Poverty, Comorbidity, and Ethnicity: COVID-19 Outcomes in a Safety Net Health System.

Objective: To determine if race-ethnicity is correlated with case-fatality rates among low-income patients hospitalized for COVID-19. Research Design: Observational cohort study using electronic health record data. Patients: All patients assessed for COVID-19 from March 2020 to January 2021 at one safety net health system. Measures: Patient demographic and clinical characteristics, and hospital care processes and outcomes. Results: Among 25,253 patients assessed for COVID-19, 6,357 (25.2%) were COVID-19 positive: 1,480 (23.3%) hospitalized; 334 (22.6%) required intensive care; and 106 (7.3%) died. More Hispanic patients tested positive (51.8%) than non-Hispanic Black (31.4%) and White patients (16.7%, P<.001]. Hospitalized Hispanic patients were younger, more often uninsured, and less likely to have comorbid conditions. Non-Hispanic Black patients had significantly more diabetes, hypertension, obesity, chronic kidney disease, and asthma (P<.05). Non-Hispanic White patients were older and had more cigarette smoking history, COPD, and cancer. Non-Hispanic White patients were more likely to receive intensive care (29.6% vs 21.1% vs 20.8%, P=.007) and more likely to die (12% vs 7.3% vs 3.5%, P<.001) compared with non-Hispanic Black and Hispanic patients, respectively. Length of stay was similar for all groups. In logistic regression models, Medicaid insurance status independently correlated with hospitalization (OR 3.67, P<.001) while only age (OR 1.076, P<.001) and cerebrovascular disease independently correlated with in-hospital mortality (OR 2.887, P=.002). Conclusions: Observed COVID-19 in-hospital mortality rate was lower than most published rates. Age, but not race-ethnicity, was independently correlated with in-hospital mortality. Safety net health systems are foundational in the care of vulnerable patients suffering from COVID-19, including patients from under-represented and low-income groups.

Review article: the role of nutrition in alcohol-associated liver disease.

BACKGROUND: Malnutrition is a commonly encountered issue in patients with alcohol-associated liver disease. The role of nutritional supplementation in the management of alcohol-associated liver disease is integral to patient outcomes-it has been shown to decrease rates of hepatic encephalopathy, improve outcomes post-liver transplant, reduce 90-day hospital readmissions and lower mortality. Despite these benefits, many studies have shown nutritional support to be an underutilised tool in the care of patients with alcohol-associated liver disease. AIMS: To review the epidemiology, pathophysiology, recommendations for nutritional assessment and supplementation, as well as future directions for research of the relationship between nutrition and alcohol-associated liver disease. METHODS: A literature search was conducted via PubMed using MeSH terms to inform this narrative review. RESULTS: Decreased dietary intake, socioeconomic status, impaired absorption of nutrients and increased free radical species are implicated in the pathophysiology of malnutrition in alcohol-associated liver disease. CONCLUSIONS: Malnutrition is common in alcohol-associated liver disease, and physicians should be aware of its association with poor clinical outcomes. Routine nutritional assessment, involvement of a dietician and nutritional supplementation are recommended to improve clinical outcomes in patients with alcohol-associated liver disease.

Alcohol Abstinence Does Not Fully Reverse Abnormalities of Mucosal-Associated Invariant T Cells in the Blood of Patients With Alcoholic Hepatitis.

OBJECTIVES: Alcoholic hepatitis (AH) develops in approximately 30% of chronic heavy drinkers. The immune system of patients with AH is hyperactivated, yet ineffective against infectious diseases. Mucosal-associated invariant T (MAIT) cells are innate-like lymphocytes that are highly enriched in liver, mucosa, and peripheral blood and contribute to antimicrobial immunity. We aimed to determine whether MAIT cells were dysregulated in heavy drinkers with and without AH and the effects of alcohol abstinence on MAIT cell recovery. METHODS: MR1 tetramers loaded with a potent MAIT cell ligand 5-(2-oxopropylideneamino)-6-d-ribitylaminouracil were used in multiparameter flow cytometry to analyze peripheral blood MAIT cells in 59 healthy controls (HC), 56 patients with AH, and 45 heavy drinkers without overt liver disease (HDC) at baseline and 6- and 12-month follow-ups. Multiplex immunoassays were used to quantify plasma levels of cytokines related to MAIT cell activation. Kinetic Turbidimetric Limulus Amebocyte Lysate Assay and ELISA were performed to measure circulating levels of 2 surrogate markers for bacterial translocation (lipopolysaccharide and CD14), respectively. RESULTS: At baseline, patients with AH had a significantly lower frequency of MAIT cells than HDC and HC. HDC also had less MAIT cells than HC (median 0.16% in AH, 0.56% in HDC, and 1.25% in HC). Further, the residual MAIT cells in patients with AH expressed higher levels of activation markers (CD69, CD38, and human leukocyte antigen [HLA]-DR), the effector molecule granzyme B, and the immune exhaustion molecule PD-1. Plasma levels of lipopolysaccharide and CD14 and several cytokines related to MAIT cell activation were elevated in patients with AH (interferon [IFN]-α, interleukin [IL]-7, IL-15, IL-17, IL-18, IL-23, IFN-γ, and tumor necrosis factor α). Decreased MAIT cell frequency and upregulated CD38, CD69, and HLA-DR correlated negatively and positively, respectively, with aspartate aminotransferase level. MAIT cell frequency negatively correlated with IL-18. HLA-DR and CD38 levels correlated with several cytokines. At follow-ups, abstinent patients with AH had increased MAIT cell frequency and decreased MAIT cell activation. However, MAIT cell frequency was not fully normalized in patients with AH (median 0.31%). DISCUSSION: We showed that HDC had a reduction of blood MAIT cells despite showing little evidence of immune activation, whereas patients with AH had a severe depletion of blood MAIT cells and the residual cells were highly activated. Alcohol abstinence partially reversed those abnormalities.

Posttraumatic Stress Disorder in Patients with Heavy Alcohol Consumption and Alcoholic Hepatitis.

BACKGROUND: Lifetime prevalence of posttraumatic stress disorder (PTSD) in the general population is reported to be 6.8%. Individuals with alcohol dependence and substance abuse have high prevalence of PTSD. However, the prevalence of PTSD in heavy drinkers with alcoholic hepatitis (AH) is not known.The study's aim was to determine the prevalence of PTSD in heavy drinkers with and without AH. METHODS: We screened for PTSD using the Primary Care-PTSD questionnaire among heavy drinkers with (n = 115) and without (n = 64) AH participating in a multicenter observational study in which participants were followed up to 12 months following their enrollment. RESULTS: The prevalence of PTSD in heavy drinkers with AH was 34% and was not different from heavy drinking controls without liver disease (34%). In the entire group screened for PTSD, the presence of PTSD was associated with higher alcohol consumption as reported by average drinks per last 30 days and average grams of alcohol consumed per day (p = 0.047 for both tests), but not associated with relapse of heavy drinking or mortality. Similarly, patients with AH and PTSD did not have higher relapse rate or higher mortality compared to patients with AH but no PTSD. CONCLUSIONS: Compared to previously reported prevalence in general population, heavy drinking individuals with or without AH have significantly higher prevalence of PTSD. However, PTSD was not associated with higher relapse rate or higher mortality in this population.

Association Between Aldehyde Dehydrogenase 2 Glu504Lys Polymorphism and Alcoholic Liver Disease.

BACKGROUND: Only a subset of patients with excessive alcohol use develop alcoholic liver disease (ALD), though the exact mechanism is not completely understood. Once ingested, alcohol is metabolized by 2 key oxidative enzymes, alcohol dehydrogenase (ADH) and aldehyde dehydrogenase (ALDH). There are 2 major ALDH isoforms, cytosolic and mitochondrial, encoded by the aldehyde ALDH1 and ALDH2 genes, respectively. The ALDH2 gene was hypothesized to alter genetic susceptibility to alcohol dependence and alcohol-induced liver diseases. The aim of this study is to determine the association between aldehyde dehydrogenase 2 (rs671) glu504lys polymorphism and ALD. METHODS: ALDH2 genotyping was performed in 535 healthy controls and 281 patients with ALD. RESULTS: The prevalence of the common form of the single nucleotide polymorphism rs671, 504glu (glu/glu) was significantly higher in patients with ALD (95.4%) compared to that of controls (73.7%, P < 0.0001). Among controls, 23.7% had the heterozygous (glu/lys) genotype compared to 4.6% in those with ALD (odds ratio [OR] = 0.16, 95% CI: 0.09-0.28). The allele frequency for 504lys allele in patients with ALD was 2.3%, compared to 14.5% in healthy controls (OR = 0.13, 95% CI: 0.07-0.24). CONCLUSIONS: Patients with ALDH2 504lys variant were less associated with ALD compared to those with ALDH2 504glu using both genotypic and allelic analyses.

Interaction between the patatin-like phospholipase domain-containing protein 3 genotype and coffee drinking and the risk for acute alcoholic hepatitis.

Only a subset of subjects with excessive alcohol consumption develops alcoholic liver disease (ALD). One of the major risk factors for ALD is the genetic variant of the patatin-like phospholipase domain-containing protein 3 (PNPLA3) gene. Coffee is one of the most commonly consumed beverages, and coffee consumption has been associated with lower levels of serum alanine aminotransferase. The aim of this study was to investigate the role of coffee drinking and PNPLA3 rs738409 and their association with alcoholic hepatitis (AH) in a well-characterized cohort of subjects from the Translational Research and Evolving Alcoholic Hepatitis Treatment consortium. AH subjects and heavy drinking controls without a history of liver disease who were enrolled between May 2013 and May 2016 were included (n = 339), and the details of alcohol and coffee consumption were assessed. The PNPLA3 variant was determined among participants of European ancestry (n = 183). Relationships between baseline data and AH status were determined, and multivariable logistic regression modeling was performed. During the study period, 189 cases with AH and 150 heavy drinking controls were prospectively enrolled. The prevalence of regular coffee consumption was significantly lower in patients with AH compared to controls (20% versus 43%; P < 0.0001). The overall minor allele frequency of the PNPLA3 variant was higher in AH cases. Multivariable logistic regression revealed that coffee consumption and PNPLA3 were significantly associated with AH status at baseline after adjusting for relevant patient characteristics. Conclusion: We found a higher prevalence of AH among heavy drinkers with PNPLA3 G/G and G/C genotypes regardless of coffee consumption status and a higher prevalence of AH among heavy drinkers who were not regular coffee drinkers. These findings remained after considering relevant baseline patient characteristics. Further studies are needed to confirm our observation. (Hepatology Communications 2018;2:29-34).

An Initial Assessment of the Utility of Validated Alcohol and Drug Screening Tools in Predicting 30-Day Readmission to Adult General Medicine Wards.

Previous studies have identified drug and alcohol use as risk factors for readmission using claims data, but not by using substance use screening scores. This preliminary study tested the hypothesis that prevalence of 30-day readmission would be higher among patients screening positive on the 10-item Alcohol Use Disorders Identification Test (AUDIT-10) or the 10-item Drug Abuse Screening Test (DAST-10) tools at intake than among the general patient population. Social workers screened 4708 adult inpatients using prescreening questions followed by the AUDIT-10 and/or DAST-10. Patients with positive screens were followed for readmissions within 30 days of discharge. A positive screening score on the AUDIT-10 or DAST-10 instrument at intake was associated with higher risk of readmission to the general medicine wards within 30 days; this relationship appears complex and subject to mediation. Post hoc chart review found that the majority of readmissions among patients with positive screens were not immediately attributable to substance use. Further study is needed to verify these preliminary findings.

Concomitant Psychiatric and Nonalcohol-Related Substance Use Disorders Among Hospitalized Patients with Alcoholic Liver Disease in the United States.

BACKGROUND: Despite that the epidemiological studies on the comorbidity of alcohol misuse and psychiatric disorders have been studied, less is known about the magnitude of these disorders among patients with alcoholic liver disease (ALD). Our aim was to determine the prevalence of psychiatric and substance use disorders among hospitalized ALD patients in the United States. METHODS: We utilized a single-level clinical classification software to identify patients with ALD and psychiatric/substance use disorders from the 2011 National Inpatient Sample data. The primary outcome was the prevalence of these disorders among hospitalized patients with ALD (n = 74,972) compared to those with chronic liver diseases not caused by alcohol (n = 350,140) and those without underlying liver diseases (n = 1,447,063). RESULTS: The prevalence of adjustment disorder, anxiety disorder, posttraumatic stress disorder, and depression was significantly higher among hospitalized patients with ALD when compared to those with chronic liver diseases not caused by alcohol (all with p-values <0.05). Younger age, female gender, and White race were the independent predictors of psychiatric/substance use disorders among hospitalized patients with ALD. CONCLUSIONS: Hospitalized patients with ALD have significantly high prevalence of concomitant psychiatric and substance abuse disorders when compared to those with chronic liver diseases not caused by alcohol and those without underlying liver diseases. Screening and appropriate intervention should be implemented as part of routine clinical care for these patients.

The circulating microbiome signature and inferred functional metagenomics in alcoholic hepatitis.

Intestinal dysbiosis is implicated in alcoholic hepatitis (AH). However, changes in the circulating microbiome, its association with the presence and severity of AH, and its functional relevance in AH is unknown. Qualitative and quantitative assessment of changes in the circulating microbiome were performed by sequencing bacterial DNA in subjects with moderate AH (MAH) (n = 18) or severe AH (SAH) (n = 19). These data were compared with heavy drinking controls (HDCs) without obvious liver disease (n = 19) and non-alcohol-consuming controls (NACs, n = 20). The data were related to endotoxin levels and markers of monocyte activation. Linear discriminant analysis effect size (LEfSe) analysis, inferred metagenomics, and predictive functional analysis using PICRUSt were performed. There was a significant increase in 16S copies/ng DNA both in MAH (P < 0.01) and SAH (P < 0.001) subjects. Compared with NACs, the relative abundance of phylum Bacteroidetes was significantly decreased in HDCs, MAH, and SAH (P < 0.001). In contrast, all alcohol-consuming groups had enrichment with Fusobacteria; this was greatest for HDCs and decreased progressively in MAH and SAH. Subjects with SAH had significantly higher endotoxemia (P = 0.01). Compared with alcohol-consuming groups, predictive functional metagenomics indicated an enrichment of bacteria with genes related to methanogenesis and denitrification. Furthermore, both HDCs and SAH showed activation of a type III secretion system that has been linked to gram-negative bacterial virulence. Metagenomics in SAH versus NACs predicted increased isoprenoid synthesis via mevalonate and anthranilate degradation, known modulators of gram-positive bacterial growth and biofilm production, respectively. CONCLUSION: Heavy alcohol consumption appears to be the primary driver of changes in the circulating microbiome associated with a shift in its inferred metabolic functions. (Hepatology 2018;67:1284-1302).

Challenges in Patient Enrollment and Retention in Clinical Studies for Alcoholic Hepatitis: Experience of the TREAT Consortium.

The TREAT Consortium has carried out clinical studies on alcoholic hepatitis (AH) for over 4 years. We encountered problems with participant recruitment, retention, and eligibility for specific protocols. To improve our ability to carry out such trials, we reviewed recruitment screening logs, end of study logs, and surveyed study coordinators to learn the reasons for missing patients, why patients declined enrollment, and the number of patients eligible for treatment trials. Associations of the recruited subjects' demographics with their adherence to follow-up appointments were examined. Three hundred eight-seven patients (AH and heavy drinking controls) were enrolled in the observational study, and 55 AH patients were recruited into treatment trials. About half of patients identified with AH could not be recruited; no specific reason could be determined for about two-thirds of these. Among the patients who gave a reason for not participating, the most common reasons were feeling too sick to participate, desire to concentrate on abstinence, and lack of interest in research. Approximately a quarter of the AH patients met eligibility criteria for treatment trials for moderate or severe AH and we were able to recruit half to two-thirds of those eligible. Approximately 35% of participants in the observational study returned for both 6- and 12-month follow-up visits. We did not identify biopsychosocial or demographic correlates of retention in the study. This analysis revealed that attempts at recruitment into trials for AH miss some subjects because of structural issues surrounding their hospital admission, and encounter a high rate of patient refusal to participate. Nonetheless, more than half of the patients who met the eligibility criteria for moderate or severe AH were entered into clinical trials. Retention rates for the observational study are relatively low. These findings need to be accounted for in clinical trial design and power analysis.

An exploratory genome-wide analysis of genetic risk for alcoholic hepatitis.

OBJECTIVES: To elucidate the genetic variability between heavy drinkers with and without alcoholic hepatitis (AH). MATERIALS AND METHODS: An exploratory genome-wide association study (GWAS; NCT02172898) was conducted comparing 90 AH cases with 93 heavy drinking matched controls without liver disease in order to identify variants or genes associated with risk for AH. Individuals were genotyped using the multi-ethnic genotyping array, after which the data underwent conventional quality control. Using bioinformatics tools, pathways associated with AH were explored on the basis of individual variants, and based on genes with a higher 'burden' of functional variation. RESULTS: Although no single variant reached genome-wide significance, an association signal was observed for PNPLA3 rs738409 (p = .01, OR 1.9, 95% CI 1.1-3.1), a common single nucleotide polymorphism that has been associated with a variety of liver-related pathologies including alcoholic cirrhosis. Using the improved gene set enrichment analysis for GWAS tool, it was shown that, based on the single variants' trait-association p-values, multiple pathways were associated with risk for AH with high confidence (false discovery rate [FDR] < 0.05), including several pathways involved in lymphocyte activation and chemokine signaling, which coincides with findings from other research groups. Several Tox Functions and Canonical Pathways were highlighted using Ingenuity Pathway Analysis, with an especially conspicuous role for pathways related to ethanol degradation, which is not surprising considering the phenotype of the genotyped individuals. CONCLUSION: This preliminary analysis suggests a role for PNPLA3 variation and several gene sets/pathways that may influence risk for AH among heavy drinkers.

Alcohol abstinence ameliorates the dysregulated immune profiles in patients with alcoholic hepatitis: A prospective observational study.

Alcoholic hepatitis (AH) develops in only a small proportion of heavy drinkers. To better understand the mechanisms underlying this disparity, we conducted a study to define the relationship between AH development and dysregulated immune responses that might be ameliorated by alcohol abstinence. Sixty-eight AH patients, 65 heavy drinking controls without liver disease (HDC), and 20 healthy controls were enrolled and followed up to 12 months. At baseline, HDC and healthy controls had no significant differences in their plasma levels of 38 inflammatory cytokines/chemokines measured using multiplex immunoassays. However, compared to HDC, AH patients had higher baseline levels of 11 cytokines/chemokines (tumor necrosis factor alpha, interleukin 6 [IL-6], IL-8, interferon gamma-induced protein 10, IL-4, IL-9, IL-10, fibroblast growth factor 2, IL-7, IL-15, and transforming growth factor alpha) but lower levels of the anti-inflammatory macrophage-derived chemokine. AH patients also had more activated yet dysfunctional immune cells as monocytes, T cells, and B cells expressed higher levels of cluster of differentiation 38 (CD38) and CD69 but low levels of human leukocyte antigen DR, CD80, and CD86 at baseline. In addition, CD4 T cells produced less interferon-gamma in response to T-cell stimulation. Up-regulated IL-6, IL-8, CD38, and CD69 and down-regulated macrophage-derived chemokine, human leukocyte antigen DR, CD86, and CD80 correlated positively and negatively, respectively, with disease severity. Longitudinal analysis indicated that levels of IL-6, IL-8, CD38, and CD69 were reduced, whereas levels of macrophage-derived chemokine, human leukocyte antigen DR, CD80, and CD86 were increased in abstinent AH patients. All of the cellular immune abnormalities were reversed by day 360 in abstinent AH patients; however, plasma levels of tumor necrosis factor alpha, IL-8, IL-10, fibroblast growth factor 2, and IL-7 remained higher. CONCLUSION: AH patients were in a highly immune-dysregulated state, whereas HDC showed little evidence of immune activation; alcohol abstinence reversed most, but not all, of the immunological abnormalities. (Hepatology 2017;66:575-590).

Acute Alcoholic Hepatitis: Natural History and Predictors of Mortality Using a Multicenter Prospective Study.

OBJECTIVE: To examine the natural history of acute alcoholic hepatitis (AH) and identify predictors of mortality for AH using data from a prospective multicenter observational study. PARTICIPANTS AND METHODS: We analyzed data from 164 patients with AH and 131 heavy-drinking controls with no liver disease. Participants underwent clinical/laboratory assessment at baseline and 6 and 12 months after enrollment. Multivariable analyses were conducted to identify variables associated with mortality and examine the association between coffee drinking and risk of AH. RESULTS: Thirty-six patients with AH died during follow-up, with estimated 30-day, 90-day, 180-day, and 1-year survival of 0.91 (95% CI, 0.87-0.96), 0.85 (95% CI, 0.80-0.91), 0.80 (95% CI, 0.74-0.87), and 0.75 (95% CI, 0.68-0.83), respectively. In the multivariable analysis, higher serum bilirubin level (hazard ratio [HR]=1.059; 95% CI, 1.022-1.089), lower hemoglobin level (HR=1.263; 95% CI, 1.012-1.575), and lower platelet count (HR=1.006; 95% CI, 1.001-1.012) were independently associated with mortality in AH. Compared with controls, fewer patients with AH regularly consumed coffee (20% vs 44%; P<.001), and this association between regular coffee drinking and lower risk of AH persisted after controlling for relevant covariates (odds ratio=0.26; 95% CI, 0.15-0.46). Time-dependent receiver operating characteristic curve analysis revealed that Model for End-Stage Liver Disease; Maddrey Discriminant Function; age, serum bilirubin, international normalized ratio, and serum creatinine; and Child-Pugh scores all provided similar discrimination performance at 30 days (area under the curve=0.73-0.77). CONCLUSION: Alcoholic hepatitis remains highly fatal, with 1-year mortality of 25%. Regular coffee consumption was associated with lower risk of AH in heavy drinkers.

Effects of Age, Sex, Body Weight, and Quantity of Alcohol Consumption on Occurrence and Severity of Alcoholic Hepatitis.

BACKGROUND & AIMS: Only a minority of heavy drinking individuals develop alcoholic hepatitis (AH), for unclear reasons. We analyzed data from the Translational Research and Evolving Alcoholic Hepatitis Treatment cohort, consisting of subjects who drink heavily with normal results from liver tests (controls) and patients with AH. We examined risk factors for the development of AH including body mass index (BMI), drinking pattern and quantity, and sex. METHODS: We compared data from 145 patients with AH and 124 controls based on BMI when they joined the cohort; groups were matched for sex and race. Drinking patterns were assessed using the timeline followback method, the Alcohol Use Disorders Identification Test, and the National Institute of Alcohol Abuse and Alcoholism 6-question survey. We performed univariable and multivariable analyses to assess the effects of these factors and their interaction in increasing the risk for AH. We also explored the association between PNPLA3 variants and AH. RESULTS: Cases with AH were older (47 vs 44 y; P = .03). For nearly all measures of quantity of alcohol consumed or frequency of binge drinking, controls drank more heavily than cases with AH. We did not find an association between BMI, sex, drinking patterns, and the presence of AH. Age and BMI were independent predictors for the severity of AH. When we analyzed cases and controls of European ancestry, the PNPLA3 single-nucleotide polymorphism rs738409 was associated with risk for AH (odds ratio, 1.89; P = .007). CONCLUSIONS: Compared with heavy drinkers without liver disease, subjects with AH consumed lower levels of alcohol and had less binge drinking, suggesting an increased sensitivity to the toxic effects of alcohol. The risk for AH may be associated with the PNPLA3 rs738409 polymorphism.

If You Teach It, They Will Screen: Advanced Practice Nursing Students' Use of Screening and Brief Intervention in the Clinical Setting.

BACKGROUND: In the United States, approximately 30% of adults drink at risky levels or meet the criteria for harmful or dependent alcohol use. Screening, brief intervention, and referral to treatment (SBIRT) in primary care settings is indicated. This study assessed whether knowledge, attitudes, and beliefs about SBIRT, evaluated after a three-part, mixed-methods training, predicted whether 21 family nurse practitioner (FNP) students screened for alcohol use during clinical patient encounters. METHOD: After training, students completed a survey and documented implementation of SBIRT during their clinical practice-specific management courses. RESULTS: FNP students who reported higher levels of perceived competence in their posttraining surveys were more likely to screen for alcohol in the clinical setting. CONCLUSION: Screening for alcohol misuse and identifying patients engaged in hazardous drinking meet important nurse practitioner competencies. Further research is needed to explore training programs that specifically emphasize activities to increase perceived competence, knowledge, and comfort regarding SBIRT.