of involvement during social interactions, intimacy of interactions, or average number of social interactions. Both people with and without schizophrenia reported more positive than negative emotion during social experiences. However, people with schizophrenia reported more loneliness, more severe negative symptoms, and impaired social functioning compared to people without schizophrenia. Further, specific qualities of social interactions (intimacy of interaction, involvement during interaction) were related to happiness during interactions only in people without schizophrenia. These results suggest that while people with and without schizophrenia report similar rates of in-the-moment social emotion experiences, the impact of social interaction quality on emotion may differ between groups.

Longitudinal assessment of the association between implementation strategy use and the uptake of hepatitis C treatment: Year 2.

BACKGROUND: To increase the uptake of evidence-based treatments for hepatitis C (HCV), the Department of Veterans Affairs (VA) established the Hepatitis Innovation Team (HIT) Collaborative. Teams of providers were tasked with choosing implementation strategies to improve HCV care. The aim of the current evaluation was to assess how site-level implementation strategies were associated with HCV treatment initiation and how the use of implementation strategies and their association with HCV treatment changed over time. METHODS: A key HCV provider at each VA site (N = 130) was asked in two consecutive fiscal years (FYs) to complete an online survey examining the use of 73 implementation strategies organized into nine clusters as described by the Expert Recommendations for Implementing Change (ERIC) study. The number of Veterans initiating treatment for HCV, or "treatment starts," at each site was captured using national data. Providers reported whether the use of each implementation strategy was due to the HIT Collaborative. RESULTS: Of 130 sites, 80 (62%) responded in Year 1 (FY15) and 105 (81%) responded in Year 2 (FY16). Respondents endorsed a median of 27 (IQR19-38) strategies in Year 2. The strategies significantly more likely to be chosen in Year 2 included tailoring strategies to deliver HCV care, promoting adaptability, sharing knowledge between sites, and using mass media. The total number of treatment starts was significantly positively correlated with total number of strategies endorsed in both years. In Years 1 and 2, respectively, 28 and 26 strategies were significantly associated with treatment starts; 12 strategies overlapped both years, 16 were unique to Year 1, and 14 were unique to Year 2. Strategies significantly associated with treatment starts shifted between Years 1 and 2. Pre-implementation strategies in the "training/educating," "interactive assistance," and "building stakeholder interrelationships" clusters were more likely to be significantly associated with treatment starts in Year 1, while strategies in the "evaluative and iterative" and "adapting and tailoring" clusters were more likely to be associated with treatment starts in Year 2. Approximately half of all strategies were attributed to the HIT Collaborative. CONCLUSIONS: These results suggest that measuring implementation strategies over time is a useful way to catalog implementation of an evidence-based practice over time and across settings.

Cellular fate decisions in the developing female anteroventral periventricular nucleus are regulated by canonical Notch signaling.

The hypothalamic anteroventral periventricular nucleus (AVPV) is the major regulator of reproductive function within the hypothalamic-pituitary-gonadal (HPG) axis. Despite an understanding of the function of neuronal subtypes within the AVPV, little is known about the molecular mechanisms regulating their development. Previous work from our laboratory has demonstrated that Notch signaling is required in progenitor cell maintenance and formation of kisspeptin neurons of the arcuate nucleus (ARC) while simultaneously restraining POMC neuron number. Based on these findings, we hypothesized that the Notch signaling pathway may act similarly in the AVPV by promoting development of kisspeptin neurons at the expense of other neuronal subtypes. To address this hypothesis, we utilized a genetic mouse model with a conditional loss of Rbpj in Nkx2.1 expressing cells (Rbpj cKO). We noted an increase in cellular proliferation, as marked by Ki-67, in the hypothalamic ventricular zone (HVZ) in Rbpj cKO mice at E13.5. This corresponded to an increase in general neurogenesis and more TH-positive neurons. Additionally, an increase in OLIG2-positive early oligodendrocytic precursor cells was observed at postnatal day 0 in Rbpj cKO mice. By 5 weeks of age in Rbpj cKO mice, TH-positive cells were readily detected in the AVPV but few kisspeptin neurons were present. To elucidate the direct effects of Notch signaling on neuron and glia differentiation, an in vitro primary hypothalamic neurosphere assay was employed. We demonstrated that treatment with the chemical Notch inhibitor DAPT increased mKi67 and Olig2 mRNA expression while decreasing astroglial Gfap expression, suggesting Notch signaling regulates both proliferation and early glial fate decisions. A modest increase in expression of TH in both the cell soma and neurite extensions was observed after extended culture, suggesting that inhibition of Notch signaling alone is enough to bias progenitors towards a dopaminergic fate. Together, these data suggest that Notch signaling restricts early cellular proliferation and differentiation of neurons and oligodendrocytes both in vivo and in vitro and acts as a fate selector of kisspeptin neurons.

Hepatitis C Care in the Department of Veterans Affairs: Building a Foundation for Success.

The Department of Veterans Affairs (VA) has made significant progress in treating hepatitis C virus, experiencing more than a 75% reduction in veterans remaining to be treated since the availability of oral direct-acting antivirals. Hepatitis C Innovation Teams use lean process improvement and system redesign, resulting in practice models that address gaps in care. The key to success is creative improvements in veteran access to providers, including expanded use of nonphysician providers, video telehealth, and electronic technologies. Population health management tools monitor and identify trends in care, helping the VA tailor care and address barriers.

Screening and Treating Hepatitis C in the VA: Achieving Excellence Using Lean and System Redesign.

The national effort to redesign care using Lean management strategies, develop local and regional teams, and centralize support allowed VA to maximize available resources to achieve higher rates of testing and treatment of patients with hepatitis C virus than that of any other health care system in the US.

The association between implementation strategy use and the uptake of hepatitis C treatment in a national sample.

BACKGROUND: Hepatitis C virus (HCV) is a common and highly morbid illness. New medications that have much higher cure rates have become the new evidence-based practice in the field. Understanding the implementation of these new medications nationally provides an opportunity to advance the understanding of the role of implementation strategies in clinical outcomes on a large scale. The Expert Recommendations for Implementing Change (ERIC) study defined discrete implementation strategies and clustered these strategies into groups. The present evaluation assessed the use of these strategies and clusters in the context of HCV treatment across the US Department of Veterans Affairs (VA), Veterans Health Administration, the largest provider of HCV care nationally. METHODS: A 73-item survey was developed and sent to all VA sites treating HCV via electronic survey, to assess whether or not a site used each ERIC-defined implementation strategy related to employing the new HCV medication in 2014. VA national data regarding the number of Veterans starting on the new HCV medications at each site were collected. The associations between treatment starts and number and type of implementation strategies were assessed. RESULTS: A total of 80 (62%) sites responded. Respondents endorsed an average of 25 ± 14 strategies. The number of treatment starts was positively correlated with the total number of strategies endorsed (r = 0.43, p < 0.001). Quartile of treatment starts was significantly associated with the number of strategies endorsed (p < 0.01), with the top quartile endorsing a median of 33 strategies, compared to 15 strategies in the lowest quartile. There were significant differences in the types of strategies endorsed by sites in the highest and lowest quartiles of treatment starts. Four of the 10 top strategies for sites in the top quartile had significant correlations with treatment starts compared to only 1 of the 10 top strategies in the bottom quartile sites. Overall, only 3 of the top 15 most frequently used strategies were associated with treatment. CONCLUSIONS: These results suggest that sites that used a greater number of implementation strategies were able to deliver more evidence-based treatment in HCV. The current assessment also demonstrates the feasibility of electronic self-reporting to evaluate ERIC strategies on a large scale. These results provide initial evidence for the clinical relevance of the ERIC strategies in a real-world implementation setting on a large scale. This is an initial step in identifying which strategies are associated with the uptake of evidence-based practices in nationwide healthcare systems.

Do people with schizophrenia experience more negative emotion and less positive emotion in their daily lives? A meta-analysis of experience sampling studies.

Research on emotion experience in response to valenced stimuli has consistently shown that people with schizophrenia have the capacity to experience emotion. Specifically, people with schizophrenia report similar experiences to both positive and negative emotion-eliciting stimuli as individuals without the disorder. However, it is less clear if people with schizophrenia experience similar levels of positive emotion and negative emotion outside of standardized laboratory contexts, as in their daily lives. One reliable method for assessing emotion experience in schizophrenia has been the Experience Sampling Method (ESM), or Ecological Momentary Assessment (EMA). Using the PRISMA guidelines for meta-analysis, we reviewed the literature for all studies that included people with and without schizophrenia, and that included a positive or negative emotion assessment during participants' daily lives. The current study is a meta-analysis of 12 EMA studies of emotion experience, which included a total of 619 people with schizophrenia and 730 healthy controls. Results indicate that people with schizophrenia consistently report more negative and less positive emotion than healthy control participants. These findings differ from laboratory-based studies, which may be due to several factors, including environmental differences, effects of the disorder that appear more clearly in daily life, or additional concerns, such as depression, which has been shown to be related to negative emotion in schizophrenia. Importantly, these findings are in line with questionnaire-based measures of emotion experience, lending some support for their use in research and clinical settings.

A Phase II Randomized, Controlled Trial of S-Adenosylmethionine in Reducing Serum α-Fetoprotein in Patients with Hepatitis C Cirrhosis and Elevated AFP.

In animal models of hepatocellular carcinoma (HCC), deficiency of S-adenosylmethionine (SAMe) increased the risk of HCC whereas administration of SAMe reduced HCC. The aim of this trial was to determine whether oral SAMe administration to patients with hepatitis C cirrhosis would decrease serum α-fetoprotein (AFP) level, a biomarker of HCC risk in hepatitis C. This was a prospective, randomized, placebo-controlled, double-blind trial of SAMe, up to 2.4 g/d, for 24 weeks as compared with placebo among subjects with hepatitis C cirrhosis and a mildly elevated serum AFP. Primary outcome was change in AFP between baseline and week 24. Secondary outcomes included changes in routine tests of liver function and injury, other biomarkers of HCC risk, SAMe metabolites, markers of oxidative stress, and quality of life. One hundred ten subjects were randomized and 87 (44 SAMe and 43 placebo) completed treatment. There was no difference in the change in AFP during 24 weeks among subjects receiving SAMe as compared with placebo. Changes in markers of liver function, liver injury, and hepatitis C viral level were not significantly different between groups. Similarly, SAMe did not change markers of oxidative stress or serum glutathione level. SAMe blood level increased significantly among subjects receiving SAMe. Changes in quality of life did not differ between groups. Overall, this trial did not find that SAMe treatment improved serum AFP in subjects with advanced hepatitis C cirrhosis and a mildly elevated AFP. SAMe did not improve tests of liver function or injury or markers of oxidative stress or antioxidant potential.