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Background: Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology. Methods: US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI). Results: Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24–1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42–1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41–2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63–0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33–0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29–2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68–0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients. Conclusions: Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality. Impact: Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.

Parents of children with autism spectrum disorder often report poorer sleep compared to parents of typically developing children. When parents do not obtain enough quality sleep, functioning may be compromised placing the onus of care on already stressed parents. However, improving sleep duration may not improve sleep quality and is not always feasible. This study aimed to measure sleep quality in parents of children with autism spectrum disorder, determine if stress and children’s sleep are associated with sleep quality and whether resources, appraisals, and coping moderate these relationships. Multivariable regression was used to determine the effects of stress and children’s sleep problems on sleep quality and test modifying effects. Mean (SD) Pittsburgh Sleep Quality Index scores was 8.81 (3.76), with 77.6% of parents scoring above the clinical cut-off. Mean (SD) Children’s Sleep Habits Questionnaire scores was 54.03 (8.32), with 96.3% of parents rating their child’s sleep above the clinical cut-off. Children’s sleep was the only significant predictor and none of the expected effect modifiers were significant. Children’s sleep may be an important target to improve parent sleep quality but requires systematic assessment with interventional research. Implications for rehabilitationBoth parents and their 4–10-year-old children with ASD experience high levels of sleep disturbances.Clinicians can start the conversation early with parents about their children’s sleep by providing them with information to increase awareness and recognize healthy sleep habits in their children.Clinicians are important in the assessment, management, and evaluation of pediatric sleep problems, which may have significant spillover effects on parents of children with ASD.There is a need for more resources and training to be available to clinicians to assess children and their parents for sleep problems, which could extend beyond the assessment of sleep and consider parent’s daytime functioning and mental health. Both parents and their 4–10-year-old children with ASD experience high levels of sleep disturbances. Clinicians can start the conversation early with parents about their children’s sleep by providing them with information to increase awareness and recognize healthy sleep habits in their children. Clinicians are important in the assessment, management, and evaluation of pediatric sleep problems, which may have significant spillover effects on parents of children with ASD. There is a need for more resources and training to be available to clinicians to assess children and their parents for sleep problems, which could extend beyond the assessment of sleep and consider parent’s daytime functioning and mental health.

Supplementary Table S5. Association between race/ethnicity and risk of cirrhosis decompensation in patients with cirrhosis overall and by cirrhosis etiology: follow-up from cirrhosis diagnosis (2001-2014) to 2020

Background:Among patients with cirrhosis, it remains unclear whether there are racial/ethnic differences in cirrhosis complications and mortality. We examined the associations between race/ethnicity and risk for hepatocellular carcinoma (HCC), cirrhosis decompensation, and all-cause mortality overall and by cirrhosis etiology.Methods:US Veterans diagnosed with cirrhosis from 2001 to 2014 (n = 120,992), due to hepatitis C virus (HCV; n = 55,814), alcohol-associated liver disease (ALD; n = 36,323), hepatitis B virus (HBV; n = 1,972), nonalcoholic fatty liver disease (NAFLD; n = 17,789), or other (n = 9,094), were followed through 2020 for incident HCC (n = 10,242), cirrhosis decompensation (n = 27,887), and mortality (n = 81,441). Multivariable Cox proportional hazards regression was used to estimate adjusted hazard ratios (aHR) and 95% confidence intervals (CI).Results:Compared with non-Hispanic White patients, Hispanic patients had higher risk for HCC overall (aHR, 1.32; 95% CI, 1.24–1.41) and by cirrhosis etiology, particularly for ALD- (aHR, 1.63; 95% CI, 1.42–1.87) and NAFLD-cirrhosis (aHR, 1.76; 95% CI, 1.41–2.20), whereas non-Hispanic Black patients had lower HCC risk in ALD- (aHR, 0.79; 95% CI, 0.63–0.98) and NAFLD-cirrhosis (aHR, 0.54; 95% CI, 0.33–0.89). Asian patients had higher HCC risk (aHR, 1.70; 95% CI, 1.29–2.23), driven by HCV- and HBV-cirrhosis. Non-Hispanic Black patients had lower risk for cirrhosis decompensation overall (aHR, 0.71; 95% CI, 0.68–0.74) and by cirrhosis etiology. There was lower risk for mortality among all other racial/ethnic groups compared with non-Hispanic White patients.Conclusions:Race/ethnicity is an important predictor for risk of developing HCC, decompensation, and mortality.Impact:Future research should examine factors underlying these racial/ethnic differences to inform prevention, screening, and treatment for patients with cirrhosis.

Safe and just Earth System Boundaries (ESBs) for surface and groundwater (blue water) have been defined for sustainable water management in the Anthropocene. We evaluate where minimum human needs can be met within the surface water ESB and, where this is not possible, identify how much groundwater is required. 2.6 billion people live in catchments where groundwater is needed because they are already outside the surface water ESB or have insufficient surface water to meet human needs and the ESB. Approximately 1.4 billion people live in catchments where demand side transformations are required as they either exceed the surface water ESB or face a decline in groundwater recharge and cannot meet minimum needs within the ESB. A further 1.5 billion people live in catchments outside the ESB with insufficient surface water to meet needs, requiring both supply and demand-side transformations. These results highlight the challenges and opportunities of meeting even basic human access needs to water and protecting aquatic ecosystems.

'Legends for Supplementary Figures'

Malignant transformation of tissue stem cells (SC) may be the root of most cancer. Accordingly, we identified miRNA expression patterns in the normal human colonic SC niche to understand how cancer stem cells (CSC) may arise. In profiling miRNA expression in SC-enriched crypt subsections isolated from fresh, normal surgical specimens, we identified 16 miRNAs that were differentially expressed in the crypt bottom, creating an SC signature for normal colonic epithelia (NCE). A parallel analysis of colorectal cancer tissues showed differential expression of 83 miRNAs relative to NCE. Within the 16 miRNA signature for the normal SC niche, we found that miR-206, miR-007-3, and miR-23b individually could distinguish colorectal cancer from NCE. Notably, miR-23b, which was increased in colorectal cancer, was predicted to target the SC-expressed G protein-coupled receptor LGR5. Cell biology investigations showed that miR-23b regulated CSC phenotypes globally at the level of proliferation, cell cycle, self-renewal, epithelial–mesenchymal transition, invasion, and resistance to the colorectal cancer chemotherapeutic agent 5-fluorouracil. In mechanistic experiments, we found that miR-23b decreased LGR5 expression and increased ALDH+ CSCs. CSC analyses confirmed that levels of LGR5 and miR-23b are inversely correlated in ALDH+ CSCs and that distinct subpopulations of LGR5+ and ALDH+ CSCs exist. Overall, our results define a critical function for miR-23b, which, by targeting LGR5, contributes to overpopulation of ALDH+ CSCs and colorectal cancer. Cancer Res; 77(14); 3778–90. ©2017 AACR.

List of 83 miRNAs which were differentially expressed in CRC vs normal colon.

Lists of predicted gene targets of miRNAs in the upper crypt. List of predicted gene targets in the crypt bottom. GO term analysis of the top 200 predicted gene targets for both the lists.

'Fig S1. Validation of miRNA chip results by quantitative PCR analysis. Fig S2. Analysis of differentially expressed miRNAs using target predictions. Fig S3. The relative abundance of the common predicted targets in relation to miRNA levels in CRC cell lines. Fig S4. The effect of miRNAs on mRNA expression levels of their predicted targets. Fig S5. Relative expression of four candidate microRNAs in HT29 ALDH+ cells as compared to ALDH- cells. Fig S6. miRNA23b targets 3' UTR of LGR5 and LRIG1 mRNA. Fig S7: miRNA23b affects cell proliferation. Fig S8: CaCo2 data on miRNA23b precursor and antimer effect on sphere forming ability as well as 5FU response.'

* List gives the number of target gene transcripts that are hit by one or more of the miRNAs in order of decreasing number of miRNAs hitting them. **List gives the number of target gene transcripts that are hit by those miRNAs that are over-expressed in the crypt bottom in addition to hsa-mir-25 and hsa-mir-007

Alcohol use can cause hepatic necroinflammation and worsening portal hypertension in patients with cirrhosis. We aimed to evaluate the associations between degree of alcohol use and clinical liver-related outcomes according to etiology of cirrhosis. In this retrospective cohort analysis, 44,349 U.S. veterans with cirrhosis from alcohol-associated liver disease (ALD), chronic hepatitis C virus (HCV) infection, or nonalcoholic fatty liver disease were identified who completed the Alcohol Use Disorders Identification Test Consumption questionnaire in 2012. Based on this score, level of alcohol use was categorized as none, low level, or unhealthy. Multivariable Cox proportional hazards regression was used to assess for associations between alcohol use and mortality, cirrhosis decompensation (new ascites, encephalopathy, or variceal bleeding), and hepatocellular carcinoma (HCC). At baseline, 36.4% of patients endorsed alcohol use and 17.1% had unhealthy alcohol use. During a mean 4.9 years of follow-up, 25,806 (57.9%) patients died, 9,409 (21.4%) developed a new decompensation, and 4,733 (11.1%) developed HCC. In patients with ALD-cirrhosis and HCV-cirrhosis, unhealthy alcohol use, compared with no alcohol use, was associated with higher risks of mortality (adjusted hazard ratio [aHR] = 1.13, 95% confidence interval [CI] = 1.07-1.19 and aHR = 1.14, 95% CI = 1.08-1.20, respectively) and decompensation (aHR = 1.18, 95% CI = 1.07-1.30 and aHR = 1.08, 95% CI = 1.00-1.16, respectively). Alcohol use was not associated with HCC, regardless of cirrhosis etiology. Conclusion: Unhealthy alcohol use was common in patients with cirrhosis and was associated with higher risks of mortality and cirrhosis decompensation in patients with HCV-cirrhosis and ALD-cirrhosis. Therefore, health care providers should make every effort to help patients achieve abstinence. The lack of association between alcohol use and HCC merits further investigation.

BACKGROUND AND AIMS: Whether patients with cirrhosis have increased risk of SARS-CoV-2 infection and the extent to which infection and cirrhosis increase the risk of adverse patient outcomes remain unclear. APPROACH AND RESULTS: We identified 88,747 patients tested for SARS-CoV-2 between 3/1/20-5/14/20 in the Veterans Affairs (VA) national healthcare system, including 75,315 with no cirrhosis-SARS-CoV-2 negative (C0-S0), 9826 with no cirrhosis-SARS-CoV-2 positive (C0-S1); 3301 with cirrhosis-SARS-CoV-2 negative (C1-S0); and 305 with cirrhosis-SARS-CoV-2 positive (C1-S1). Patients were followed through 6/22/20. Hospitalization, mechanical ventilation and death were modeled in time-to-event analyses using Cox proportional hazards regression. Patients with cirrhosis were less likely to test positive than patients without cirrhosis (8.5% vs. 11.5%, adjusted odds ratio 0.83, 95% CI 0.69-0.99). Thirty-day mortality and ventilation rates increased progressively from C0-S0 (2.3% and 1.6%), to C1-S0 (5.2% and 3.6%), to C0-S1 (10.6% and 6.5%), to C1-S1(17.1% and 13.0%). Among patients with cirrhosis, those who tested positive for SARS-CoV-2 were 4.1 times more likely to undergo mechanical ventilation (adjusted hazard ratio [aHR] 4.12, 95% CI 2.79-6.10) and 3.5 times more likely to die (aHR 3.54, 95% CI 2.55-4.90) than those who tested negative. Among patients with SARS-CoV-2 infection, those with cirrhosis were more likely to be hospitalized (aHR 1.37, 95% CI 1.12-1.66), undergo ventilation (aHR 1.61, 95% CI 1.05-2.46) or die (aHR 1.65, 95% CI 1.18-2.30) than patients without cirrhosis. Among patients with cirrhosis and SARS-CoV-2 infection, the most important predictors of mortality were advanced age, cirrhosis decompensation and high MELD score. CONCLUSIONS: SARS-CoV-2 infection was associated with a 3.5-fold increase in mortality in patients with cirrhosis. Cirrhosis was associated with a 1.7-fold increase in mortality in patients with SARS-CoV-2 infection.

Background We aimed to describe trends in adverse outcomes among patients who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) between February and September 2020 within a national healthcare system. Methods We identified enrollees in the national United States Veterans Affairs healthcare system who tested positive for SARS-CoV-2 between 28 February 2020 and 30 September 2020 (n = 55 952), with follow-up extending to 19 November 2020. We determined trends over time in incidence of the following outcomes that occurred within 30 days of testing positive: hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death. Results Between February and July 2020, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), which subsequently plateaued between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, documented symptoms, and laboratory tests, including among subgroups of patients hospitalized, admitted to the ICU, or treated with mechanical ventilation. From February to September, there were decreases in the use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%), vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) and increases in the use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%), and remdesivir (1.7% to 45.4%) among hospitalized patients. Conclusions The risk of adverse outcomes in SARS-CoV-2–positive patients decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics and may reflect changing treatment practices or viral pathogenicity.

Background Identifying risk factors for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection could help health systems improve testing and screening strategies. The aim of this study was to identify demographic factors, comorbid conditions, and symptoms independently associated with testing positive for SARS-CoV-2. Methods This was an observational cross-sectional study at the Veterans Health Administration, including persons tested for SARS-CoV-2 nucleic acid by polymerase chain reaction (PCR) between 28 February and 14 May 2020. Associations between demographic characteristics, diagnosed comorbid conditions, and documented symptoms with testing positive for SARS-CoV-2 were measured. Results Of 88 747 persons tested, 10 131 (11.4%) were SARS-CoV-2 PCR positive. Positivity was associated with older age (≥80 vs Conclusions The majority of positive SARS-CoV-2 tests were attributed to geographic location, demographic characteristics, and obesity, with a minor contribution of chronic comorbid conditions.

Outcomes related to alcohol use after hepatitis C virus (HCV) treatment are unknown in the direct‐acting antiviral (DAA) era. We assessed levels of alcohol use before and after HCV treatment and their association with long‐term outcomes in a cohort of U.S. veterans. In this retrospective cohort analysis, 29,037 patients who initiated DAA regimens between 2013 and 2015 were followed for a mean of 3.04 years. We categorized alcohol use into three categories (nondrinking, low‐level drinking, and unhealthy drinking) using Alcohol Use Disorders Identification Test‐Consumption questionnaires administered within 1 year before (baseline) and after treatment. Multivariable Cox proportional hazards regression was used to determine the associations between alcohol use and mortality or liver‐related outcomes. Before DAA treatment, 68% of veterans reported nondrinking, 22.9% reported low‐level drinking, and 9.1% reported unhealthy drinking. Compared to patients with baseline non‐drinking, those with unhealthy drinking had a higher risk of mortality (adjusted hazard ratio [HR] 1.53, 95% confidence interval [CI]: 1.34‐1.75) and decompensated cirrhosis (adjusted HR 1.30, 95% CI: 1.06‐1.59) and lower likelihood of liver transplantation (adjusted HR 0.24, 95% CI: 0.06‐0.92). These associations were greater in patients without sustained virologic response than in those with sustained virologic response. When alcohol use before and after treatment was modeled as a time‐varying covariate, similar associations were observed. Survival analysis also found that unhealthy drinking was significantly associated with a lower probability of survival compared with nondrinking. Low‐level alcohol use was not associated with increased risk of adverse outcomes. Conclusion: In this large cohort of U.S. veterans with HCV who received DAAs, unhealthy drinking was common and associated with a higher risk of posttreatment mortality. Interventions to achieve alcohol cessation before and during antiviral treatment should be encouraged., In a cohort of 29,037 U.S. veterans who received hepatitis C virus treatment with direct‐acting antivirals, we assessed levels of alcohol use and their association with long‐term outcomes. Unhealthy drinking was associated with a higher risk of posttreatment mortality. Interventions to achieve alcohol cessation before and during antiviral treatment should be encouraged.

Background We examined whether key sociodemographic and clinical risk factors for Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and mortality changed over time in a population-based cohort study. Methods and findings In a cohort of 9,127,673 persons enrolled in the United States Veterans Affairs (VA) healthcare system, we evaluated the independent associations of sociodemographic and clinical characteristics with SARS-CoV-2 infection (n = 216,046), SARS-CoV-2–related mortality (n = 10,230), and case fatality at monthly intervals between February 1, 2020 and March 31, 2021. VA enrollees had a mean age of 61 years (SD 17.7) and were predominantly male (90.9%) and White (64.5%), with 14.6% of Black race and 6.3% of Hispanic ethnicity. Black (versus White) race was strongly associated with SARS-CoV-2 infection (adjusted odds ratio [AOR] 5.10, [95% CI 4.65 to 5.59], p-value, George Ioannou and co-workers study the distribution of SARS-CoV-2 infections and outcomes among the United States population., Author summary Why was this study done? As the Coronavirus Disease 2019 (COVID-19) pandemic continues to evolve, some risk factors for infection with COVID-19 and death due to COVID-19 that were described early in the pandemic may be changing. Recognizing such changes is important in informing population-based approaches to prevent infection and reduce mortality. What did the researchers do and find? We investigated how the associations of key sociodemographic and clinical factors with COVID-19 infection, mortality, or case fatality changed between February 2020 and March 2021 among a cohort of approximately 9.1 million persons enrolled in the national US Veterans Affairs (VA) healthcare system, including 216,046 who tested positive and 10,230 who died of COVID-19 during the study period. Black (versus White) race was strongly associated with a 5-fold higher risk of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, a 4-fold higher risk of mortality, and a 2.5-fold higher risk of case fatality in February to March 2020, but these associations attenuated over time and were no longer statistically significant by November 2020 for infection and mortality and were reversed for case fatality. American Indian/Alaska Native (AI/AN versus White) race was associated with SARS-CoV-2 infection early in the pandemic, but this association declined over time and reversed by March 2021. Urban (versus rural) residence was associated with 2-fold higher risk of infection, a 2.5-fold higher risk of mortality, and 2.2-fold higher risk of case fatality in February to April 2020, but these associations attenuated over time and reversed by September 2020. Throughout the observation period, high comorbidity burden, younger age, Hispanic ethnicity, and obesity were consistently associated with infection, while high comorbidity burden, older age, Hispanic ethnicity, and male sex were consistently associated with mortality. What do these findings mean? Early in the pandemic, there were strongly positive associations of Black and AI/AN (versus White) race and urban (versus rural) residence with SARS-CoV-2 infection, mortality, and case fatality, but these were ameliorated or even reversed by March 2021. Our results apply directly to VA enrollees who are predominantly male and have access to universal healthcare; they need to be confirmed in other populations.

BackgroundOlder age and comorbid burden are both associated with adverse outcomes in SARS-CoV-2, but it is not known whether the association between comorbid burden and adverse outcomes differs in older and younger adults.ObjectiveTo compare the relationship between comorbid burden and adverse outcomes in adults with SARS-CoV-2 of different ages (18–64, 65–79 and ≥ 80 years).Design, setting, and participantsObservational longitudinal cohort study of 170,528 patients who tested positive for SARS-CoV-2 in the US Department of Veterans Affairs (VA) Health Care System between 2/28/20 and 12/31/2020 who were followed through 01/31/2021.MeasurementsCharlson Comorbidity Index (CCI); Incidence of hospitalization, intensive care unit (ICU) admission, mechanical ventilation, and death within 30 days of a positive SARS-CoV-2 test.ResultsThe cumulative 30-day incidence of death was 0.8% in cohort members p LimitationsThe CCI is calculated based on diagnostic codes, which may not provide an accurate assessment of comorbid burden.ConclusionsAge differences in the distribution and prognostic significance of overall comorbid burden could inform clinical management, vaccination prioritization and population health during the pandemic and argue for more work to understand the role of age and comorbidity in shaping the care of hospitalized patients with SARS-CoV-2.

ObjectivesWe aimed to describe trends in the incidence of adverse outcomes among patients who tested positive for SARS-CoV-2 between February and September 2020 within a national healthcare system.SettingUS Veterans Affairs national healthcare system.ParticipantsEnrollees in the VA healthcare system who tested positive for SARS-CoV-2 between 2/28/2020 and 9/30/2020 (n=55,952).OutcomesDeath, hospitalization, intensive care unit (ICU) admission and mechanical ventilation within 30 days of testing positive.The incidence of these outcomes was examined among patients infected each month and trends were evaluated using an interrupted time-series analysis.ResultsBetween February and July 2020, during the first wave of the US pandemic, there were marked downward trends in the 30-day incidence of hospitalization (44.2% to 15.8%), ICU admission (20.3% to 5.3%), mechanical ventilation (12.7% to 2.2%), and death (12.5% to 4.4%), with subsequent stabilization between July and September 2020. These trends persisted after adjustment for sociodemographic characteristics, comorbid conditions, and documented symptoms and after additional adjustment for laboratory test results among hospitalized patients, including among subgroups admitted to the ICU and treated with mechanical ventilation. Among hospitalized patients, use of hydroxychloroquine (56.5% to 0%), azithromycin (48.3% to 16.6%) vasopressors (20.6% to 8.7%), and dialysis (11.6% to 3.8%) decreased while use of dexamethasone (3.4% to 53.1%), other corticosteroids (4.9% to 29.0%) and remdesivir (1.7% to 45.4%) increased from February to September.ConclusionsAmong patients who tested positive for SARS-CoV-2 in a large national US healthcare system, risk for a range of adverse outcomes decreased markedly between February and July, with subsequent stabilization from July to September. These trends were not explained by changes in measured baseline patient characteristics.

It is unclear whether eradication of hepatitis C virus (HCV) leads to a reduction in the risk of hematologic malignancies. We aimed to determine the impact of sustained virologic response (SVR) induced by either direct‐acting antivirals (DAAs) or interferon (IFN) on the risk of hematologic malignancies. We identified 69,581 patients who initiated antiviral treatment in the Veterans Affairs national health care system from January 1, 1999, to December 31, 2015, including 40,410 (58%) IFN‐only regimens, 4,546 (6.5%) DAA + IFN regimens, and 24,625 (35%) DAA‐only regimens. We retrospectively followed patients to identify incident cases of hematologic malignancies or monoclonal gammopathy of unknown significance (MGUS), a premalignant precursor of multiple myeloma. Among patients treated with IFN, SVR was significantly associated with a reduction in the risk of lymphoma (adjusted hazard ratio [AHR], 0.70; 95% confidence interval [CI], 0.51‐0.97), multiple myeloma (AHR, 0.40; 95% CI, 0.20‐0.77), MGUS (AHR, 0.65; 95% CI, 0.42‐0.99), or all hematologic malignancies and MGUS combined (AHR, 0.67; 95% CI, 0.53‐0.84) over a mean follow‐up of 10.6 years. In contrast, among patients treated with DAA, SVR was not associated with the risk of lymphoma, multiple myeloma, MGUS, or all hematologic malignancies and MGUS combined (AHR, 1.08; 95% CI, 0.66‐1.78) during a mean follow‐up of 2.9 years. Neither IFN‐induced SVR nor DAA‐induced SVR was associated with risk of colon cancer or prostate cancer, which were chosen a priori as comparison/control malignancies. Conclusion: We describe novel strong associations between IFN‐induced SVR and lymphoma, multiple myeloma, MGUS, and all hematologic malignancies combined. Surprisingly, these associations were not observed with DAA‐induced SVR.

Diabetes self-management education (DSME) and medical nutrition therapy (MNT) improve glycemic control and reduce risk of chronic comorbid disease.Document outcomes for patients with type 2 diabetes (T2D) completing DSME and MNT through American Diabetes Association-recognized programs.Descriptive, retrospective chart review.Four random samples of 100 records of patients with T2D completing DSME and MNT at each of four regional centers in Alabama, June 2013 to 2014, were chosen for review; after exclusions, 392 records were retained.Weight, body mass index (BMI), hemoglobin A1c (HbA1c), total cholesterol, low-density lipoprotein, high-density lipoproteins (HDL), triglycerides (TG), and TG-to-HDL ratio.Mixed-model analysis of variance was used to determine differences between continuous variables. McNemar test was used to assess frequency of patients reaching glycemic targets. Paired t tests were used to determine significance of lipid parameters.Significant reductions were observed at end of program and 1 year in weight (2.67±5.54 kg, P0.001; 2.25±5.45 kg, P=0.001), BMI (0.93±1.91, P0.001; 0.76±1.93, P=0.001), and HbA1c (1.82%±2.23%, P0.001; 1.22%±2.15%, P0.001). Patients managed by diet alone had a mean baseline HbA1c of 6.95% and exhibited a 0.8% reduction in HbA1c (P0.001) at end of program. Those managed with diet plus drug therapy had a baseline HbA1c of 9% and exhibited a 2.09% reduction in HbA1c (P0.001). Following DSME and MNT, 62% of patients reached glycemic targets (HcA1c≤7%), as compared with 32% at baseline (P0.001). Significant reductions in TG were observed from baseline (162±74 mg/dL [4.19±1.91 mmol/L]) to follow-up (109±36 mg/dL [2.82±0.92 mmol/L]) (P0.001). HDL increased from baseline (45±13 mg/dL [1.16±0.34 mmol/L]) to follow-up (48±11 mg/dL [1.24±0.28 mmol/L]) (P=0.05). The TG-to-HDL ratio improved from a baseline of 4.07±2.41 to 2.48±1.26 at follow-up (P0.001).Reductions were observed in weight, BMI, HbA1c, TG, and TG-to-HDL ratio. Improved patient outcomes were achieved in the clinical setting and support universal coverage to increase patient access to DSME and MNT.

Key Points Question How can the risk of SARS-CoV-2–related death be estimated in the general population to be used for vaccination prioritization? Findings In this prognostic study of more than 7.6 million individuals enrolled in the Veterans Affairs health care system, a logistic regression model (COVIDVax) was developed to estimate risk of SARS-CoV-2–related death using the following 10 characteristics: sex, age, race, ethnicity, body mass index, Charlson Comorbidity Index, diabetes, chronic kidney disease, congestive heart failure, and the Care Assessment Need score. The model was estimated to save more lives than prioritizing vaccination based on age or on the US Centers for Disease Control and Prevention vaccination allocation. Meaning These findings suggest that prioritizing vaccination based on the model developed in this study could prevent a substantial number of SARS-CoV-2–related deaths during vaccine rollout., This prognostic study develops a model that estimates the risk of SARS-CoV-2–related mortality among all enrollees of the US Department of Veterans Affairs (VA) health care system., Importance A strategy that prioritizes individuals for SARS-CoV-2 vaccination according to their risk of SARS-CoV-2–related mortality would help minimize deaths during vaccine rollout. Objective To develop a model that estimates the risk of SARS-CoV-2–related mortality among all enrollees of the US Department of Veterans Affairs (VA) health care system. Design, Setting, and Participants This prognostic study used data from 7 635 064 individuals enrolled in the VA health care system as of May 21, 2020, to develop and internally validate a logistic regression model (COVIDVax) that predicted SARS-CoV-2–related death (n = 2422) during the observation period (May 21 to November 2, 2020) using baseline characteristics known to be associated with SARS-CoV-2–related mortality, extracted from the VA electronic health records (EHRs). The cohort was split into a training period (May 21 to September 30) and testing period (October 1 to November 2). Main Outcomes and Measures SARS-CoV-2–related death, defined as death within 30 days of testing positive for SARS-CoV-2. VA EHR data streams were imported on a data integration platform to demonstrate that the model could be executed in real-time to produce dashboards with risk scores for all current VA enrollees. Results Of 7 635 064 individuals, the mean (SD) age was 66.2 (13.8) years, and most were men (7 051 912 [92.4%]) and White individuals (4 887 338 [64.0%]), with 1 116 435 (14.6%) Black individuals and 399 634 (5.2%) Hispanic individuals. From a starting pool of 16 potential predictors, 10 were included in the final COVIDVax model, as follows: sex, age, race, ethnicity, body mass index, Charlson Comorbidity Index, diabetes, chronic kidney disease, congestive heart failure, and Care Assessment Need score. The model exhibited excellent discrimination with area under the receiver operating characteristic curve (AUROC) of 85.3% (95% CI, 84.6%-86.1%), superior to the AUROC of using age alone to stratify risk (72.6%; 95% CI, 71.6%-73.6%). Assuming vaccination is 90% effective at preventing SARS-CoV-2–related death, using this model to prioritize vaccination was estimated to prevent 63.5% of deaths that would occur by the time 50% of VA enrollees are vaccinated, significantly higher than the estimate for prioritizing vaccination based on age (45.6%) or the US Centers for Disease Control and Prevention phases of vaccine allocation (41.1%). Conclusions and Relevance In this prognostic study of all VA enrollees, prioritizing vaccination based on the COVIDVax model was estimated to prevent a large proportion of deaths expected to occur during vaccine rollout before sufficient herd immunity is achieved.

OBJECTIVE: The purpose of this study is to examine the associations of BMI with testing positive for severe acute respiratory coronavirus 2 (SARS-CoV-2) and risk of adverse outcomes in a cohort of Veterans Affairs enrollees. METHOD: Adjusted relative risks/hazard ratios (HRs) were calculated for the associations between BMI category (underweight, normal weight, overweight, class 1 obesity, class 2 obesity, and class 3 obesity) and testing positive for SARS-CoV-2 or experiencing hospitalization, intensive care unit admission, mechanical ventilation, and death among those testing positive. RESULTS: Higher BMI categories were associated with higher risk of a positive SARS-CoV-2 test compared with the normal weight category (class 3 obesity adjusted relative risk: 1.34, 95% CI: 1.28-1.42). Among 25,952 patients who tested positive for SARS-CoV-2, class 3 obesity was associated with higher risk of mechanical ventilation (adjusted HR [aHR]: 1.77, 95% CI: 1.35-2.32) and mortality (aHR: 1.42, 95% CI: 1.12-1.78) compared with normal weight individuals. These associations were present primarily in patients younger than 65 and were attenuated or absent in older age groups (interaction P < 0.05). CONCLUSION: Veterans Affairs enrollees with higher BMI were more likely to test positive for SARS-CoV-2 and were more likely to be mechanically ventilated or die if infected with SARS-CoV-2. Higher BMI contributed relatively more to the risk of death in those younger than 65 years of age as compared with other age categories.

Key Points Question What are the risk factors associated with hospitalization, mechanical ventilation, and death among patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection? Findings In this national cohort study of 88 747 veterans tested for SARS-CoV-2, hospitalization, mechanical ventilation, and mortality were significantly higher in patients with positive SARS-CoV-2 test results than among those with negative test results. Significant risk factors for mortality included older age, high regional coronavirus disease 2019 burden, higher Charlson Comorbidity Index score, fever, dyspnea, and abnormal results in many routine laboratory tests; however, obesity, Black race, Hispanic ethnicity, chronic obstructive pulmonary disease, hypertension, and smoking were not associated with mortality. Meaning In this study, most deaths from SARS-CoV-2 occurred in patients with age of 50 years or older, male sex, and greater comorbidity burden., This cohort study identifies excess risk and risk factors associated with hospitalization, mechanical ventilation, and mortality in patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)., Importance Identifying independent risk factors for adverse outcomes in patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can support prognostication, resource utilization, and treatment. Objective To identify excess risk and risk factors associated with hospitalization, mechanical ventilation, and mortality in patients with SARS-CoV-2 infection. Design, Setting, and Participants This longitudinal cohort study included 88 747 patients tested for SARS-CoV-2 nucleic acid by polymerase chain reaction between Feburary 28 and May 14, 2020, and followed up through June 22, 2020, in the Department of Veterans Affairs (VA) national health care system, including 10 131 patients (11.4%) who tested positive. Exposures Sociodemographic characteristics, comorbid conditions, symptoms, and laboratory test results. Main Outcomes and Measures Risk of hospitalization, mechanical ventilation, and death were estimated in time-to-event analyses using Cox proportional hazards models. Results The 10 131 veterans with SARS-CoV-2 were predominantly male (9221 [91.0%]), with diverse race/ethnicity (5022 [49.6%] White, 4215 [41.6%] Black, and 944 [9.3%] Hispanic) and a mean (SD) age of 63.6 (16.2) years. Compared with patients who tested negative for SARS-CoV-2, those who tested positive had higher rates of 30-day hospitalization (30.4% vs 29.3%; adjusted hazard ratio [aHR], 1.13; 95% CI, 1.08-1.13), mechanical ventilation (6.7% vs 1.7%; aHR, 4.15; 95% CI, 3.74-4.61), and death (10.8% vs 2.4%; aHR, 4.44; 95% CI, 4.07-4.83). Among patients who tested positive for SARS-CoV-2, characteristics significantly associated with mortality included older age (eg, ≥80 years vs 89 U/L vs ≤25 U/L: aHR, 1.86; 95% CI, 1.35-2.57), creatinine (>3.80 mg/dL vs 0.98 mg/dL: aHR, 3.79; 95% CI, 2.62-5.48), and neutrophil to lymphocyte ratio (>12.70 vs ≤2.71: aHR, 2.88; 95% CI, 2.12-3.91). With the exception of geographic region, the same covariates were independently associated with mechanical ventilation along with Black race (aHR, 1.52; 95% CI, 1.25-1.85), male sex (aHR, 2.07; 95% CI, 1.30-3.32), diabetes (aHR, 1.40; 95% CI, 1.18-1.67), and hypertension (aHR, 1.30; 95% CI, 1.03-1.64). Notable characteristics that were not significantly associated with mortality in adjusted analyses included obesity (body mass index ≥35 vs 18.5-24.9: aHR, 0.97; 95% CI, 0.77-1.21), Black race (aHR, 1.04; 95% CI, 0.88-1.21), Hispanic ethnicity (aHR, 1.03; 95% CI, 0.79-1.35), chronic obstructive pulmonary disease (aHR, 1.02; 95% CI, 0.88-1.19), hypertension (aHR, 0.95; 95% CI, 0.81-1.12), and smoking (eg, current vs never: aHR, 0.87; 95% CI, 0.67-1.13). Most deaths in this cohort occurred in patients with age of 50 years or older (63.4%), male sex (12.3%), and Charlson Comorbidity Index score of at least 1 (11.1%). Conclusions and Relevance In this national cohort of VA patients, most SARS-CoV-2 deaths were associated with older age, male sex, and comorbidity burden. Many factors previously reported to be associated with mortality in smaller studies were not confirmed, such as obesity, Black race, Hispanic ethnicity, chronic obstructive pulmonary disease, hypertension, and smoking.

This study describes trends in the incidence of hepatocellular carcinoma within the Veterans Health Administration from 2002 to 2018 before and after widespread direct-acting anti–hepatitis C virus (HCV) treatment.

Background & Aims Patients with chronic hepatitis B (CHB) infection routinely undergo screening for hepatocellular carcinoma (HCC), but the efficacy of screening remains unclear. We aimed to evaluate the impact of screening with ultrasound and/or serum alpha-fetoprotein (AFP) on HCC-related mortality in patients with CHB. Methods We performed a matched case-control study of patients with CHB receiving care through the Veterans Affairs (VA) health administration. Cases were patients who died of HCC between 01/01/2004 and 12/31/2017, while controls were patients with CHB who did not die of HCC. Cases were matched to controls by CHB diagnosis date, age, sex, race/ethnicity, cirrhosis, antiviral therapy exposure, hepatitis B e antigen status, and viral load. We identified screening ultrasound and AFPs obtained in the 4 years preceding HCC diagnosis in cases and the equivalent index date in controls. Using conditional logistic regression, we compared cases and controls with respect to receipt of screening. A lower likelihood of screening in cases corresponds to an association between screening and reduced risk of HCC-related mortality. Results We identified 169 cases, matched to 169 controls. Fewer cases than controls underwent screening with either screening modality (33.7% vs. 58.6%) or both modalities (19.5% vs. 34.4%). In multivariable conditional logistic regression, screening with either modality was associated with a lower risk of HCC-related mortality (adjusted odds ratio [aOR] 0.21, 95% CI 0.09–0.50), as was screening with both modalities (aOR of 0.13; 95% CI 0.04–0.43). Conclusions HCC screening was associated with a substantial reduction in HCC-related mortality in VA patients with CHB. Lay summary Patients with hepatitis B infection have a high risk of developing liver cancer. It is therefore recommended that they undergo frequent screening for liver cancer, but whether this leads to a lower risk of dying from liver cancer is not clear. In this study, we show that liver cancer screening is associated with a reduction in the mortality from liver cancer in patients with hepatitis B infection.

Objective To describe the incidence and risk factors for mortality and morbidity in patients with cirrhosis undergoing elective or emergent abdominal surgeries. Background Postoperative morbidity and mortality are higher in patients with cirrhosis; variation by surgical procedure type and cirrhosis severity remain unclear. Methods We analyzed prospectively-collected data from the Veterans Affairs (VA) Surgical Quality Improvement Program for 8193 patients with cirrhosis, 864 noncirrhotic controls with chronic hepatitis B infection, and 5468 noncirrhotic controls without chronic liver disease, who underwent abdominal surgery from 2001 to 2017. Data were analyzed using random-effects models controlling for potential confounders. Results Patients with cirrhosis had significantly higher 30-day mortality than noncirrhotic patients with chronic hepatitis B [4.4% vs 1.3%, adjusted odds ratio (aOR) 2.80, 95% confidence interval (CI) 1.57-4.98] or with no chronic liver disease (0.8%, aOR 4.68, 95% CI 3.27-6.69); mortality difference was highest in patients with Model for End-stage Liver Disease (MELD) score ≥10. Among patients with cirrhosis, postoperative mortality was almost 6 times higher after emergent rather than elective surgery (17.2% vs. 2.1%, aOR 5.82, 95% CI 4.66-7.27). For elective surgeries, 30-day mortality was highest after colorectal resection (7.0%) and lowest after inguinal hernia repair (0.6%). Predictors of postoperative mortality included cirrhosis-related characteristics (high MELD score, low serum albumin, ascites, encephalopathy), surgery-related characteristics (emergent vs elective, type of surgery, intraoperative blood transfusion), comorbidities (chronic obstructive pulmonary disease, cancer, sepsis, ventilator dependence, functional status), and age. Conclusions Accurate preoperative risk assessments in patients with cirrhosis should account for cirrhosis severity, comorbidities, type of procedure, and whether the procedure is emergent versus elective.

BACKGROUND & AIMS: Hepatitis C virus (HCV) treatment for patients with hepatocellular carcinoma (HCC) was uncommon before direct-acting antiviral (DAA) medications. Real-world effectiveness of DAAs for HCV in patients with HCC is unclear. We describe rates of sustained virologic response (SVR) with DAA regimens by HCV genotype in patients with a history of HCC. METHODS: We identified patients who initiated antiviral treatment between January 1, 2014 and June 30, 2015 in the national Veterans Affairs health care system. Regimens included sofosobu-vir, ledipasvir/sofosbuvir, and paritaprevir/ritonavir/ombitasvir and dasabuvir with or without ribavirin. HCC patients were divided into those who were treated with liver transplantation after HCC diagnosis (“HCC/LT” group) and those treated with other modalities prior to antiviral therapy (“HCC” group). RESULTS: Of 17,487 HCV treatment recipients, 624 (3.6%) had prior HCC, including 142 with HCC/LT and 482 with HCC. Overall SVR was 91.1% in non-HCC, 74.4% in HCC, and 94.0% in HCC/LT. Among HCC patients, genotype 1 had the highest SVR overall (79.1% in HCC and 96.4% in HCC/LT), and genotype 3 the lowest (47.0% in HCC and 88.9% in HCC/LT). After adjustment for con-founders, the presence of HCC was associated with lower likelihood of SVR overall (AOR 0.38 [95% Cl 0.29, 0.48], p

OBJECTIVE Hepatitis C virus (HCV) infection is associated with diabetes and may worsen glycemic control in patients with diabetes. We aimed to investigate whether eradication of HCV infection with direct-acting antiviral (DAA) agents is associated with improved glycemic control in patients with diabetes. RESEARCH DESIGN AND METHODS We identified 2,435 patients with diabetes who underwent interferon-free and ribavirin-free DAA-based antiviral treatment for HCV in the national Veterans Affairs health care system. Changes in average hemoglobin A1c (HbA1c) level and use of antidiabetic medications 1 year before and after antiviral treatment were compared between patients who achieved sustained virologic response (SVR) and those who did not. RESULTS Among patients with elevated baseline HbA1c, the drop in HbA1c associated with antiviral treatment was greater in those who achieved SVR (0.98%) than in those who sustained treatment failure (0.65%) (adjusted mean difference 0.34, P = 0.02). Use of antidiabetic medications decreased more in patients who achieved SVR than in those who sustained treatment failure, especially for the use of insulin, which dropped significantly from 41.3% to 38% in patients achieving SVR compared with a slight increase from 49.8% to 51% in those who sustained treatment failure. CONCLUSIONS DAA-based eradication of HCV is associated with improved glycemic control in patients with diabetes as evidenced by decreased mean HbA1c and decreased insulin use. These endocrine benefits of SVR provide additional justification for considering antiviral treatment in all patients with diabetes.

SummaryBackground Highly effective direct antiviral agents (DAAs) for hepatitis C virus (HCV) were introduced recently. Their utilisation has been limited by high cost and low access to care. Aim To describe the effect of DAAs on HCV treatment and cure rates in the United States Veterans Affairs (VA) national healthcare system. Methods We identified all HCV antiviral treatment regimens initiated from 1 January 1999 to 31 December 2015 (n = 105 369) in the VA national healthcare system, and determined if they resulted in sustained virological response (SVR). Results HCV antiviral treatment rates were low (1981–6679 treatments/year) in the interferon era (1999–2010). The introduction of simeprevir and sofosbuvir in 2013 and ledipasvir/sofosbuvir and paritaprevir/ombitasvir/ritonavir/dasabuvir in 2014 were followed by increases in annual treatment rates to 9180 in 2014 and 31 028 in 2015. The number of patients achieving SVR was 1313 in 2010, the last year of the interferon era, and increased 5.6-fold to 7377 in 2014 and 21-fold to 28 084 in 2015. The proportion of treated patients who achieved SVR increased from 19.2% in 1999 and 36.0% in 2010 to 90.5% in 2015. Within 2015, monthly treatment rates ranged from 727 in July to 6868 in September correlating with the availability of funds for DAAs. Conclusions DAAs resulted in a 21-fold increase in the number of patients achieving HCV cure. Treatment rates in 2015 were limited primarily by the availability of funds. Further increases in funding and cost reductions of DAAs in 2016 suggest that the VA could cure the majority of HCV-infected Veterans in VA care within the next few years.

Background & Aims It is unclear whether a sustained virologic response (SVR) to direct-acting antiviral (DAA) therapy reduces the risk of incident hepatic encephalopathy (HE) in patients with hepatitis C virus (HCV) infection or whether it leads to resolution of pre-existent HE. Methods We identified 71,457 patients who initiated antiviral treatments in the Veterans Affairs Healthcare System from January 1, 1999 through December 31, 2015; 35,871 patients (58%) received only interferon, 4535 patients (7.2%) received DAAs plus interferon, and 21,948 patients (35%) received DAA-only regimens. We collected data from patients through October 31, 2018, for an average of 6.6 years. We evaluated the association between SVR and the development of incident HE or the resolution of pre-existent HE (defined by cessation of pharmacotherapy) as well as the risk of hospitalization with HE after adjusting for potential confounders. Results Compared to no SVR, SVR after DAA therapy was associated with a significantly lower risk of developing HE (0.28 vs 1.39 per 100 person-years; adjusted hazard ratio [AHR] 0.41; 95% CI, 0.32–0.51). This association persisted among patients with co-morbid alcohol use disorder and diabetes as well as patients with cirrhosis (AHR, 0.36; 95% CI, 0.31–0.43) and model for end-stage liver disease (MELD) scores of 9 or more (AHR, 0.36; 95% CI, 0.30–0.44). SVR was also associated with reduced risk of hospitalization with HE (AHR, 0.59; 95% CI, 0.43–0.81). Among 2396 patients who were receiving pharmacotherapy for HE at the time of antiviral treatment, SVR was associated with a significantly increased likelihood of HE resolution for those with MELD scores below 9 (AHR, 2.26; 95% CI, 1.74–2.93) but not those with MELD scores of 9 or more. Conclusions In a retrospective study of veterans, we found DAA eradication of HCV infection to be associated with a 59% reduction in risk of development of HE and a > 2-fold increased likelihood of resolution of pre-existing HE in all subgroups except patients with MELD scores of 9 or more.

Background The real-world, long-term benefits of sustained virologic response (SVR) on the risk of variceal bleeding remain unclear. Aim To assess the association between DAA-induced SVR and post-treatment variceal bleeding METHODS: We identified patients who initiated DAA-only anti-viral treatments in the United States Veterans Affairs healthcare system from 2013 to 2015. We followed patients until 1 January 2019 for the development of gastro-oesophageal variceal bleeding defined by diagnostic codes. We used multivariable Cox proportional hazards regression to assess the association between SVR and development of variceal bleeding, adjusting for potential confounders. Results Among 33 582 DAA-treated patients, 549 (1.6%) developed variceal bleeding after treatment (mean follow-up 3.1 years). Compared to no SVR, SVR was associated with a significantly lower incidence of variceal bleeding among all patients (0.46 vs 1.26 per 100 patient-years, adjusted hazard ratio [AHR] 0.66, 95% CI 0.52-0.83), among patients with pre-treatment cirrhosis (1.55 vs 2.96 per 100 patient-years, AHR 0.73, 95% CI 0.57-0.93) and among patients without pre-treatment cirrhosis (0.07 vs 0.29 per 100 patient-years, AHR 0.33, 95% CI 0.17-0.65). The risk of variceal bleeding after treatment was lower in those who achieved SVR vs no SVR among patients who had non-bleeding varices (3.5 vs 4.9 per 100 patient-years) or bleeding varices (12.9 vs 16.4 per 100 patient-years) diagnosed before treatment, but these differences were not statistically significant in adjusted analyses. Conclusion DAA-induced SVR is independently associated with a lower risk of variceal bleeding during long-term follow-up in patients with and without pre-treatment cirrhosis. These findings demonstrate an important real-world benefit of DAA treatment.

Background and aims It is unclear whether there are differences between direct-acting antivirals (DAAs) for hepatitis C virus in risk of hepatocellular carcinoma (HCC) after antiviral therapy. We aimed to compare different DAA regimens with respect to risk of de novo HCC following antiviral therapy. Patients and methods We identified 33 137 patients who initiated hepatitis C virus antiviral treatment in the Veterans Affair healthcare system between 6 December 2013 and 31 December 2015 with one of four DAA-only regimens (± ribavirin): paritaprevir/ritonavir/ombitasvir/dasabuvir (n=6289), sofosbuvir (n=4356), sofosbuvir+simeprevir (n=3210), and ledipasvir/sofosbuvir (n=19 282). We retrospectively followed patients until 15 June 2017 to identify incident (de novo) cases of HCC. We used propensity score-adjusted Cox proportional hazards regression to compare different DAA regimens with respect to HCC risk. Results During a mean follow-up of 1.52 years, 741 new cases of HCC were diagnosed after antiviral treatment (annual incidence=1.47%). Patients treated with sofosbuvir+simeprevir had the highest annual HCC incidence (2.47%), followed by sofosbuvir (1.91%), ledipasvir/sofosbuvir (1.26%), and paritaprevir/ritonavir/ombitasvir/dasabuvir (0.95%). However, there were great differences between DAA-treated patients in the prevalence of cirrhosis, markers of advanced fibrosis, thrombocytopenia, and other HCC risk factors. After adjustment for baseline characteristics associated with HCC, there were no significant differences in HCC risk between the four DAA regimens. Conclusion There are no significant differences between DAA regimens in HCC risk after antiviral treatment. This suggests that DAAs do not have direct carcinogenic effects as it would be unlikely that different DAAs would have identical carcinogenic effects.

Background & Aims Hepatocellular carcinoma (HCC) risk varies dramatically in patients with cirrhosis according to well-described, readily available predictors. We aimed to develop simple models estimating HCC risk in patients with alcohol-related liver disease (ALD)-cirrhosis or non-alcoholic fatty liver disease (NAFLD)-cirrhosis and calculate the net benefit that would be derived by implementing HCC surveillance strategies based on HCC risk as predicted by our models. Methods We identified 7,068 patients with NAFLD-cirrhosis and 16,175 with ALD-cirrhosis who received care in the Veterans Affairs (VA) healthcare system in 2012. We retrospectively followed them for the development of incident HCC until January 2018. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at entry into the cohort in 2012. We plotted decision curves of net benefit against HCC screening thresholds. Results We identified 1,278 incident cases of HCC during a mean follow-up period of 3.7 years. Mean annualized HCC incidence was 1.56% in NAFLD-cirrhosis and 1.44% in ALD-cirrhosis. The final models estimating HCC were developed separately for NAFLD-cirrhosis and ALD-cirrhosis and included 7 predictors: age, gender, diabetes, body mass index, platelet count, serum albumin and aspartate aminotransferase to √alanine aminotransferase ratio. The models exhibited very good measures of discrimination and calibration and an area under the receiver operating characteristic curve of 0.75 for NAFLD-cirrhosis and 0.76 for ALD-cirrhosis. Decision curves showed higher standardized net benefit of risk-based screening using our prediction models compared to the screen-all approach. Conclusions We developed simple models estimating HCC risk in patients with NAFLD-cirrhosis or ALD-cirrhosis, which are available as web-based tools (www.hccrisk.com). Risk stratification can be used to inform risk-based HCC surveillance strategies in individual patients or healthcare systems or to identify high-risk patients for clinical trials. Lay summary Patients with cirrhosis of the liver are at risk of getting hepatocellular carcinoma (HCC or liver cancer) and therefore it is recommended that they undergo surveillance for HCC. However, the risk of HCC varies dramatically in patients with cirrhosis, which has implications on if and how patients get surveillance, how providers counsel patients about the need for surveillance, and how healthcare systems approach and prioritize surveillance. We used readily available predictors to develop models estimating HCC risk in patients with cirrhosis, which are available as web-based tools at www.hccrisk.com.

Parents of children with Neurodevelopmental Disabilities (NDDs) are at risk of sleep loss. No comprehensive systematic reviews examining parental sleep outcomes in caregivers of children with NDDs exist. A systematic search was conducted between June and August 2016 examining sleep quantity, quality, sleepiness, and fatigue outcomes of caregivers of children with NDDs. Of 7,534 citations retrieved, 33 met eligibility criteria. Most studies ( n = 27) were cross-sectional, included a range of NDDs and were of "poor" ( n = 14) or "fair" ( n = 17) quality. Few good quality studies compared objectively measured sleep in parents of children with NDDs with parents with typically developing children. Parents of children with NDDs consistently reported significantly poorer subjective sleep quality. There is a paucity of good quality comparative studies, using well-validated measures, examining parental sleep outcomes. Future research should aim to fill this gap, providing greater insight to parents' experiences, and identifying targets for intervention design and evaluation.

Background and aims Hepatocellular carcinoma (HCC) risk is high in cirrhosis. We sought to describe differences in HCC risk, predictors and trends over time according to etiology of cirrhosis. Methods We identified 116,404 patients with cirrhosis diagnosed between 2001–2014 in the VA healthcare system and determined incident HCC cases occurring from the date of cirrhosis diagnosis until 01/31/2017. Patients were divided by cirrhosis etiology into hepatitis C virus (HCV, n = 52,671), alcoholic liver disease (ALD, n = 35,730), nonalcoholic fatty liver disease (NAFLD, n = 17,354), or OTHER (n = 10,649). Results During a mean follow-up of 4.3 years, 10,042 new HCC cases were diagnosed. Patients with HCV had >3 times higher incidence of HCC (3.3 per 100 patient-years) than patients with ALD (0.86/100 patient-years), NAFLD (0.90/100 patient-years) or OTHER (1.0/100 patient-years), an association that persisted after adjusting for baseline characteristics. HCC incidence was 1.6 times higher in patients with cirrhosis diagnosed in 2008–2014 (2.47/100 patient-years) than in 2001–2007 (1.55/100 patient-years). Independent predictors of HCC among all cirrhosis etiologies included: age, male sex, Hispanic ethnicity, high serum alpha fetoprotein, alkaline phosphatase and AST/√ALT ratio and low serum albumin and platelet count. Diabetes was associated with HCC in ALD-cirrhosis and NAFLD-cirrhosis, and BMI in ALD-cirrhosis. Conclusions HCC risk is 3 times greater in cirrhotic patients with HCV than ALD or NAFLD. HCC risk continues to increase over time in analyses extending to 2017 in cirrhosis of all etiologies. Multiple readily available risk factors for HCC were identified that were influenced by cirrhosis etiology and could be used to develop HCC risk estimation models.

Background & Aims Most patients with hepatitis C virus (HCV) infection will undergo antiviral treatment with direct-acting antivirals (DAAs) and achieve sustained virologic response (SVR). We aimed to develop models estimating hepatocellular carcinoma (HCC) risk after antiviral treatment. Methods We identified 45,810 patients who initiated antiviral treatment in the Veterans Affairs (VA) national healthcare system from 1/1/2009 to 12/31/2015, including 29,309 (64%) DAA-only regimens and 16,501 (36%) interferon ± DAA regimens. We retrospectively followed patients until 6/15/2017 to identify incident cases of HCC. We used Cox proportional hazards regression to develop and internally validate models predicting HCC risk using baseline characteristics at the time of antiviral treatment. Results We identified 1,412 incident cases of HCC diagnosed at least 180 days after initiation of antiviral treatment during a mean follow-up of 2.5 years (range 1.0–7.5 years). Models predicting HCC risk after antiviral treatment were developed and validated separately for four subgroups of patients: cirrhosis/SVR, cirrhosis/no SVR, no cirrhosis/SVR, no cirrhosis/no SVR. Four predictors (age, platelet count, serum aspartate aminotransferase/√alanine aminotransferase ratio and albumin) accounted for most of the models’ predictive value, with smaller contributions from sex, race-ethnicity, HCV genotype, body mass index, hemoglobin and serum alpha-fetoprotein. Fitted models were well-calibrated with very good measures of discrimination. Decision curves demonstrated higher net benefit of using model-based HCC risk estimates to determine whether to recommend screening or not compared to the screen-all or screen-none strategies. Conclusions We developed and internally validated models that estimate HCC risk following antiviral treatment. These models are available as web-based tools that can be used to inform risk-based HCC surveillance strategies in individual patients. Lay summary Most patients with hepatitis C virus have been treated or will be treated with direct-acting antivirals. It is important that we can model the risk of hepatocellular carcinoma in these patients, so that we develop the optimum screening strategy that avoids unnecessary screening, while adequately screening those at increased risk. Herein, we have developed and validated models that are available as web-based tools that can be used to guide screening strategies.