Global prevalence, clinical characteristics, surveillance, treatment allocation, and outcomes of alcohol-associated hepatocellular carcinoma.

BACKGROUND AND AIMS: Although the burden of alcohol-associated hepatocellular carcinoma (HCC) is increasing with rising alcohol consumption, clinical presentation and outcomes of alcohol-associated HCC have not been systematically assessed. We aimed to determine the prevalence, clinical characteristics, surveillance rates, treatment allocation, and outcomes of alcohol-associated HCC. METHODS: Medline and Embase were searched from inception to January 2023. Proportional data were analyzed using a generalized linear mixed model. The odds ratio (OR) or mean difference comparing alcohol-associated HCC and other causes was obtained with pairwise meta-analysis. Survival outcomes were evaluated using a pooled analysis of hazard ratios. RESULTS: Of 4,824 records identified, 55 articles (86,345 patients) were included. Overall, 30.4% (CI: 24.0%-37.7%) of HCC were alcohol-associated, with the highest proportion in Europe and the lowest in the Americas. People with alcohol-associated HCC were more likely male, but similar in age and comorbidities, compared to other causes. 20.8% (CI: 11.4%-34.9%) of people with alcohol-associated HCC underwent surveillance compared to 35.0%, 31.6%, and 21.4% in hepatitis B virus, hepatitis C virus, and metabolic dysfunction-associated HCC, respectively (all P<0.05). Alcohol-associated HCC had a lower likelihood of BCLC stage (0/A) (OR: 0.7, CI: 0.6-0.9; P=0.018) and curative therapy (24.5% vs 33.9%; OR 0.7, CI: 0.5-0.9; P=0.003), and higher mortality (HR: 1.3, CI: 1.1-1.5, P=0.012) when compared to other causes. CONCLUSIONS: Alcohol-associated HCC is associated with lower surveillance rates, more advanced BCLC stage, lower likelihood of receiving curative therapy, and poorer survival. These data call for measures to reduce heavy alcohol consumption and improve strategies for effective HCC surveillance in high-risk individuals.

Screening for Hepatocellular Carcinoma and Survival in Patients With Cirrhosis After Hepatitis C Virus Cure.

Importance: The risk of hepatocellular carcinoma (HCC) declines over time after hepatitis C virus (HCV) cure by direct-acting antiviral (DAA) therapies. Liver society guidelines recommend continuing HCC screening for these patients, but data on screening outcomes are lacking. Objective: To evaluate the association of HCC screening after HCV cure with overall survival. Design, Setting, and Participants: This cohort study evaluated patients with HCV cirrhosis who achieved DAA-induced HCV cure in the Veterans Affairs health care system between January 2014 and December 2022. Data analysis occurred from October 2023 to January 2024. Exposures: The percentage of time spent up to date with recommended HCC screening was calculated by year of follow-up and during the 4 years preceding HCC diagnosis (the detectable asymptomatic phase). Main Outcomes and Measures: The primary outcome was overall survival after HCC diagnosis and was compared by percentage of time spent up to date with screening using Kaplan-Meier analyses and Cox proportional hazards regression. Early-stage HCC at diagnosis and curative treatment were secondary outcomes assessed using logistic regression. Results: A total of 16 902 individuals were included (median [IQR] age, 64.0 [60.5-67.4] years; 16 426 male [97.2%]), of whom 1622 developed HCC. The cumulative incidence of HCC declined from 2.4% (409 of 16 902 individuals) to 1.0% (27 of 2833 individuals) from year 1 to year 7 of follow-up. Being up to date with screening for at least 50% of time during the 4 years preceding HCC diagnosis was associated with improved overall survival (log-rank test of equality over strata P = .002). In multivariate analysis, each 10% increase in follow-up spent up to date with screening was associated with a 3.2% decrease in the hazard of death (hazard ratio, 0.97; 95% CI, 0.95-0.99). There was a statistically significant interaction between time since HCV cure and screening, with no association observed among those who received a diagnosis of HCC more than 5 years after HCV cure. Each 10% of time spent up to date with screening was associated with a 10.1% increased likelihood of diagnosis with early-stage HCC (95% CI, 6.3%-14.0%) and a 6.8% increased likelihood of curative treatment (95% CI, 2.8%-11.0%). Conclusions and Relevance: In this cohort study of persons with HCV-related cirrhosis who achieved HCV cure and subsequently developed HCC, remaining up to date with screening was associated with improved overall survival, supporting the screening of eligible individuals.

Sex and Race-Ethnic Disparities in Metabolic Dysfunction-Associated Steatotic Liver Disease: An Analysis of 40,166 Individuals.

BACKGROUND: To overcome the limitations of the term "non-alcoholic fatty liver disease" (NAFLD), the term metabolic-associated steatotic liver disease (MASLD) was introduced. While epidemiologic studies have been conducted on MASLD, there is limited evidence on its associated sex and ethnic variations. AIMS: This study assesses the differences across sex and race-ethnicity on the prevalence, associated risk factors and adverse outcomes in individuals with MASLD. METHODS: Data retrieved from the National Health and Nutrition Examination Survey between 1999 to 2018 was analyzed. Prevalence, clinical characteristics, and outcomes were evaluated according to sex and race-ethnicity. Adverse outcomes and mortality events were analyzed using multivariate analyses. RESULTS: Of 40,166 individuals included, 37.63% had MASLD. There was a significant increase in MASLD prevalence from 1999 to 2018 among Mexican Americans (Annual Percentage Change [APC] + 1.889%, p < 0.001), other Hispanics (APC + 1.661%, p = 0.013), NH Whites (APC + 1.084%, p = 0.018), NH Blacks (APC + 1.108%, p = 0.007), and females (APC + 0.879%, p = 0.030), but not males. Females with MASLD were at lower risk of all-cause (HR: 0.766, 95%CI 0.711 to 0.825, p < 0.001), cardiovascular disease-related (CVD) (SHR: 0.802, 95% CI 0.698 to 0.922, p = 0.002) and cancer-related mortality (SHR: 0.760, 95% CI 0.662 to 0.873, p < 0.001). Significantly, NH Blacks have the highest risk of all-cause and CVD-related mortality followed by NH Whites then Mexican Americans. CONCLUSION: There has been an increase in prevalence in most race-ethnicities over time. While the change in definition shows no significant differences in previous associations found in NAFLD, the increased mortality in NH Whites relative to Mexican Americans remains to be explored.

Identifying Veterans Who Benefit From Nirmatrelvir-Ritonavir: A Target Trial Emulation.

BACKGROUND: Nirmatrelvir-ritonavir is recommended for persons at risk for severe coronavirus disease 2019 (COVID-19) but remains underutilized. Information on which eligible groups are likely to benefit from treatment is needed. METHODS: We conducted a target trial emulation study in the Veterans Health Administration comparing nirmatrelvir-ritonavir treated versus matched untreated veterans at risk for severe COVID-19 who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from April 2022 through March 2023. We measured incidence of any hospitalization or all-cause mortality at 30 days. Outcomes were measured for the entire cohort, as well as among subgroups defined by 30-day risk of death or hospitalization, estimated using an ensemble risk prediction model. RESULTS: Participants were 87% male with median age 66 years and 16% unvaccinated. Compared with matched untreated participants, those treated with nirmatrelvir-ritonavir (n = 24 205) had a lower 30-day risk for hospitalization (1.80% vs 2.30%; risk difference [RD], -0.50% points [95% confidence interval {CI}: -.69 to -.35]) and death (0.11% vs 0.30%; RD, -0.20 [95% CI: -.24 to -.13]). The greatest reductions in combined hospitalization or death were observed in the highest risk quartile (RD -2.85 [95% CI: -3.94 to -1.76]), immunocompromised persons (RD -1.91 [95% CI: -3.09 to -.74]), and persons aged ≥75 years (RD -1.16 [95% CI: -1.73 to -.59]). No reductions were observed in the 2 lowest risk quartiles or persons younger than 65 years. CONCLUSIONS: Nirmatrelvir-ritonavir was effective in reducing 30-day hospitalization and death in older veterans, those at highest predicted risk for severe outcomes, and immunocompromised groups. Benefit was not observed in younger veterans or groups at lower predicted risk for hospitalization and death.

Regional variation in financial hardship among US veterans during the COVID-19 pandemic.

Geographic variation in hardship, especially health-related hardship, was identified prior to and during the pandemic, but we do not know whether this variation is consistent among Veterans Health Administration (VHA)-enrolled veterans, who reported markedly high rates of financial hardship during the pandemic, despite general and veteran-specific federal policy efforts aimed at reducing hardship. In a nationwide, regionally stratified sample of VHA-enrolled veterans, we examined whether the prevalence of financial hardship during the pandemic varied by US Census region. We found veterans in the South, compared with those in other census regions, reported higher rates of severe-to-extreme financial strain, using up all or most of their savings, being unable to pay for necessities, being contacted by collections, and changing their employment due to the kind of work they could perform. Regional variation in veteran financial hardship demonstrates a need for further research about the role and interaction of federal and state financial-assistance policies in shaping risks for financial hardship as well as potential opportunities to mitigate risks among veterans and reduce variation across regions.

Statewide Survey of Primary Care and Subspecialty Providers on Hepatocellular Carcinoma Risk-Stratification and Surveillance Practices.

BACKGROUND: Hepatocellular carcinoma (HCC) surveillance in patients with cirrhosis is associated with improved survival. Provision of HCC surveillance is low in the US, particularly in primary care settings. AIMS: To evaluate current hepatitis C virus (HCV) and HCC surveillance practices and physician attitudes regarding HCC risk-stratification among primary care and subspecialty providers. METHODS: Using the Tailored Design Method, we delivered a 34-item online survey to 7654 North Carolina-licensed internal/family medicine or gastroenterology/hepatology physicians and advanced practice providers in 2022. We included the domains of HCV treatment, cirrhosis diagnosis, HCC surveillance practices, barriers to surveillance, and interest in risk-stratification tools. We performed descriptive analyses to summarize responses. Tabulations were weighted based on sampling weights accounting for non-response and inter-specialty comparisons were made using chi-squared or t test statistics. RESULTS: After exclusions, 266 responses were included in the final sample (response rate 3.8%). Most respondents (78%) diagnosed cirrhosis using imaging and a minority used non-invasive tests that were blood-based (~ 15%) or transient elastography (31%). Compared to primary care providers, subspecialists were more likely to perform HCC surveillance every 6-months (vs annual) (98% vs 35%, p < 0.0001). Most respondents (80%) believed there were strong data to support HCC surveillance, but primary care providers did not know which liver disease patients needed surveillance. Most providers (> 70%) expressed interest in potential solutions to improve HCC risk-stratification. CONCLUSIONS: In this statewide survey, there were great knowledge gaps in HCC surveillance among PCPs and most respondents expressed interest in strategies to increase appropriate HCC surveillance.

Risk of Potentially Preventable Hospitalizations After SARS-CoV-2 Infection.

Importance: Research demonstrates that SARS-CoV-2 infection is associated with increased risk of all-cause hospitalization. However, no prior studies have assessed the association between SARS-CoV-2 and potentially preventable hospitalizations-that is, hospitalizations for conditions that can usually be effectively managed in ambulatory care settings. Objective: To examine whether SARS-CoV-2 is associated with potentially preventable hospitalization in a nationwide cohort of US veterans. Design, Setting, and Participants: This cohort study used an emulated target randomized trial design with monthly sequential trials to compare risk of a potentially preventable hospitalization among veterans with SARS-CoV-2 and matched comparators without SARS-CoV-2. A total of 189 136 US veterans enrolled in the Veterans Health Administration (VHA) who were diagnosed with SARS-CoV-2 between March 1, 2020, and April 30, 2021, and 943 084 matched comparators were included in the analysis. Data were analyzed from May 10, 2023, to January 26, 2024. Exposure: SARS-CoV-2 infection. Main Outcomes and Measures: The primary outcome was a first potentially preventable hospitalization in VHA facilities, VHA-purchased community care, or Medicare fee-for-service care. Extended Cox models were used to examine adjusted hazard ratios (AHRs) of potentially preventable hospitalization among veterans with SARS-CoV-2 and comparators during follow-up periods of 0 to 30, 0 to 90, 0 to 180, and 0 to 365 days. The start of follow-up was defined as the date of each veteran's first positive SARS-CoV-2 diagnosis, with the same index date applied to their matched comparators. Results: The 1 132 220 participants were predominantly men (89.06%), with a mean (SD) age of 60.3 (16.4) years. Most veterans were of Black (23.44%) or White (69.37%) race. Veterans with SARS-CoV-2 and comparators were well-balanced (standardized mean differences, all <0.100) on observable baseline clinical and sociodemographic characteristics. Overall, 3.10% of veterans (3.81% of those with SARS-CoV-2 and 2.96% of comparators) had a potentially preventable hospitalization during 1-year follow-up. Risk of a potentially preventable hospitalization was greater among veterans with SARS-CoV-2 than comparators in 4 follow-up periods: 0- to 30-day AHR of 3.26 (95% CI, 3.06-3.46); 0- to 90-day AHR of 2.12 (95% CI, 2.03-2.21); 0- to 180-day AHR of 1.69 (95% CI, 1.63-1.75); and 0- to 365-day AHR of 1.44 (95% CI, 1.40-1.48). Conclusions and Relevance: In this cohort study, an increased risk of preventable hospitalization in veterans with SARS-CoV-2, which persisted for at least 1 year after initial infection, highlights the need for research on ways in which SARS-CoV-2 shapes postinfection care needs and engagement with the health system. Solutions are needed to mitigate preventable hospitalization after SARS-CoV-2.

Organizational and Implementation Factors Associated with Cirrhosis Care in the Veterans Health Administration.

BACKGROUND: The Veterans Health Administration provides care to more than 100,000 Veterans with cirrhosis. AIMS: This implementation evaluation aimed to understand organizational resources and barriers associated with cirrhosis care. METHODS: Clinicians across 145 Department of Veterans Affairs (VA) medical centers (VAMCs) were surveyed in 2022 about implementing guideline-concordant cirrhosis care. VA Corporate Data Warehouse data were used to assess VAMC performance on two national cirrhosis quality measures: HCC surveillance and esophageal variceal surveillance or treatment (EVST). Organizational factors associated with higher performance were identified using linear regression models. RESULTS: Responding VAMCs (n = 124, 86%) ranged in resource availability, perceived barriers, and care processes. In multivariable models, factors independently associated with HCC surveillance included on-site interventional radiology and identifying patients overdue for surveillance using a national cirrhosis population management tool ("dashboard"). EVST was significantly associated with dashboard use and on-site gastroenterology services. For larger VAMCs, the average HCC surveillance rate was similar between VAMCs using vs. not using the dashboard (47% vs. 41%), while for smaller and less resourced VAMCs, dashboard use resulted in a 13% rate difference (46% vs. 33%). Likewise, higher EVST rates were more strongly associated with dashboard use in smaller (55% vs. 50%) compared to larger (57% vs. 55%) VAMCs. CONCLUSIONS: Resources, barriers, and care processes varied across diverse VAMCs. Smaller VAMCs without specialty care achieved HCC and EVST surveillance rates nearly as high as more complex and resourced VAMCs if they used a population management tool to identify the patients due for cirrhosis care.

Impact of SARS-CoV-2 Infection on Long-Term Depression Symptoms among Veterans.

BACKGROUND: Prior research demonstrates that SARS-COV-2 infection can be associated with a broad range of mental health outcomes including depression symptoms. Veterans, in particular, may be at elevated risk of increased depression following SARS-COV-2 infection given their high rates of pre-existing mental and physical health comorbidities. However, few studies have tried to isolate SARS-COV-2 infection associations with long term, patient-reported depression symptoms from other factors (e.g., physical health comorbidities, pandemic-related stress). OBJECTIVE: To evaluate the association between SARS-COV-2 infection and subsequent depression symptoms among United States Military Veterans. DESIGN: Survey-based non-randomized cohort study with matched comparators. PARTICIPANTS: A matched-dyadic sample from a larger, stratified random sample of participants with and without known to SARS-COV-2 infection were invited to participate in a survey evaluating mental health and wellness 18-months after their index infection date. Sampled participants were stratified by infection severity of the participant infected with SARS-COV-2 (hospitalized or not) and by month of index date. A total of 186 participants in each group agreed to participate in the survey and had sufficient data for inclusion in analyses. Those in the uninfected group who were later infected were excluded from analyses. MAIN MEASURES: Participants were administered the Patient Health Questionnaire-9 as part of a phone interview survey. Demographics, physical and mental health comorbidities were extracted from VHA administrative data. KEY RESULTS: Veterans infected with SARS-COV-2 had significantly higher depression symptoms scores compared with those uninfected. In particular, psychological symptoms (e.g., low mood, suicidal ideation) scores were elevated relative to the comparator group (MInfected = 3.16, 95%CI: 2.5, 3.8; MUninfected = 1.96, 95%CI: 1.4, 2.5). Findings were similar regardless of history of depression. CONCLUSION: SARS-COV-2 infection was associated with more depression symptoms among Veterans at 18-months post-infection. Routine evaluation of depression symptoms over time following SARS-COV-2 infection is important to facilitate adequate assessment and treatment.

Self-Reported Everyday Functioning After COVID-19 Infection.

Importance: Changes in everyday functioning are crucial to assessing the long-term impact of COVID-19 infection. Objective: To examine the impact of COVID-19 infection on everyday functioning 18 months after infection among veterans with and without histories of COVID-19 infection. Design, Setting, and Participants: This cohort study used data from the US Veterans Affairs (VA) and included 186 veterans who had COVID-19 between October 2020 and April 2021 (ie, COVID-19 cohort) and 186 matched comparators who did not have documented COVID-19 infections (ie, control cohort). This match balanced the risk of COVID-19 based on 39 variables measured in the 24 months before infection or match, using principles of target trial emulation. Data were analyzed from December 2022 to December 2023. Exposure: First documented COVID-19. Main Outcome and Measures: The differences in self-reported everyday functioning 18 months after COVID-19 infection were estimated and compared with their matched comparators. Within-matched pair logistic and linear regressions assessed differences in outcomes and were weighted to account for sampling and nonresponse. Results: Among the 186 matched pairs of participants, their weighted mean age was 60.4 (95% CI, 57.5 to 63.2) years among veterans in the COVID-19 cohort (weighted sample, 91 459 of 101 133 [90.4%] male; 30 611 [30.3%] Black or African American veterans; 65 196 [64.4%] White veterans) and 61.1 (95% CI, 57.8 to 64.4) years among their comparators in the control cohort (91 459 [90.4%] male; 24 576 [24.3%] Black or African American veterans; 70 157 [69.4%] White veterans). A high proportion of veterans in the COVID-19 cohort (weighted percentage, 44.9% [95% CI, 34.2% to 56.2%]) reported that they could do less than what they felt they could do at the beginning of 2020 compared with the control cohort (weighted percentage, 35.3%; [95% CI, 25.6% to 46.4%]; within-matched pair adjusted odds ratio [OR], 1.52 [95% CI, 0.79 to 2.91]). There was no association of documented COVID-19 infection with fatigue, substantial pain, limitations in either activities of daily living and instrumental activities of daily living, severely curtailed life-space mobility, employment, or mean health-related quality of life on a utility scale. Conclusions and Relevance: In this cohort study of veterans with and without documented COVID-19, many reported a substantial loss of everyday functioning during the pandemic regardless of whether or not they had a documented infection with COVID-19. Future work with larger samples is needed to validate the estimated associations.

Changes in Outpatient Health Care Use After COVID-19 Infection Among Veterans.

Importance: The association of COVID-19 infection with outpatient care utilization is unclear. Many studies reported population surveillance studies rather than comparing outpatient health care use between COVID-19-infected and uninfected cohorts. Objective: To compare outpatient health care use across 6 categories of care (primary care, specialty care, surgery care, mental health, emergency care, and diagnostic and/or other care) between veterans with or without COVID-19 infection. Design, Setting, and Participants: In a retrospective cohort study of Veterans Affairs primary care patients, veterans with COVID-19 infection were matched to a cohort of uninfected veterans. Data were obtained from the Veterans Affairs Corporate Data Warehouse and the Centers for Medicare & Medicaid Services Fee-for-Service Carrier/Physician Supplier file from January 2019 through December 2022. Data analysis was performed from September 2022 to April 2023. Exposure: COVID-19 infection. Main Outcomes and Measures: The primary outcome was the count of outpatient visits after COVID-19 infection. Negative binomial regression models compared outpatient use over a 1-year preinfection period, and peri-infection (0-30 days), intermediate (31-183 days), and long-term (184-365 days) postinfection periods. Results: The infected (202 803 veterans; mean [SD] age, 60.5 [16.2] years; 178 624 men [88.1%]) and uninfected (202 803 veterans; mean [SD] age, 60.4 [16.5] years; 178 624 men [88.1%]) cohorts were well matched across all covariates. Outpatient use in all categories (except surgical care) was significantly elevated during the peri-infection period for veterans with COVID-19 infection compared with the uninfected cohort, with an increase in all visits of 5.12 visits per 30 days (95% CI, 5.09-5.16 visits per 30 days), predominantly owing to primary care visits (increase of 1.86 visits per 30 days; 95% CI, 1.85-1.87 visits per 30 days). Differences in outpatient use attenuated over time but remained statistically significantly higher at 184 to 365 days after infection (increase of 0.25 visit per 30 days; 95% CI, 0.23-0.27 visit per 30 days). One-half of the increased outpatient visits were delivered via telehealth. The utilization increase was greatest for veterans aged 85 years and older (6.1 visits, 95% CI, 5.9-6.3 visits) vs those aged 20 to 44 years (4.8 visits, 95% CI, 4.7-4.8 visits) and unvaccinated veterans (4.5 visits, 95% CI, 4.3-4.6 visits) vs vaccinated veterans (3.2 visits; 95% CI, 3.4-4.8 visits). Conclusions and Relevance: This study found that outpatient use increased significantly in the month after infection, then attenuated but remained greater than the uninfected cohorts' use through 12 months, which suggests that there are sustained impacts of COVID-19 infection.

Perspectives of clinical stakeholders and patients from four VA liver clinics to tailor practice facilitation for implementing evidence-based alcohol-related care.

BACKGROUND: Unhealthy alcohol use (UAU) is particularly dangerous for people with chronic liver disease. Liver clinics may be an important setting in which to provide effective alcohol-related care by integrating evidence-based strategies, such as brief intervention and medications for alcohol use disorder. We conducted qualitative interviews with clinical stakeholders and patients at liver clinics in four Veterans Health Administration (VA) medical centers to understand barriers and facilitators of integrating alcohol-related care and to support tailoring of a practice facilitation implementation intervention. METHODS: Data collection and analysis were guided by the Consolidated Framework for Implementation Research (CFIR). Interviews were transcribed and qualitatively analyzed using a Rapid Assessment Process (RAP) guided by the CFIR. RESULTS: We interviewed 46 clinical stakeholders and 41 patient participants and analyzed findings based on the CFIR. Clinical stakeholders described barriers and facilitators that ranged from operations/clinic resource-based (e.g., time and capacity, desire for additional provider types, referral processes) to individual perspective and preference-based (e.g., supportiveness of leadership, individual experiences/beliefs). Patient participants shared barriers and facilitators that ranged from relationship-based (e.g., trusting the provider and feeling judged) to resource and education-based (e.g., connection to a range of treatment options, education about impact of alcohol). Many barriers and facilitators to integrating alcohol-related care in liver clinics were similar to those identified in other clinical settings (e.g., time, resources, role clarity, stigmatizing beliefs). However, some barriers (e.g., fellow-led care and lack of integration of liver clinics with addictions specialists) and facilitators (e.g., presence of quality improvement staff in clinics and integrated pharmacists and behavioral health specialists) were more unique to liver clinics. CONCLUSIONS: These findings support the possibility of integrating alcohol-related care into liver clinics but highlight the importance of tailoring efforts to account for variation in provider beliefs and experiences and clinic resources. The barriers and facilitators identified in these interviews were used to tailor a practice facilitation implementation intervention in each clinic setting.

Discrimination of lipid composition and cellular localization in human liver tissues by stimulated Raman scattering microscopy.

Significance: The molecular mechanisms driving the progression from nonalcoholic fatty liver (NAFL) to fibrosing steatohepatitis (NASH) are insufficiently understood. Techniques enabling the characterization of different lipid species with both chemical and spatial information can provide valuable insights into their contributions to the disease progression. Aim: We extend the utility of stimulated Raman scattering (SRS) microscopy to characterize and quantify lipid species in liver tissue sections from patients with NAFL and NASH. Approach: We applied a dual-band hyperspectral SRS microscopy system for imaging tissue sections in both the C-H stretching and fingerprint regions. The same sections were imaged with polarization microscopy for detecting birefringent liquid crystals in the tissues. Results: Our imaging and analysis pipeline provides accurate classification and quantification of free cholesterol, saturated cholesteryl esters (CEs), unsaturated CE, and triglycerides in liver tissue sections. The subcellular resolution enables investigations of the heterogeneous distribution of saturated CE, which has been under-examined in previous studies. We also discovered that the birefringent crystals, previously found to be associated with NASH development, are predominantly composed of saturated CE. Conclusions: Our method allows for a detailed characterization of lipid composition in human liver tissues and enables further investigation into the potential mechanism of NASH progression.

Hepatocellular Carcinoma Diagnosis and Management in 2021: A National Veterans Affairs Quality Improvement Project.

BACKGROUND & AIMS: The coronavirus disease-2019 pandemic profoundly disrupted preventative health care services including cancer screening. As the largest provider of cirrhosis care in the United States, the Department of Veterans Affairs (VA) National Gastroenterology and Hepatology Program aimed to assess factors associated with hepatocellular carcinoma (HCC) stage at diagnosis, treatment, and survival. METHODS: Veterans with a new diagnosis of HCC in 2021 were identified from electronic health records (N = 2306). Structured medical record extraction was performed by expert reviewers in a 10% random subsample of Veterans with new HCC diagnoses. Factors associated with stage at diagnosis, receipt of treatment, and survival were assessed using multivariable models. RESULTS: Among 199 patients with confirmed HCC, the average age was 71 years and most (72%) had underlying cirrhosis. More than half (54%) were at an early stage (T1 or T2) at diagnosis. Less-advanced liver disease, number of imaging tests adequate for HCC screening, HCC diagnosis in the VA, and receipt of VA primary care were associated significantly with early stage diagnosis. HCC-directed treatments were administered to 145 (73%) patients after a median of 37 days (interquartile range, 19-54 d) from diagnosis, including 70 (35%) patients who received potentially curative treatments. Factors associated with potentially curative (vs no) treatments included HCC screening, early stage at diagnosis, and better performance status. Having fewer comorbidities and better performance status were associated significantly with noncurative (vs no) treatment. Early stage diagnosis, diagnosis in the VA system, and receipt of curative treatment were associated significantly with survival. CONCLUSIONS: These results highlight the importance of HCC screening and engagement in care for HCC diagnosis, treatment, and survival while demonstrating the feasibility of developing a national quality improvement agenda for HCC screening, diagnosis, and treatment.

Hepatocellular carcinoma risk decreases as time accrues following hepatitis C virus eradication.

BACKGROUND: It is unclear whether the risk of hepatocellular carcinoma (HCC) decreases over time following hepatitis C virus (HCV) eradication. AIM: To determine if patients who have accrued longer time since sustained virologic response (SVR) have a lower risk of HCC than those with less time since SVR METHODS: We conducted a retrospective cohort study of all HCV-infected Veterans Affairs patients who achieved SVR before 1 January 2018 and remained alive without a diagnosis of HCC as of 1 January 2019 (n = 75,965). We ascertained their baseline characteristics as of 1 January 2019 (time zero), including time accrued since SVR and followed them for the subsequent 12 months for incident HCC. We used multivariable Cox proportional hazards regression to determine the association between time since SVR and HCC risk after adjusting for age, race/ethnicity, sex, diabetes, hypertension, body mass index, alcohol use, Charlson Comorbidity Index, Fibrosis-4 score, HCV genotype, hepatitis B virus co-infection and HIV co-infection. RESULTS: 96.0% were male; mean age was 64.6 years. Among those with cirrhosis (n = 19,678, 25.9%), compared to patients who had accrued only ≥1 to 2 years since SVR (HCC incidence 2.71/100 person-years), those who had accrued >2 to 4 years (2.11/100 person-years, aHR 0.80, 95% CI 0.63-1.01) and >4 to 6 years (1.65/100 person-years, aHR 0.61, 95% CI 0.41-0.90) had progressively lower HCC risk. However, HCC risk appeared to plateau for those with >6 years since SVR (1.68/100 person-years, aHR 0.70, 95% CI 0.46-1.07). Among those without cirrhosis, HCC risk was 0.23-0.27/100 person-years without a significant association between time since SVR and HCC risk. CONCLUSIONS: Among patients with cirrhosis and cured HCV infection, HCC risk declined progressively up to 6 years post-SVR-although it remained well above thresholds that warrant screening. This suggests that time since SVR can inform HCC surveillance strategies in patients with cured HCV infection and can be incorporated into HCC risk prediction models.

Risk of Suicide-Related Outcomes After SARS-COV-2 Infection: Results from a Nationwide Observational Matched Cohort of US Veterans.

BACKGROUND: Negative mental health-related effects of SARS-COV-2 infection are increasingly evident. However, the impact on suicide-related outcomes is poorly understood, especially among populations at elevated risk. OBJECTIVE: To determine risk of suicide attempts and other self-directed violence (SDV) after SARS-COV-2 infection in a high-risk population. DESIGN: We employed an observational design supported by comprehensive electronic health records from the Veterans Health Administration (VHA) to examine the association of SARS-COV-2 infection with suicide attempts and other SDV within one year of infection. Veterans with SARS-COV-2 infections were matched 1:5 with non-infected comparators each month. Three periods after index were evaluated: days 1-30, days 31-365, and days 1-365. PARTICIPANTS: VHA patients infected with SARS-COV-2 between March 1, 2020 and March 31, 2021 and matched non-infected Veteran comparators. MAIN MEASURES: Suicide attempt and other SDV events for the COVID-19 and non-infected comparator groups were analyzed using incidence rates per 100,000 person years and hazard ratios from Cox regressions modeling time from matched index date to first event. Subgroups were also examined. KEY RESULTS: 198,938 veterans with SARS-COV-2 (COVID-19 group) and 992,036 comparators were included. Unadjusted one-year incidence per 100,000 for suicide attempt and other SDV was higher among the COVID-19 group: 355 vs 250 and 327 vs 235, respectively. The COVID-19 group had higher risk than comparators for suicide attempts: days 1-30 hazard ratio (HR) = 2.54 (CI:2.05, 3.15), days 31-365 HR = 1.30 (CI:1.19, 1.43) and days 1-365 HR = 1.41 (CI:1.30, 1.54), and for other SDV: days 1-30 HR = 1.94 (CI:1.51, 2.49), days 31-365 HR = 1.32 (CI:1.20, 1.45) and days 1-365 HR = 1.38 (CI:1.26, 1.51). CONCLUSIONS: COVID-19 patients had higher risks of both suicide attempts and other forms of SDV compared to uninfected comparators, which persisted for at least one year after infection. Results support suicide risk screening of those infected with SARS-COV-2 to identify opportunities to prevent self-harm.

Rates of ICD-10 Code U09.9 Documentation and Clinical Characteristics of VA Patients With Post-COVID-19 Condition.

Importance: A significant proportion of SARS-CoV-2 infected individuals experience post-COVID-19 condition months after initial infection. Objective: To determine the rates, clinical setting, risk factors, and symptoms associated with the documentation of International Statistical Classification of Diseases Tenth Revision (ICD-10), code U09.9 for post-COVID-19 condition after acute infection. Design, Setting, and Participants: This retrospective cohort study was performed within the US Department of Veterans Affairs (VA) health care system. Veterans with a positive SARS-CoV-2 test result between October 1, 2021, the date ICD-10 code U09.9 was introduced, and January 31, 2023 (n = 388 980), and a randomly selected subsample of patients with the U09.9 code (n = 350) whose symptom prevalence was assessed by systematic medical record review, were included in the analysis. Exposure: Positive SARS-CoV-2 test result. Main Outcomes and Measures: Rates, clinical setting, risk factors, and symptoms associated with ICD-10 code U09.9 in the medical record. Results: Among the 388 980 persons with a positive SARS-CoV-2 test, the mean (SD) age was 61.4 (16.1) years; 87.3% were men. In terms of race and ethnicity, 0.8% were American Indian or Alaska Native, 1.4% were Asian, 20.7% were Black, 9.3% were Hispanic or Latino, 1.0% were Native Hawaiian or Other Pacific Islander; and 67.8% were White. Cumulative incidence of U09.9 documentation was 4.79% (95% CI, 4.73%-4.87%) at 6 months and 5.28% (95% CI, 5.21%-5.36%) at 12 months after infection. Factors independently associated with U09.9 documentation included older age, female sex, Hispanic or Latino ethnicity, comorbidity burden, and severe acute infection manifesting by symptoms, hospitalization, or ventilation. Primary vaccination (adjusted hazard ratio [AHR], 0.80 [95% CI, 0.78-0.83]) and booster vaccination (AHR, 0.66 [95% CI, 0.64-0.69]) were associated with a lower likelihood of U09.9 documentation. Marked differences by geographic region and facility in U09.9 code documentation may reflect local screening and care practices. Among the 350 patients undergoing systematic medical record review, the most common symptoms documented in the medical records among patients with the U09.9 code were shortness of breath (130 [37.1%]), fatigue or exhaustion (78 [22.3%]), cough (63 [18.0%]), reduced cognitive function or brain fog (22 [6.3%]), and change in smell and/or taste (20 [5.7%]). Conclusions and Relevance: In this cohort study of 388 980 veterans, documentation of ICD-10 code U09.9 had marked regional and facility-level variability. Strong risk factors for U09.9 documentation were identified, while vaccination appeared to be protective. Accurate and consistent documentation of U09.9 is needed to maximize its utility in tracking patients for clinical care and research. Future studies should examine the long-term trajectory of individuals with U09.9 documentation.

Mechanisms of Lipid Droplet Accumulation in Steatotic Liver Diseases.

The steatotic diseases of metabolic dysfunction-associated steatotic liver disease (MASLD), alcohol-associated liver disease (ALD), and chronic hepatitis C (HCV) account for the majority of liver disease prevalence, morbidity, and mortality worldwide. While these diseases have distinct pathogenic and clinical features, dysregulated lipid droplet (LD) organelle biology represents a convergence of pathogenesis in all three. With increasing understanding of hepatocyte LD biology, we now understand the roles of LD proteins involved in these diseases but also how genetics modulate LD biology to either exacerbate or protect against the phenotypes associated with steatotic liver diseases. Here, we review the history of the LD organelle and its biogenesis and catabolism. We also review how this organelle is critical not only for the steatotic phenotype of liver diseases but also for their advanced phenotypes. Finally, we summarize the latest attempts and challenges of leveraging LD biology for therapeutic gain in steatotic diseases. In conclusion, the study of dysregulated LD biology may lead to novel therapeutics for the prevention of disease progression in the highly prevalent steatotic liver diseases of MASLD, ALD, and HCV.