PNPLA3 rs738409, environmental factors and liver-related mortality in the U.S. Population.

BACKGROUND & AIMS: Little is known about the interplay between patatin-like phospholipase domain protein 3 (PNPLA3 rs738409 C>G), environmental factors, and the risk of liver-related death (LRD). METHODS: 4,361 adults were selected from NHANES III, 1991-1994. All participants were linked to the National Death Index until 2019 (mean follow-up: 23.2 years). LRD was the study outcome. Associations of PNPLA3, diet, light alcohol intake, smoking, and BMI (kg/m2) with LRD were examined using competing risk regression models. RESULTS: PNPLA3 G-allele was significantly associated with LRD (adjusted subhazard ratio [adj.sHR]: 2.9, 95% CI: 1.4-5.8). Non-heavy alcohol intake (adj.sHR: 2.2, 95% CI: 1.1-4.5), top quartiles of monounsaturated fat (MUFA) (adj.sHR: 0.43, 95% CI: 0.12-0.99), and cholesterol (adj.sHR: 2.6, 95% CI: 1.00-8.8) and coffee intake ≥3 cups/day (adj.sHR: 0.05, 95% CI: 0.06-0.10), former/current smoking (adj.sHR: 1.8, 95% CI: 1.2-2.6), BMI (adj.sHR: 1.1, 95% CI: 1.03-1.2), and healthy eating index (HEI) (adj.sHR: 0.96, 95% CI: 0.93-0.98) were associated with LRD. Joint effects between PNPLA3 and environmental factors showed that the risk of LRD was significantly increased in carriers of the G-allele with non-heavy alcohol intake (adj.sHR: 3.7), higher consumption (top quartile) of cholesterol (adj.sHR: 4.1), former (adj.sHR: 4.3) or current (adj.sHR: 3.5) smoking, or BMI ≥30 (adj.sHR: 4.0) kg/m2. The effects of the G-allele on the risk of LRD were significantly attenuated in those with top quartile consumption of MUFA (adj.sHR: 0.5) or ≥3 cups/day of coffee (adj.sHR: 0.09). HEI was inversely associated with LRD across all PNPLA3 genotypes (adj.sHR: 0.94, 0.96, and 0.97 for CC, CG, and GG, respectively). CONCLUSIONS: PNPLA3 is associated with LRD and this relationship is significantly modified by anthropometric and environmental factors.

Clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis.

BACKGROUND AND AIMS: Little is known about the clinical characteristics and prognosis of hospitalized patients with moderate alcohol-associated hepatitis (mAH) as compared to severe alcohol-associated hepatitis (sAH). Therefore, we aimed to describe the clinical characteristics and risk factors associated with mortality in hospitalized mAH patients. METHODS: Patients hospitalized with alcohol-associated hepatitis (AH) from 1 January 2010 to 31 December 2020 at a large US healthcare system [11 hospitals, one liver transplant centre] were retrospectively analysed for outcomes. Primary outcome was 90-day mortality. AH and mAH were defined according to NIAAA Alcoholic Hepatitis Consortia and Model for End-stage Liver Disease Score ≤ 20 respectively. Multivariable Cox regression analysis was performed to identify independent risk factors associated with 90-day mortality. RESULTS: 1504 AH patients were hospitalized during the study period, of whom 39% (n = 590) had mAH. Compared to sAH patients, mAH patients were older (50 vs. 48 years, p < 0.001) and less likely to have underlying cirrhosis (74% vs. 83%, p < 0.001). There were no differences between the two groups for median alcohol intake g/day (mAH 140.0 vs. sAH 112.0, p = 0.071). The cumulative proportion surviving at 90 days was 88% in mAH versus 62% in sAH (p < 0.001). On multivariable analysis, older age [HR 1.03 (95% CI 1.00-1.06), p = 0.020], corticosteroid use [HR 1.80 (95% CI 1.06-3.06), p = 0.030] and acute kidney injury (AKI) [HR 2.43 (95% CI 1.33-4.47), p = 0.004] were independently associated with 90-day mortality. CONCLUSIONS: mAH carries a 12% mortality rate at 90 days. Age, AKI and corticosteroid use were associated with an increased risk for 90-day mortality. Avoidance of corticosteroids and strategies to reduce the risk of AKI could improve outcomes in mAH patients.

The prognostic impact of acute kidney injury recovery patterns in critically ill patients with cirrhosis.

BACKGROUND: The prognostic impact of acute kidney injury (AKI) recovery patterns in critically ill patients with cirrhosis is unknown. We aimed to compare mortality stratified by AKI recovery patterns and identify predictors of mortality in patients with cirrhosis and AKI admitted to the intensive care unit. MATERIALS AND METHODS: Patients with cirrhosis and AKI from 2016 to 2018 at 2 tertiary care intensive care units were analyzed (N=322). AKI recovery was defined by Acute Disease Quality Initiative consensus: return of serum creatinine <0.3 mg/dL of baseline within 7 days of AKI onset. Recovery patterns were categorized by Acute Disease Quality Initiative consensus: 0-2 days, 3-7 days, and no-recovery (persistence of AKI >7 d). Landmark competing risk univariable and multivariable models (liver transplant as competing risk) was used to compare 90-day mortality between AKI recovery groups and to determine independent predictors of mortality. RESULTS: Sixteen percent (N=50) and 27% (N=88) achieved AKI recovery within 0-2 and 3-7 days, respectively; 57% (N=184) had no-recovery. Acute on chronic liver failure was prevalent (83%) and patients with no-recovery were more likely to have grade 3 acute on chronic liver failure (N=95, 52%) compared to patients with AKI recovery [0-2: 16% (N=8); 3-7: 26% (N=23); p<0.001]. Patients with no-recovery had significantly higher probability of mortality [unadjusted-sub-HR (sHR): 3.55; 95% CI: 1.94-6.49; p<0.001] compared to patients with recovery within 0-2 days, while the probability was similar between 3-7 and 0-2 days (unadjusted-sub-HR: 1.71; 95% CI: 0.91-3.20; p=0.09). On multivariable analysis, AKI no-recovery (sub-HR: 2.07; 95% CI: 1.33-3.24; p=0.001), severe alcohol-associated hepatitis (sub-HR: 2.41; 95% CI: 1.20-4.83; p=0.01), and ascites (sub-HR: 1.60; 95% CI: 1.05-2.44; p=0.03) were independently associated with mortality. CONCLUSION: AKI no-recovery occurs in over half of critically ill patients with cirrhosis and AKI and is associated with worse survival. Interventions that facilitate AKI recovery may improve outcomes in this patient population.

Decreased Quality of Life Is Significantly Associated With Body Composition in Patients With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: We studied impaired quality of life (QOL) and its determinants among individuals with nonalcoholic fatty liver disease (NAFLD). METHODS: We collected data from 341 patients with NAFLD who completed the short form 36 (SF-36) questionnaire. Body composition and liver fibrosis were assessed in patients with NAFLD using bioelectrical impedance and transient elastography, respectively. Advanced fibrosis was defined as liver stiffness measurements (LSMs) of 12.1 kPa or greater. SF-36 scores of patients with NAFLD were compared with SF36 scores of individuals with chronic medical illnesses and the general population obtained from the published literature. RESULTS: Among patients with NAFLD, percent body fat was negatively associated with scores from all 8 SF-36 scales, whereas lean body mass was positively associated with scores from 5 of 8 SF-36 scales. On multivariable analysis, SF-36 PF scores were negatively associated with type 2 diabetes, body mass index, and LSM and positively associated with lean body mass and level of alanine aminotransferase. Patients with NAFLD, and even those without advanced fibrosis, had significantly lower mean QOL scores than the control group or the general population. CONCLUSIONS: Individuals with NAFLD, even those without advanced fibrosis, have lower QOL than controls. Body composition associates with QOL in patients with NAFLD; both of the modifiable factors independently associated with QOL are related to body composition. Further studies are needed to investigate if interventions to improve body composition can increase QOL for patients with NAFLD.

Gender Matters: Characteristics of Hepatocellular Carcinoma in Women From a Large, Multicenter Study in the United States.

INTRODUCTION: Hepatocellular carcinoma (HCC) is the fourth leading cause of cancer-related death worldwide, affecting men to women at a ratio of about 4:1. Risk factors, characteristics, and outcomes for HCC in women in the United States remain poorly understood; therefore, we aim to explore gender differences further. METHODS: Patients diagnosed with HCC between January 2000 and June 2014 at 5 large centers were identified. Clinical information, tumor characteristics, and survival data were extracted manually. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5,327 patients with HCC in our cohort, 1,203 (22.6%) were women. There were important differences in the underlying etiology of liver disease between the 2 genders (P < 0.0001): women had a significantly higher frequency of nonalcoholic fatty liver disease (23% vs 12%) and lower frequency of alcoholic liver disease (5% vs 15%). The proportion of noncirrhotic HCC was significantly higher among women (17% vs 10%, P < 0.0001). Women had less-advanced HCC at presentation by tumor, node, metastasis staging (P < 0.0001) and a higher proportion within Milan criteria (39% vs 35%, P = 0.002). Women had a greater overall survival (2.5 ± 2.9 years vs 2.2 ± 2.7 years, P = 0.0031). DISCUSSION: The frequency of underlying nonalcoholic fatty liver disease and noncirrhotic HCC were significantly higher in women than men in this large cohort. Women presented with less-advanced HCC and had a greater overall survival. Further investigation is warranted to explore potential mechanisms and implications for these gender differences, especially with noncirrhotic HCC (see Visual Abstract, Supplementary Digital Content 1, http://links.lww.com/AJG/B535).

Associations Between Mean Arterial Pressure and Poor ICU Outcomes in Critically Ill Patients With Cirrhosis: Is 65 The Sweet Spot?

OBJECTIVES: Mean arterial pressure is critically important in patients with cirrhosis in the ICU, however, there is limited data to guide therapies and targets. DESIGN: Retrospective observational study. SETTING: Tertiary care ICU. PATIENTS: Two hundred and seventy-three critically ill patients with cirrhosis. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: We performed a comprehensive time-weighted mean arterial pressure analysis (time-weighted-average-mean arterial pressure and cumulative-time-below various mean arterial pressure-thresholds) during the first 24-hours after ICU admission (median: 25 mean arterial pressure measurements per-patient). Time-weighted-average-mean arterial pressure captures both the severity and duration of hypotension below a mean arterial pressure threshold and cumulative-time-below is the total time spent below a mean arterial pressure threshold. Individual univariable and multivariable logistic regression models were assessed for each time-weighted-average-mean arterial pressure and cumulative-time-below mean arterial pressure threshold (55, 60, 65, 70, and 75 mm Hg) for ICU-mortality. Time-weighted-average-mean arterial pressure: for 1 mm Hg decrease in mean arterial pressure below 75, 70, 65, 60, and 55 mm Hg, the odds for ICU-mortality were 14%, 18%, 26%, 41%, and 74%, respectively (p < 0.01, all thresholds). The association between time-weighted-average-mean arterial pressure and ICU-mortality for each threshold remained significant after adjusting for model for end-stage liver disease-sodium score, mechanical ventilation, vasopressor use, renal replacement therapy, grade 3/4 hepatic encephalopathy, WBC count, and albumin. Cumulative-time-below: odds for ICU-mortality were 4%, 6%, 10%, 12%, and 12% for each-hour spent below 75, 70, 65, 60, and 55 mm Hg, respectively. In the adjusted models, significant associations only remained for mean arterial pressure less than 65 mm Hg (odds ratio, 1.07; 95% CI, 1.00-1.14; p = 0.05) and < 60 mm Hg (odds ratio, 1.10; 95% CI, 1.01-1.18; p = 0.04). CONCLUSIONS: These data suggest that maintaining a mean arterial pressure of greater than 65 mm Hg may be a reasonable target in patients with cirrhosis admitted to the ICU. However, further prospective randomized trials are needed to determine the optimal mean arterial pressure-targets in this patient population.

ARDaC Common Data Model Facilitates Data Dissemination and Enables Data Commons for Modern Clinical Studies.

Modern clinical studies collect longitudinal and multimodal data about participants, treatments and responses, biospecimens, and molecular and multiomics data. Such rich and complex data requires new common data models (CDM) to support data dissemination and research collaboration. We have developed the ARDaC CDM for the Alcoholic Hepatitis Network (AlcHepNet) Research Data Commons (ARDaC) to support clinical studies and translational research in the national AlcHepNet consortium. The ARDaC CDM bridges the gap between the data models used by the AlcHepNet electronic data capture platform (REDCap) and the Genomic Data Commons (GDC) data model used by the Gen3 data commons framework. It extends the GDC data model for clinical studies; facilitates the harmonization of research data across consortia and programs; and supports the development of the ARDaC. ARDaC CDM is designed as a general and extensible CDM for addressing the needs of modern clinical studies. The ARDaC CDM is available at https://dev.ardac.org/DD.

Development and evaluation of objective trial performance metrics for multisite clinical studies: Experience from the AlcHep Network.

BACKGROUND: Recruitment and retention are critical in clinical studies but there are limited objective metrics of trial performance. We tested if development of trial performance metrics will allow for objective evaluation of study quality. Performance metrics were developed using data from the observational cohort (OBS) and randomized clinical trial (RCT) arms of the prospective Alcoholic Hepatitis Network. METHODS: Yield-rate (%YR; eligible/screened), recruitment index (RI; mean recruitment time/patient), completion index (CI; average number of days to complete the follow-up/patient), and protocol adherence index (AI; average number of deviations/subject recruited) were determined. RESULTS: 2250 patients (1168 for OBS; 1082 for RCT) were screened across 8 sites. Recruitment in the RCT (57% target) was similar to that in the OBS (59% target). Of those screened, 743 (63.6%) subjects in the OBS and 147 (13.6%) subjects in the RCT were enrolled in the study. In OBS study, 253 (34.1%) subjects, and in the RCT, 68 (46.3%) subjects, completed the study or reached a censoring event. Across all sites (range), YR for OBS was 63.6% (41.3-98.3%) and for RCT was 13.6% (5.5-92.6%); RI for OBS was 1.66 (8.79-19.85) and for RCT was 4.05 (19.76-36.43); CI for OBS was 4.87 (22.6-118.3) and for RCT was 8.75 (27.27-161.5); and AR for OBS was 0.56 (0.08-1.04) and for RCT was 1.55 (0.39-3.21. Factors related to participants, research design, study team, and research sponsors contributed to lower performance metrics. CONCLUSIONS: Objective measures of clinical trial performance allow for strategies to enhance study quality and development of site-specific improvement plans. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov NCT4072822 NCT03850899.

Comparative effectiveness of two interventions to increase colorectal cancer screening among females living in the rural Midwest.

PURPOSE: To assess the comparative effectiveness of a tailored, interactive digital video disc (DVD) intervention versus DVD plus patient navigation (PN) intervention versus usual care (UC) on the uptake of colorectal cancer (CRC) screening among females living in Midwest rural areas. METHODS: As part of a larger study, 663 females (ages 50-74) living in rural Indiana and Ohio and not up-to-date (UTD) with CRC screening at baseline were randomized to one of three study groups. Demographics , health status/history, and beliefs and attitudes about CRC screening were measured at baseline. CRC screening was assessed at baseline and 12 months from medical records and self-report. Multivariable logistic regression was used to determine whether females in each group were UTD for screening and which test they completed. RESULTS: Adjusted for covariates, females in the DVD plus PN group were 3.5× more likely to complete CRC screening than those in the UC group (odds ratio [OR] 3.62; 95% confidence interval [CI]: 2.09, 6.47) and baseline intention to receive CRC screening (OR 3.45, CI: 2.21,5.42) at baseline. Adjusting for covariates, there was no difference by study arm whether females who became UTD for CRC screening chose to complete a colonoscopy or fecal occult blood test/fecal immunochemical test. CONCLUSIONS: Many females living in the rural Midwest are not UTD for CRC screening. A tailored intervention that included an educational DVD and PN improved knowledge, addressed screening barriers, provided information about screening test options, and provided support was more effective than UC and DVD-only to increase adherence to recommended CRC screening.

Lean body mass index is a marker of advanced tumor features in patients with hepatocellular carcinoma.

BACKGROUND: Obesity is an independent risk factor for the development of hepatocellular carcinoma (HCC) and may influence its outcomes. However, after diagnosis of HCC, like other malignancies, the obesity paradox may exist where higher body mass index (BMI) may in fact confer a survival benefit. This is frequently observed in patients with advanced HCC and cirrhosis, who often present late with advanced tumor features and cancer related weight loss. AIM: To explore the relationship between BMI and survival in patients with cirrhosis and HCC. METHODS: This is a retrospective cohort study of over 2500 patients diagnosed with HCC between 2009-2019 at two United States academic medical centers. Patient and tumor characteristics were extracted manually from medical records of each institutions' cancer registries. Patients were stratified according to BMI classes: < 25 kg/m2 (lean), 25-29.9 kg/m2 (overweight), and > 30 kg/m2 (obese). Patient and tumor characteristics were compared according to BMI classification. We performed an overall survival analysis using Kaplan Meier by the three BMI classes and after adjusting for Milan criteria. A multivariable Cox regression model was then used to assess known risk factors for survival in patients with cirrhosis and HCC. RESULTS: A total of 2548 patients with HCC were included in the analysis of which 11.2% (n = 286) were classified as non-cirrhotic. The three main BMI categories: Lean (n = 754), overweight (n = 861), and obese (n = 933) represented 29.6%, 33.8%, and 36.6% of the total population overall. Within each BMI class, the non-cirrhotic patients accounted for 15% (n = 100), 12% (n = 94), and 11% (n = 92), respectively. Underweight patients with a BMI < 18.5 kg/m2 (n = 52) were included in the lean cohort. Of the obese cohort, 42% (n = 396) had a BMI ≥ 35 kg/m2. Out of 2262 patients with cirrhosis and HCC, 654 (29%) were lean, 767 (34%) were overweight, and 841 (37%) were obese. The three BMI classes did not differ by age, MELD, or Child-Pugh class. Chronic hepatitis C was the dominant etiology in lean compared to the overweight and obese patients (71%, 62%, 49%, P < 0.001). Lean patients had significantly larger tumors compared to the other two BMI classes (5.1 vs 4.2 vs 4.2 cm, P < 0.001), were more likely outside Milan (56% vs 48% vs 47%, P < 0.001), and less likely to undergo transplantation (9% vs 18% vs 18%, P < 0.001). While both tumor size (P < 0.0001) and elevated alpha fetoprotein (P < 0.0001) were associated with worse survival by regression analysis, lean BMI was not (P = 0.36). CONCLUSION: Lean patients with cirrhosis and HCC present with larger tumors and are more often outside Milan criteria, reflecting cancer related cachexia from delayed diagnosis. Access to care for hepatitis C virus therapy and liver transplantation confer a survival benefit, but not overweight or obese BMI classifications.

A composite score using quantitative magnetic resonance cholangiopancreatography predicts clinical outcomes in primary sclerosing cholangitis.

Background & Aims: Magnetic resonance cholangiopancreatography (MRCP) for evaluation of biliary disease currently relies on subjective assessment with limited prognostic value because of the lack of quantitative metrics. Artificial intelligence-enabled quantitative MRCP (MRCP+) is a novel technique that segments biliary anatomy and provides quantitative biliary tree metrics. This study investigated the utility of MRCP+ as a prognostic tool for the prediction of clinical outcomes in primary sclerosing cholangitis (PSC). Methods: MRCP images of patients with PSC were post-processed using MRCP+ software. The duration between the MRCP and clinical event (liver transplantation or death) was calculated. Survival analysis and stepwise Cox regression were performed to investigate the optimal combination of MRCP+ metrics for the prediction of clinical outcomes. The resulting risk score was validated in a separate validation cohort and compared with an existing prognostic score (Mayo risk score). Results: In this retrospective study, 102 patients were included in a training cohort and a separate 50 patients formed a validation cohort. Between the two cohorts, 34 patients developed clinical outcomes over a median duration of 3 years (23 liver transplantations and 11 deaths). The proportion of bile ducts with diameter 3-5 mm, total bilirubin, and aspartate aminotransferase were independently associated with transplant-free survival. Combined as a risk score, the overall discriminative performance of the MRCP+ risk score (M+BA) was excellent; area under the receiver operator curve 0.86 (95% CI: 0.77, 0.95) at predicting clinical outcomes in the validation cohort with a hazard ratio 5.8 (95% CI: 1.5, 22.1). This was superior to the Mayo risk score. Conclusions: A composite score combining MRCP+ with total bilirubin and aspartate aminotransferase (M+BA) identified PSC patients at high risk of liver transplantation or death. Prospective studies are warranted to evaluate the clinical utility of this novel prognostic tool. Impact and Implications: Primary sclerosis cholangitis (PSC) is a disease of the biliary tree where inflammation and fibrosis cause areas of narrowing (strictures) and expansion (dilatations) within the biliary ducts leading to liver failure and/or cancer (cholangiocarcinoma). In this study, we demonstrate that quantitative assessment of the biliary tree can better identify patients with PSC who are at high risk of either death or liver transplantation than a current blood-based risk score (Mayo risk score).

Incidence, clinical characteristics, and risk factors associated with recurrent alcohol-associated hepatitis.

BACKGROUND: Alcohol relapse occurs frequently in alcohol-associated hepatitis (AH) survivors, but data on the frequency and course of recurrent alcohol-associated hepatitis (rAH) are sparse. We investigated the incidence, risk factors, and outcomes of rAH. METHODS: Hospitalized patients with AH from 2010 to 2020 at a large health care system were followed until death/liver transplant, last follow-up, or end of study (December 31, 2021). AH was defined by NIAAA Alcoholic Hepatitis Consortium criteria; rAH was defined a priori as a discrete AH episode >6 months from index AH hospitalization with interim >50% improvement or normalization of total bilirubin. Multivariable competing risk analysis was performed to identify factors associated with rAH. Landmark Kaplan-Meier analysis was performed to compare survival between patients who did versus those who did not develop rAH. RESULTS: Of 1504 hospitalized patients with AH, 1317 (87.6%) survived and were analyzed. During a 3055 person-year follow-up, 116 (8.8%) developed rAH at an annual incidence rate of 3.8% (95% CI: 2.8-4.8). On multivariable competing risk analysis, marital status [sub-HR 0.54 (95% CI: 0.34, 0.92), p=0.01] and medications for alcohol use disorder [sub-HR 0.56 (95% CI: 0.34, 0.91), p=0.02] were associated with a lower risk for rAH. On landmark Kaplan-Meier analysis, the cumulative proportion surviving at 1 year (75% vs. 90%) and 3 years (50% vs. 78%) was significantly lower in patients who developed rAH compared to those who did not develop rAH (log-rank p<0.001). CONCLUSIONS: rAH develops in ~1 in 10 AH survivors and is associated with lower long-term survival. Medications for alcohol use disorder lower the risk for rAH and, therefore, could be a key preventative strategy to improve outcomes.

Comparative Effectiveness of 2 Interventions to Increase Breast, Cervical, and Colorectal Cancer Screening Among Women in the Rural US: A Randomized Clinical Trial.

Importance: Women living in rural areas have lower rates of breast, cervical, and colorectal cancer screening compared with women living in urban settings. Objective: To assess the comparative effectiveness of (1) a mailed, tailored digital video disc (DVD) intervention; (2) a DVD intervention plus telephonic patient navigation (DVD/PN); and (3) usual care with simultaneously increased adherence to any breast, cervical, and colorectal cancer screening that was not up to date at baseline and to assess cost-effectiveness. Design, Setting, and Participants: This randomized clinical trial recruited and followed up women from rural Indiana and Ohio (community based) who were not up to date on any or all recommended cancer screenings. Participants were randomly assigned between November 28, 2016, and July 1, 2019, to 1 of 3 study groups (DVD, DVD/PN, or usual care). Statistical analyses were completed between August and December 2021 and between March and September 2022. Intervention: The DVD interactively assessed and provided messages for health beliefs, including risk of developing the targeted cancers and barriers, benefits, and self-efficacy for obtaining the needed screenings. Patient navigators counseled women on barriers to obtaining screenings. The intervention simultaneously supported obtaining screening for all or any tests outside of guidelines at baseline. Main Outcomes and Measures: Receipt of any or all needed cancer screenings from baseline through 12 months, including breast, cervical, and colorectal cancer, and cost-effectiveness of the intervention. Binary logistic regression was used to compare the randomized groups on being up to date for all and any screenings at 12 months. Results: The sample included 963 women aged 50 to 74 years (mean [SD] age, 58.6 [6.3] years). The DVD group had nearly twice the odds of those in the usual care group of obtaining all needed screenings (odds ratio [OR], 1.84; 95% CI, 1.02-3.43; P = .048), and the odds were nearly 6 times greater for DVD/PN vs usual care (OR, 5.69; 95% CI, 3.24-10.5; P < .001). The DVD/PN intervention (but not DVD alone) was significantly more effective than usual care (OR, 4.01; 95% CI, 2.60-6.28; P < .001) for promoting at least 1 (ie, any) of the needed screenings at 12 months. Cost-effectiveness per woman who was up to date was $14 462 in the DVD group and $10 638 in the DVD/PN group. Conclusions and Relevance: In this randomized clinical trial of rural women who were not up to date with at least 1 of the recommended cancer screenings (breast, cervical, or colorectal), an intervention designed to simultaneously increase adherence to any or all of the 3 cancer screening tests was more effective than usual care, available at relatively modest costs, and able to be remotely delivered, demonstrating great potential for implementing an evidence-based intervention in remote areas of the midwestern US. Trial Registration: ClinicalTrials.gov Identifier: NCT02795104.

The Effect of Two Interventions to Increase Breast Cancer Screening in Rural Women.

Guideline-based mammography screening is essential to lowering breast cancer mortality, yet women residing in rural areas have lower rates of up to date (UTD) breast cancer screening compared to women in urban areas. We tested the comparative effectiveness of a tailored DVD, and the DVD plus patient navigation (PN) intervention vs. Usual Care (UC) for increasing the percentage of rural women (aged 50 to 74) UTD for breast cancer screening, as part of a larger study. Four hundred and two women who were not UTD for breast cancer screening, eligible, and between the ages of 50 to 74 were recruited from rural counties in Indiana and Ohio. Consented women were randomly assigned to one of three groups after baseline assessment of sociodemographic variables, health status, beliefs related to cancer screening tests, and history of receipt of guideline-based screening. The mean age of participants was 58.2 years with 97% reporting White race. After adjusting for covariates, 54% of women in the combined intervention (DVD + PN) had a mammogram within the 12-month window, over 5 times the rate of becoming UTD compared to UC (OR = 5.11; 95% CI = 2.57, 10.860; p < 0.001). Interactions of the intervention with other variables were not significant. Significant predictors of being UTD included: being in contemplation stage (intending to have a mammogram in the next 6 months), being UTD with other cancer screenings, having more disposable income and receiving a reminder for breast screening. Women who lived in areas with greater Area Deprivation Index scores (a measure of poverty) were less likely to become UTD with breast cancer screening. For rural women who were not UTD with mammography screening, the addition of PN to a tailored DVD significantly improved the uptake of mammography. Attention should be paid to certain groups of women most at risk for not receiving UTD breast screening to improve breast cancer outcomes in rural women.

Increasing breast, cervical, and colorectal cancer screening among rural women: Baseline characteristics of a randomized control trial.

BACKGROUND: Rural women suffer disproportionately from breast, cervical, and colorectal cancer mortality compared to those in urban areas. Screening behaviors for these three cancers share many similar beliefs and barriers. Unfortunately, published interventions have not attempted to simultaneously bring women up to date with screening for three cancers (breast, cervical, and colorectal) even though multiple behavior change interventions are effective. The aim of this randomized controlled study was to compare the effectiveness of a mailed interactive and tailored DVD vs. DVD plus telephonic patient navigation (DVD + PN) vs. Usual Care (UC) to increase the percentage of rural women (aged 50-74) up to date for breast, cervical, and colorectal cancer screening. METHODS: Nine hundred eighty-three participants needing one, two, or three cancer screening tests were consented and randomized to one of three groups. Prior to randomization, women were assessed for baseline characteristics including sociodemographics, health status, and cancer screening test beliefs. Screening status was assessed by medical record review. RESULTS: At baseline, the average age of participants was 58.6 years. Nineteen percent of the sample was not up to date with screenings for all three cancers. Colorectal cancer had the highest percentage of women (69%) who were not up to date with screening followed by cervical (57%) and then breast cancer (41%). Sixty percent of women reported receiving a reminder for mammography; 30%, for cervical cancer screening; 15% for colonoscopy; and 6% for FOBT/FIT. DISCUSSION: Increasing adherence to colorectal cancer screening may be the most urgent need among all screening tests. This clinical trial is registered at clinicaltrials.gov with identifier NCT02795104.

Severe Alcohol-Associated Hepatitis Is Associated With Worse Survival in Critically Ill Patients With Acute on Chronic Liver Failure.

Differences in mortality between critically ill patients with severe alcohol-associated hepatitis (sAH) and acute-on-chronic liver failure (ACLF) and non-sAH ACLF (i.e., ACLF not precipitated by sAH) are unknown. Such differences are important, as they may inform on prognosis and optimal timing of liver transplantation (LT). Thus, we aimed to compare short-term and longer-term mortality between patients with sAH ACLF and patients with non-sAH ACLF who were admitted to the intensive care unit. Patients with ACLF admitted from 2016-2018 at two tertiary care intensive care units were analyzed. SAH was defined by the National Institute on Alcohol Abuse and Alcoholism's Alcoholic Hepatitis Consortium and Model for End-Stage Liver Disease score >20. Mortality without LT was compared between sAH ACLF and non-sAH ACLF using Fine and Gray's competing-risks regression. A total of 463 patients with ACLF (18% sAH and 82% non-sAH) were included. Compared to patients with non-sAH ACLF, patients with sAH ACLF were younger (49 vs. 56 years; P < 0.001) and had higher admission Model for End-Stage Liver Disease (MELD) (35 vs. 25; P < 0.001) and Chronic Liver Failure Consortium (CLIF-C) scores (61 vs. 57; P = 0.002). There were no significant differences between the two groups for vasopressor, mechanical ventilation, and hemodialysis use. The cumulative incidence of death was significantly higher in patients with sAH ACLF compared to patients with non-sAH ACLF: 30-day 74.7% versus 45.3%; 90-day 81.9% versus 57.4%; 180-day 83.2% versus 63.0% (unadjusted subdistribution hazard ratio [sHR] 1.88 [95% confidence interval (CI) 1.44-2.46]; P < 0.001). After adjusting for CLIF-C score and infection in a multivariable competing-risk model, patients with sAH ACLF had significantly higher risk of death (sHR 1.57 [95% CI 1.20-2.06]; P = 0.001) compared to patients with non-sAH ACLF. Conclusion: Critically ill patients with sAH ACLF have worse mortality compared to patients with non-sAH ACLF. These data may inform prognosis in patients with sAH and ACLF, and early LT referral in potentially eligible patients.

An RCT to Increase Breast and Colorectal Cancer Screening.

INTRODUCTION: Adherence to breast and colorectal cancer screenings reduce mortality from these cancers, yet screening rates remain suboptimal. This 2 × 2 RCT compared 3 theory-based interventions to usual care to simultaneously increase breast and colon cancer screening in women who were nonadherent to both screenings at study entry. DESIGN: RCT. SETTING/PARTICIPANTS: Women (n=692) who were nonadherent to both breast and colon cancer screenings and aged 51-75 years were recruited. Enrollment, intervention delivery, and data collection were completed between 2013 and 2017, and data analyzed in 2018. INTERVENTION: The randomized intervention included the following 4 groups: 3 intervention arms (personally tailored messages using a web-based intervention, phone delivery by a trained navigator, or both) compared with usual care. Women at an average risk for colon cancer were allowed to select either colonoscopy or stool test as their preferred colon cancer screening. Mammography was promoted for breast cancer screening. MAIN OUTCOME MEASURES: Outcome data at 6 months included self-report and medical records for screening activity. RESULTS: All intervention arms significantly increased receipt of either a mammogram or stool test compared with control (web: p<0.0249, phone: p<0.0001, web + phone: p<0.0001). When considering receipt of both mammogram and stool test, all intervention arms were significantly different from usual care (web: p<0.0249, phone: p<0.0003, web + phone: p<0.0001). In addition, women who were adherent to mammography had a 4.5 times greater odds of becoming adherent to colonoscopy. CONCLUSIONS: The tailored intervention simultaneously supporting both breast and colon cancer screenings significantly improved rates of obtaining one of the screenings and increased receipt of both tests. TRIAL REGISTRATION: This study is registered with the clinical trials identifier NCT03279198 at www.clinicaltrials.gov.

Distinctive Features and Outcomes of Hepatocellular Carcinoma in Patients With Alcohol-Related Liver Disease: A US Multicenter Study.

INTRODUCTION: The burden of hepatocellular carcinoma (HCC) occurring in patients with alcoholic liver disease (ALD) is increasing at an alarming rate. The aims of this study were to compare the patient and tumor characteristics of HCC occurring in ALD-alone relative to and in addition to other chronic liver diseases. METHODS: Patients diagnosed with HCC between 2000 and 2014 were identified at 5 US clinical centers. The patients were categorized as ALD-alone, ALD plus viral hepatitis, or a non-ALD etiology. Clinical and tumor characteristics among the 3 groups were compared, and survival probability was estimated by the Kaplan-Meier method. The frequency of noncirrhotic HCC was compared across the 3 groups. RESULTS: A total of 5,327 patients with HCC were analyzed. Six hundred seventy (12.6%) developed HCC due to underlying ALD. Ninety-one percent of ALD-related HCC arose in men, in contrast to non-ALD etiologies where men accounted for 70% of HCCs cases (P < 0.001). Patients with ALD-alone-related HCC were older at diagnosis and had tumors less likely to be detected as part of routine surveillance. The ALD-alone cohort was least likely to be within the Milan criteria and to undergo liver transplantation. Overall survival in the ALD-alone HCC cohort was lower than the other 2 groups (1.07 vs 1.31 vs 1.41 years, P < 0.001). HCC in the noncirrhotic ALD cohorts occurred in only 3.5% of the patients compared with 15.7% in patients with non-ALD etiologies (P < 0.001). DISCUSSION: HCC occurring in patients with ALD occurred mostly in older men and almost exclusively in a cirrhotic background. They present with advanced tumors, and their survival is lower than HCCs occurring in non-ALD.

Hepatocellular Carcinoma in Hispanic Patients: Trends and Outcomes in a Large United States Cohort.

Hepatocellular carcinoma (HCC) has a strong racial and ethnic association, with Hispanic patients having a higher incidence and mortality. However, there are limited data regarding clinical features and outcomes. This study includes Hispanic and non-Hispanic White patients with HCC diagnosed between January 2000 and June 2014 from five United States academic medical centers. The chi-square test for categorical variables and analysis of variance for continuous variables were used for statistical analysis, with two-tailed P < 0.05 considered statistically significant. Of 5,327 patients, 4,217 met inclusion criteria, of whom 12.3% were Hispanic patients. Compared to their non-Hispanic White counterparts, Hispanic patients were older at age of diagnosis (mean ± SD, 64.2 ± 10.9 vs. 61.9 ± 10.5 years; P < 0.0001), with higher body mass index (29.6 ± 6.5 vs. 28.8 ± 5.9 kg/m2; P = 0.01), and were more likely to have diabetes and hypertension. Hispanic patients had significantly more nonalcoholic fatty liver disease and alcohol-related liver disease (both P < 0.0001). Hispanic patients presented with larger tumors, more advanced stage disease, and increased rates of macrovascular invasion and extrahepatic spread. HCCs in Hispanic patients were less likely to be within Milan criteria (26% vs. 38%; P < 0.0001) and were less likely to be treated with resection (9% vs. 13%; P = 0.03) or transplantation (8% vs. 19%; P < 0.0001). Hispanic patients had a median overall survival of 1.4 years (95% confidence interval [CI], 1.22-1.56), which was similar to that of non-Hispanic White patients (1.3 years; 95% CI, 1.26-1.41; P = 0.07). Conclusion: Hispanic patients with HCC were more likely to have metabolic risk factors for chronic liver disease, including obesity. Despite diagnosis at more advanced stages with less curative intervention than non-Hispanic White patients, median overall survival was similar between groups.

Characteristics, aetiologies and trends of hepatocellular carcinoma in patients without cirrhosis: a United States multicentre study.

BACKGROUND: Limited data exist on the burden and features of non-cirrhotic hepatocellular carcinoma (HCC) in the United States. AIM: To evaluate characteristics, aetiologies, trends and outcomes of non-cirrhotic HCC from 2000 to 2014 at five large US centres METHODS: Patient, tumour and liver disease aetiology data were collected. The presence of underlying cirrhosis was assessed based on published criteria. RESULTS: Of 5144 eligible patients with HCC, 11.7% had no underlying cirrhosis. Non-cirrhotic patients were older (64.1 vs 61.2 years), more frequently females (33.9% vs 20.8%) and less frequently black (8.3% vs 12.4%) (P < .001 for all). Among non-cirrhotic patients, non-alcoholic fatty liver disease (NAFLD) was the most common liver disease (26.3%), followed by hepatitis C virus (HCV) (12.1%) and hepatitis B virus (HBV) (10%) infections. As of 2014, there was increased percentage of cirrhotic HCC and a decline in non-cirrhotic HCC mainly due to significant annual increases in cirrhotic HCC due to HCV (0.96% [P < .0001]) and NAFLD (0.66% [P = .003]). Patients with non-cirrhotic HCC had larger tumours (8.9 vs 5.3 cm), were less frequently within Milan criteria (15% vs 39%), more frequently underwent resection (43.6% vs 8%) (P < .001 for all) and had better overall survival than cirrhotic HCC patients (median 1.8 vs 1.3 years, P = .004). CONCLUSIONS: Nearly 12% of HCCs occurred in patients without underlying cirrhosis. NAFLD was the most common liver disease in these patients. During the study, the frequency of non-cirrhotic HCC decreased, whereas that of cirrhotic HCC increased. Although non-cirrhotic patients presented with more advanced HCC, their survival was better.