The road to pandemic recovery: Tracking COVID-19's impact on cirrhosis care and outcomes among 111,558 Veterans.

BACKGROUND AIMS: This study aimed to evaluate quarterly trends in process and health outcomes among Veterans with cirrhosis and assess the factors associated with cirrhosis outcomes before and during the COVID-19 pandemic. APPROACH RESULTS: US Veterans with cirrhosis were identified using the Veterans Health Administration Corporate Data Warehouse. Quarterly measures were evaluated from September 30, 2018, through March 31, 2022, including twice yearly screening for hepatocellular carcinoma (HCC-6), new HCC, surveillance for or treatment of esophageal varices, variceal bleeding, all-cause hospitalization, and mortality. Joinpoint analyses were used to assess the changes in trends over time. Logistic regression models were used to identify the demographic and medical factors associated with each outcome over time. Among 111,558 Veterans with cirrhosis with a mean Model for End-stage Liver Disease-Sodium of 11±5, rates of HCC-6 sharply declined from a prepandemic peak of 41%, to a nadir of 28%, and rebounded to 36% by March 2022. All-cause mortality did not significantly change over the pandemic, but new HCC diagnosis, EVST, variceal bleeding, and all-cause hospitalization significantly declined over follow-up. Quarterly HCC diagnosis declined from 0.49% to 0.38%, EVST from 50% to 41%, variceal bleeding from 0.15% to 0.11%, and hospitalization from 9% to 5%. Rurality became newly, significantly associated with nonscreening over the pandemic (aOR for HCC-6=0.80, 95% CI 0.74 to 0.86; aOR for EVST=0.95, 95% CI 0.90 to 0.997). CONCLUSIONS: The pandemic continues to impact cirrhosis care. Identifying populations at the highest risk of care disruptions may help to address ongoing areas of need.

Non-technical skills training for Nigerian interprofessional surgical teams: a cross-sectional survey.

INTRODUCTION: Non-technical skills (NTS) including communication, teamwork, leadership, situational awareness, and decision making, are essential for enhancing surgical safety. Often perceived as tangential soft skills, NTS are many times not included in formal medical education curricula or continuing medical professional development. We aimed to explore exposure of interprofessional teams in North-Central Nigeria to NTS and ascertain perceived facilitators and barriers to interprofessional training in these skills to enhance surgical safety and inform design of a relevant contextualized curriculum. METHODS: Six health facilities characterised by high surgical volumes in Nigeria's North-Central geopolitical zone were purposively identified. Federal, state, and private university teaching hospitals, non-teaching public and private hospitals, and a not-for-profit health facility were included. A nineteen-item, web-based, cross-sectional survey was distributed to 71 surgical providers, operating room nurses, and anaesthesia providers by snowball sampling through interprofessional surgical team leads from August to November 2021. Data were analysed using Fisher's exact test, proportions, and constant comparative methods for free text responses. RESULTS: Respondents included 17 anaesthesia providers, 21 perioperative nurses, and 29 surgeons and surgical trainees, with a 95.7% survey completion rate. Over 96% had never heard of any NTS for surgery framework useful for variable resource contexts and only 8% had ever received any form of NTS training. Interprofessional teams identified communication and teamwork as the most deficient personal skills (38, 57%), and as the most needed for surgical team improvement (45, 67%). There was a very high demand for NTS training by all surgical team members (64, 96%). The main motivations for training were expectations of resultant improved patient safety and improved interprofessional team dynamics. Week-long, hybrid training courses (with combined in-person and online components) were the preferred format for delivery of NTS education. Factors that would facilitate attendance included a desire for patient safety and self-improvement, while barriers to attendance were conflicts of time, and training costs. CONCLUSIONS: Interprofessional surgical teams in the Nigerian context have a high degree of interest in NTS training, and believe it can improve team dynamics, personal performance, and ultimately patient safety. Implementation of NTS training programs should emphasize interprofessional communication and teamworking.

Dementia Frequently Coexists With Hepatic Encephalopathy but Not Other Cirrhosis Complications in US Veterans.

INTRODUCTION: Hepatic encephalopathy (HE) is a common decompensating event in patients with cirrhosis. Because of the aging population of patients with cirrhosis, differentiating HE from nonhepatic etiologies of cognitive impairment, such as dementia, is increasingly important. METHODS: Veterans with cirrhosis were identified via International Classification of Diseases -10 codes between October 1, 2019, and September 30, 2021, using the VA Corporate Data Warehouse. Baseline characteristics were compared between cohorts based on the presence vs absence of dementia. Factors associated with having a diagnosis of dementia were evaluated using multivariate logistic regression models, adjusting for demographics, comorbid illnesses, cirrhosis etiology, and cirrhosis complications. RESULTS: A total of 71,552 veterans with cirrhosis were identified, of which, 5,647 (7.89%) veterans had a diagnosis of dementia. Veterans with dementia were older, more frequently White, urban located, and diagnosed with alcohol-related cirrhosis, metabolic syndrome, brain trauma, and cerebrovascular disease more frequently. On multivariable analysis, the presence of any decompensating event was associated with dementia. Multivariable analysis of individual decompensating events revealed HE to be associated with a dementia diagnosis, but not ascites, independent of other risk factors analyzed. DISCUSSION: Dementia is commonly diagnosed in patients with cirrhosis and correlates with a diagnosis of HE, independent of alcohol use, brain injury, age, and other metabolic risk factors. Dementia did not correlate with other decompensating events. Increased awareness of the overlap between dementia and HE, as well as reliable diagnostic and treatment strategies, is needed for the aging population of veterans with cirrhosis.

Alcohol treatment discussions and clinical outcomes among patients with alcohol-related cirrhosis.

BACKGROUND: Alcohol cessation is the cornerstone of treatment for alcohol-related cirrhosis. This study evaluated associations between medical conversations about alcohol use disorder (AUD) treatment, AUD treatment engagement, and mortality. METHODS: This retrospective cohort study included all patients with ICD-10 diagnosis codes for cirrhosis and AUD who were engaged in hepatology care in a single healthcare system in 2015. Baseline demographic, medical, liver disease, and AUD treatment data were assessed. AUD treatment discussions and initiation, alcohol cessation, and subsequent 5-year mortality were collected. Multivariable models were used to assess the factors associated with subsequent AUD treatment and 5-year mortality. RESULTS: Among 436 patients with cirrhosis due to alcohol, 65 patients (15%) received AUD treatment at baseline, including 48 (11%) receiving behavioral therapy alone, 11 (2%) receiving pharmacotherapy alone, and 6 (1%) receiving both. Over the first year after a baseline hepatology visit, 37 patients engaged in AUD treatment, 51 were retained in treatment, and 14 stopped treatment. Thirty percent of patients had hepatology-documented AUD treatment recommendations and 26% had primary care-documented AUD treatment recommendations. Most hepatology (86%) and primary care (88%) recommendations discussed behavioral therapy alone. Among patients with ongoing alcohol use at baseline, AUD treatment one year later was significantly, independently associated with AUD treatment discussions with hepatology (adjusted odds ratio (aOR): 3.23, 95% confidence interval (CI): 1.58, 6.89) or primary care (aOR: 2.95; 95% CI: 1.44, 6.15) and negatively associated with having Medicaid insurance (aOR: 0.43, 95% CI: 0.18, 0.93). When treatment was discussed in both settings, high rates of treatment ensued (aOR: 10.72, 95% CI: 3.89, 33.52). Over a 5-year follow-up period, 152 (35%) patients died. Ongoing alcohol use, age, hepatic decompensation, and hepatocellular carcinoma were significantly associated with mortality in the final survival model. CONCLUSION: AUD treatment discussions were documented in less than half of hepatology and primary care encounters in patients with alcohol-related cirrhosis, though such discussions were significantly associated with receipt of AUD treatment.

The Impact of Night-time Emergency Department Presentation on Upper Gastrointestinal Hemorrhage Outcomes.

GOALS: The aim was to investigate the impact of night-time emergency department (ED) presentation on outcomes of patients admitted for acute upper gastrointestinal hemorrhage (UGIH). BACKGROUND: The relationship between time of ED presentation and outcomes of gastrointestinal hemorrhage is unclear. STUDY: Using the 2016 and 2017 Florida State Inpatient Databases which provide times of ED arrival, we identified and categorized adults hospitalized for UGIH to daytime (07:00 to 18:59 h) and night-time (19:00 to 06:59 h) based on the time of ED presentation. We matched both groups with propensity scores, and assessed their clinical outcomes including all-cause in-hospital mortality, in-hospital endoscopy utilization, length of stay (LOS), total hospitalization costs, and 30-day all-cause readmission rates. RESULTS: Of the identified 38,114 patients with UGIH, 89.4% (n=34,068) had acute nonvariceal hemorrhage (ANVH), while 10.6% (n=4046) had acute variceal hemorrhage (AVH). Compared with daytime patients, ANVH patients admitted at night-time had higher odds of in-hospital mortality (odds ratio: 1.32; 95% confidence interval: 1.06-1.60), lower odds of in-patient endoscopy (odds ratio: 0.83; 95% confidence interval: 0.77-0.90), higher total hospital costs ($9911 vs. $9545, P <0.016), but similar LOS and readmission rates. Night-time AVH patients had a shorter LOS (5.4 vs. 5.8 d, P =0.045) but similar mortality rates, endoscopic utilization, total hospitalization costs, and readmission rates as daytime patients. CONCLUSIONS: Patients arriving in the ED at night-time with ANVH had worse outcomes (mortality, hospitalization costs, and endoscopy utilization) compared with daytime patients. However, those with AVH had comparable outcomes irrespective of ED arrival time.

Chronic Pancreatitis Patients Who Leave Against Medical Advice: Prevalence, Trend, and Predictors.

BACKGROUND AND AIMS: Leaving against medical advice (LAMA) is an unfortunate occurrence in 1-2% of all hospitalized patients and is associated with worse outcomes. While this has been investigated across multiple clinical conditions, studies on patients with chronic pancreatitis (CP) are lacking. We aimed to determine the prevalence and determinants of this event among patients with CP. METHODS: The Healthcare Cost and Utilization Project-Nationwide Inpatient Sample (NIS), 2007-2014, was used in the study. Patients with LAMA were identified, and the temporal trend of LAMA was estimated and compared among patients with and without CP. We then extracted patients with a discharge diagnosis of CP from the recent years of HCUP-NIS (2012-2014) and described the characteristics of LAMA in these patients. Multivariate logistic regression models were used to evaluate predictors of LAMA. RESULTS: 3.39% of patients with CP discharged against medical advice. LAMA rate in CP patients was higher and increased more steeply at quadruple the rate of those without. More likely to self-discharge were patients who were young, males, non-privately insured, or engaged in alcohol and substance abuse, likewise were those with psychosis and those admitted on a weekend or non-electively. The northeast and for-profit hospitals also had higher odds of LAMA. However, patients transferred from other healthcare facilities have reduced LAMA odds. Among all patients with CP, those with LAMA had shorter length of stay (2.74 [2.62-2.85] days vs. 5.78 [5.71-5.83] days) and lower hospitalization cost $23,271 [$22,171-$24,370] versus $45,472 [$44,381-$46,562] compared to the no-LAMA group. CONCLUSION: LAMA occurs in approximately 1 in 29 patients with CP and is increasing at almost quadruple the rate of those without. Clinicians need to pay closer attention to the identified at-risk groups for ameliorative targeted interventions.

Gender and Racial Differences in Hospitalizations for Primary Biliary Cholangitis in the USA.

BACKGROUND/AIM: The prevalence, characteristics, burden and trends of primary biliary cholangitis (PBC) hospitalizations in the USA remain unclear. METHOD: We identified primary PBC hospitalizations from the National Inpatient Sample (NIS) 2007 through 2014 using ICD-9-CM codes. We calculated the rates and trends of hospitalization for PBC per 100,000 US population among each gender (males and females) and racial categories (Whites, Blacks, Hispanics and other racial minorities), and measured the predictors of hospitalization, and of mortality, charges and length of stay (LOS) among PBC hospitalizations. RESULT: There were 8460 (weighted: 41,191) PBC hospitalizations between 2007 and 2014. The mean national PBC hospitalization rate was 2.2 cases per 100,000 population (2.2/100,000), increasing from 1.7/100,000 (2007) to 2.5/100,000 (2014). From 2007 to 2014, the in-hospital mortality and LOS were unchanged while the charges increased from $65,993 to $73,093 ($225 million to $447 million overall expenses). Compared to Whites, the PBC hospitalization rate was 12% higher among Hispanics (RR: 1.12 [1.09-1.16]), 53% lower in Blacks (RR: 0.47 [0.45-0.49]) and 5% lower among other racial minorities (0.95 [0.91-0.99]). The rate was higher among females (RR:4.02 [3.93-4.12]) compared to males. On multivariate analysis, Blacks and other racial minorities, respectively, had higher odds of mortality (AOR: 1.47 [1.03-2.10] and 1.33 [0.96-1.84]), while other racial minorities had longer LOS (7.0 vs. 5.6 days) and higher hospital charges ($48,984 vs. $41,495) when compared to Whites. CONCLUSION: The hospitalization rate and burden of PBC in the USA have increased disproportionately among females and Hispanics with higher mortality in Blacks.

Trends in Mortality From Extrahepatic Complications in Patients With Chronic Liver Disease, From 2007 Through 2017.

BACKGROUND & AIMS: Trends of mortality associated with extrahepatic complications of chronic liver disease might be changing. We studied trends in mortality from extrahepatic complications of viral hepatitis, alcoholic liver disease (ALD), and nonalcoholic fatty liver disease in the United States. METHODS: We performed a population-based study using US Census and the National Center for Health Statistics mortality records from 2007 through 2017. We identified trends in age-standardized mortality using Joinpoint trend analysis with estimates of annual percent change. RESULTS: The liver-related mortality among patients with hepatitis C virus (HCV) infection increased from 2007 through 2013 and then decreased once patients began receiving treatment with direct-acting antiviral (DAA) agents, from 2014 through 2017. Among patients with HCV infection, the age-standardized mortality for extrahepatic cancers was 2.6%, for cardiovascular disease was 1.9%, and for diabetes was 3.3%. Among individuals with hepatitis B virus infection, liver-related mortality decreased steadily from 2007 through 2017. During the study, age-standardized mortality from hepatitis B virus-related extrahepatic complications increased by an average of 2.0% each year. Although liver-related mortality from ALD continued to increase, mortality from extrahepatic complications of ALD did not change significantly during the 11-year study. Among patients with nonalcoholic fatty liver disease, the cause of death was most frequently cardiovascular disease, which increased gradually over the study period, whereas liver-related mortality increased rapidly. CONCLUSIONS: In an analysis of US Census and the National Center for Health Statistics mortality records, we found that after widespread use of DAA agents for treatment of viral hepatitis, cause-specific mortality from extrahepatic cancers increased, whereas mortality from cardiovascular disease or diabetes increased only among patients with HCV infection. These findings indicate the need to reassess risk and risk factors for extrahepatic cancer, cardiovascular disease, and diabetes in individuals successfully treated for HCV infection with DAA agents.

Biomarkers of Macrophage Activation and Immune Danger Signals Predict Clinical Outcomes in Alcoholic Hepatitis.

Although mortality due to acute alcoholic hepatitis (AH) correlates with Model for End-Stage Liver Disease (MELD) scores, biomarkers are critically needed to manage this disease. Increases in inflammatory markers and macrophage activation are associated with acute AH and could be potential biomarkers of clinical events and/or mortality. We enrolled 89 clinically diagnosed AH patients in four US academic medical centers. Plasma from AH patients had a significant increase in gut microbial translocation indicators (endotoxin, bacterial 16S ribosomal DNA) and host response indicators (soluble cluster of differentiation 14 [sCD14] and lipopolysaccharide binding protein [LBP]) compared to controls. Patient MELD score and Glasgow Alcoholic Hepatitis score (GAHS) correlated with endotoxin levels. AH patients also had a significant increase in high mobility group protein 1 (HMGB1), a sterile danger signal molecule, and osteopontin (OPN), a multifunctional phosphoprotein involved in neutrophil activation, compared to controls. Increased levels of OPN positively correlated with increasing MELD score, GAHS, and LBP levels. Consistent with these results, AH patients had significantly increased circulating levels of macrophage activation (sCD163 and sCD206) markers compared to healthy controls, and sCD163 and sCD206 significantly and positively correlated with OPN, HMGB1, and LBP levels as well as with MELD score and GAHS. These findings indicate a connection between microbial translocation, immune cell activation, and AH severity. Plasma sCD14, OPN, sCD163, and sCD206 levels were significantly higher in nonsurvivors than survivors. In multivariate regression models, we identified sCD14, sCD163, and OPN as independent predictors of 90-day mortality, infection, and organ failure development, respectively. Conclusion: Our study suggests that sCD14, LBP, OPN, sCD163, and sCD206 are biomarkers to indicate severity and predict clinical outcomes in AH.

Pharmacological Inhibition of CCR2/5 Signaling Prevents and Reverses Alcohol-Induced Liver Damage, Steatosis, and Inflammation in Mice.

Kupffer cell and macrophage (MØ) activation contributes to steatosis, inflammation, and fibrosis in alcoholic liver disease (ALD). We found increased frequency of MØ, T cells, and expression of C-C chemokine receptor type 2 (Ccr2) and C-C chemokine receptor type 5 (Ccr5) in the livers of patients with ALD, and increased circulating chemokines, C-C chemokine ligand types 2 (CCL2), and C-C chemokine ligand types 5 (CCL5) in patients with alcoholic hepatitis. We hypothesized that inhibition of CCL2 signaling with the dual CCR2/5 inhibitor, cenicriviroc (CVC), would attenuate ALD. In a mouse model of ALD, liver injury (alanine aminotransferase [ALT]) and steatosis were prevented by CVC whether administered as "prevention" throughout the alcohol feeding or as "treatment" started after the development of ALD. Alcohol-induced increases in early liver fibrosis markers (sirius red, hydroxyproline, and collagen-1) were normalized by both modes of CVC administration. We found that prevention and treatment with CVC reversed alcohol-related increases in liver mRNA and protein expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1ß, IL-6, and CCL2. CVC administration regimens prevented the increase in infiltrating MØ (F4/80lo CD11bhi ) and reduced proinflammatory Ly6Chi MØ in livers of alcohol-fed mice. CVC increased liver T-cell numbers and attenuated Il-2 expression without an effect on CD69+ or CD25+ T-cell expression. In vitro, CVC inhibited CCL2-induced increases in hepatocyte fatty acid synthase (Fasn) and adipose differentiation-related protein (Adrp), whereas it augmented acyl-coenzyme A oxidase 1 (Acox-1), proliferator-activated receptor gamma co-activator alpha (Pgc1α) and uncoupling protein 2 expression, suggesting mechanisms for attenuated hepatocyte steatosis. We found that CCL2 and CCL5 sensitized hepatocytes to lipopolysaccharide-induced liver injury (TNF-α, ALT, and lactate dehydrogenase release). Alcohol feeding induced apoptosis (poly ADP-ribose polymerase [PARP] and caspase-3 [CASP-3] cleavage) and pyroptosis (gasdermin D [GSDMD] cleavage) in livers, and CVC prevented both of these forms of cell death. Conclusion: Together, our data demonstrate preclinical evidence for CCR2/CCR5 inhibition with CVC as a potent intervention to ameliorate alcohol-induced steatohepatitis and liver damage.

Readmission Rates and Associated Outcomes for Alcoholic Hepatitis: A Nationwide Cohort Study.

BACKGROUND/AIMS: Alcoholic hepatitis (AH) can lead to sudden and severe hepatic decompensation necessitating recurrent hospitalizations. We evaluated the trends, predictors, and healthcare cost burden of AH-related readmissions in the USA. METHODS: Utilizing the National Readmissions Database 2010-2014, we performed a retrospective longitudinal analysis to identify the index readmission with AH for up to 90 days after discharge. Annual trends of 30- and 90-day AH-related readmissions were calculated. Predictors of 30- and 90-day readmission were determined by multivariate logistic regression. Annual healthcare cost burden associated with AH-linked readmissions was estimated. RESULTS: Of the 21,572 (unweighted: 50,769) AH-related hospitalizations, 4917 (22.8%) and 7890 (36.6%) were readmitted in 30 and 90 day, respectively, with rates that were statistically unchanged from 2010 to 2014. Predictors of 30-day readmissions included female gender, hepatitis C virus infection, cirrhosis, ascites, acute kidney injury, urinary tract infection, history of bariatric surgery, chronic pancreatitis, and high medical comorbidity index. Acute pancreatitis and palliative care consultation were associated with a lower risk of 30-day readmission. Predictors of 90-day readmission were similar to risk factors for 30-day readmission. From 2010 to 2014, the annual cost (and total hospitalization days) burden increased in 2014 to $164 million (22,244 days) and $321 million (42,772 days) for 30- and 90-day AH-related readmissions, respectively. CONCLUSION: Despite relatively stable trends in AH-related readmission, the total LOS and cost has been rising. A target-directed approach with a focus on high-risk subpopulations may help understand the unique challenges associated with the rising cost of AH-related readmissions.

Cannabis use and risk of Clostridioides difficile infection: Analysis of 59,824 hospitalizations.

BACKGROUND: The prevalence of Clostridioides difficile Infection (CDI), the most notorious hospital acquired disease, and of excessive cannabis use (cannabis use disorder (CUD)) have both been steadily rising. Although cannabidiol, an active ingredient of cannabis, maintains gut integrity and suppresses entero-toxins from Clostridioides difficile, the relationship between CUD and CDI has not been studied. METHODS: We selected adult records (age ≥ 18 years) from the Nationwide Inpatient Sample 2014, and identified CUD and other clinical conditions using ICD-9-CM codes. We used propensity scores derived from a multivariate logistic model to match CUD to non-CUD in a 1:1 ratio (29,912:29,912). We estimated the relative risk for CDI using log-binomial regression models with generalized estimating equations [SAS 9.4]. RESULTS: Among the matched hospitalizations (n = 59,824), cannabis usage was associated with a reduced prevalence of CDI (prevalence: 455.5 [95% CI: 385.1-538.8] vs. 636.4 [95% CI: 549.9-736.5] per 100,000 hospitalizations), resulting in a 28% reduced risk of CDI (relative risk: 0.72 [95% CI: 0.58-0.88]; p = 0002). Non-dependent and dependent CUD respectively had 23% and 80% reduced likelihood of CDI when compared to non-cannabis users (0.77 [95% CI: 0.60-0.95] and 0.20 [95% CI: 0.06-0.54]; p < 0.05). Furthermore, dependent users had less risk of CDI compared to non-dependent users (0.26 [95% CI: 0.08-0.88]; p = 0.01). CONCLUSIONS: CUD was associated with a decreased risk of CDI amongst hospitalized patients. Prospective and molecular mechanistic studies are required to elucidate how cannabis and its contents impacts CDI.

Relationship Between Recreational Marijuana Use and Bowel Function in a Nationwide Cohort Study.

OBJECTIVES: Although the endogenous cannabinoid system modulates bowel function, our understanding of the impact of recreational marijuana (MJ) use on bowel motility is limited. This study examines the effect of MJ on self-reported bowel function among a large cohort of US adults. METHODS: We identified adults (age: 20-59 years) who completed both the drug use and bowel health questionnaires in the National Health and Nutrition Examination Survey over a 6-year period from 2005 to 2010 (n = 9,645). Constipation and diarrhea were defined according to stool form (Bristol Stool Form Scale) and/or frequency criteria. Adjusted odds ratios (AORs) for likelihood of constipation or diarrhea were estimated in a multinomial logistic model according to MJ use status. RESULTS: Overall, constipation prevalence was lower among those with recent MJ use compared with those with past/never use (7.5% vs 10.2%, P = 0.03). Recent MJ use was associated with a 30% decreased odds of constipation (crude odds ratio: 0.71 [0.56-0.98], P = 0.005), which persisted after stepwise adjustment for age and other demographic factors including sex, ethnicity, education, body mass index, and socioeconomic status (AOR: 0.64 [0.49-0.83], P = 0.001); comorbidities, substance use (alcohol, tobacco, heroin, and cocaine), constipating medications, general health condition, rigorous physical activity, and emotional disturbances (AOR: 0.68 [0.48-0.93], P = 0.016); and diet (AOR: 0.68 [0.52-0.89], P = 0.006). There was no association between recent MJ use and diarrhea. DISCUSSION: In a nationally representative sample of community-dwelling US adults, recent MJ use was associated with decreased odds of constipation, counter to the known physiologic effects of cannabinoids on colonic motility.

Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90.

A salient feature of alcoholic liver disease (ALD) is Kupffer cell (KC) activation and recruitment of inflammatory monocytes and macrophages (MØs). These key cellular events of ALD pathogenesis may be mediated by extracellular vesicles (EVs). EVs transfer biomaterials, including proteins and microRNAs, and have recently emerged as important effectors of intercellular communication. We hypothesized that circulating EVs from mice with ALD have a protein cargo characteristic of the disease and mediate biological effects by activating immune cells. The total number of circulating EVs was increased in mice with ALD compared to pair-fed controls. Mass spectrometric analysis of circulating EVs revealed a distinct signature for proteins involved in inflammatory responses, cellular development, and cellular movement between ALD EVs and control EVs. We also identified uniquely important proteins in ALD EVs that were not present in control EVs. When ALD EVs were injected intravenously into alcohol-naive mice, we found evidence of uptake of ALD EVs in recipient livers in hepatocytes and MØs. Hepatocytes isolated from mice after transfer of ALD EVs, but not control EVs, showed increased monocyte chemoattractant protein 1 mRNA and protein expression, suggesting a biological effect of ALD EVs. Compared to control EV recipient mice, ALD EV recipient mice had increased numbers of F4/80hi cluster of differentiation 11b (CD11b)lo KCs and increased percentages of tumor necrosis factor alpha-positive/interleukin 12/23-positive (inflammatory/M1) KCs and infiltrating monocytes (F4/80int CD11bhi ), while the percentage of CD206+ CD163+ (anti-inflammatory/M2) KCs was decreased. In vitro, ALD EVs increased tumor necrosis factor alpha and interleukin-1ß production in MØs and reduced CD163 and CD206 expression. We identified heat shock protein 90 in ALD EVs as the mediator of ALD-EV-induced MØ activation. CONCLUSION: Our study indicates a specific protein signature of ALD EVs and demonstrates a functional role of circulating EVs containing heat shock protein 90 in mediating KC/MØ activation in the liver. (Hepatology 2018;67:1986-2000).

Reduced Risk of Alcohol-Induced Pancreatitis With Cannabis Use.

BACKGROUND: Pancreatitis is an increasingly common clinical condition that causes significant morbidity and mortality. Cannabis use causes conflicting effects on pancreatitis development. We conducted a larger and more detailed assessment of the impact of cannabis use on pancreatitis. METHODS: We analyzed data from 2012 to 2014 of the Healthcare Cost and Utilization Project-Nationwide Inpatient Sample discharge records of patients 18 years and older. We used the International Classification of Disease, Ninth Edition codes, to identify 3 populations: those with gallstones (379,125); abusive alcohol drinkers (762,356); and non-alcohol-non-gallstones users (15,255,464). Each study population was matched for cannabis use record by age, race, and gender, to records without cannabis use. The estimation of the adjusted odds ratio (aOR) of having acute and chronic pancreatitis (AP and CP) made use of conditional logistic models. RESULTS: Concomitant cannabis and abusive alcohol use were associated with reduced incidence of AP and CP (aOR: 0.50 [0.48 to 0.53] and 0.77 [0.71 to 0.84]). Strikingly, for individuals with gallstones, additional cannabis use did not impact the incidence of AP or CP. Among non-alcohol-non-gallstones users, cannabis use was associated with increased incidence of CP, but not AP (1.28 [1.14 to 1.44] and 0.93 [0.86 to 1.01]). CONCLUSIONS: Our findings suggest a reduced incidence of only alcohol-associated pancreatitis with cannabis use.

Reduced Prevalence of Alcoholic Gastritis in Hospitalized Individuals Who Consume Cannabis.

BACKGROUND: Alcoholic gastritis, a superficial erosive disease of the stomach, is a common manifestation of risky alcohol use. In contrast, cannabis which is frequently co-used with alcohol suppresses gastric acidity and might counteract the deleterious effect of alcohol on the gastric mucosa. However, no clinical study has examined the impact of cannabis use on the development of alcoholic gastritis among risky alcohol users. METHODS: We analyzed hospital discharge records of adults (age ≥ 18 years), from 2014 of the Nationwide Inpatient Sample, with a diagnosis of risky alcohol use (n = 316,916). We used a propensity-based matching algorithm to match cannabis users to nonusers on 1:1 ratio (30,713: 30,713). We then measured the adjusted relative risk (aRR) for having alcoholic gastritis using conditional Poisson regression models with generalized estimating equations. RESULTS: Our study revealed that among risky alcohol users, cannabis co-users have a lower prevalence of alcoholic gastritis compared to noncannabis users (1,289 [1,169 to 1,421] vs. 1,723 [1,583 to 1,875] per 100,000 hospitalizations for risky alcohol use), resulting in a 25% decreased probability of alcoholic gastritis (aRR: 0.75 [0.66 to 0.85]; p-value <0.0001). Furthermore, dependent cannabis usage resulted in a lower prevalence of alcoholic gastritis when compared to both nondependent cannabis users (0.72 [0.52 to 0.99]) and to noncannabis users (0.56 [0.41 to 0.76]). CONCLUSIONS: We reveal that risky alcohol drinking combined with cannabis use is associated with reduced prevalence of alcohol-associated gastritis in patients. Given increased cannabis legislation globally, understanding whether and how the specific ingredients in cannabis plant extract can be used in the treatment of alcoholic gastritis is paramount. In this regard, further molecular mechanistic studies are needed to delineate the mechanisms of our novel findings not only for alcoholic gastritis but also for gastritis from other causes.

Circulating and Exosome-Packaged Hepatitis C Single-Stranded RNA Induce Monocyte Differentiation via TLR7/8 to Polarized Macrophages and Fibrocytes.

Monocytes and macrophages (MΦs) play a central role in the pathogenesis of chronic hepatitis C virus (HCV) infection. The tissue microenvironment triggers monocyte differentiation into MΦs, with polarization ranging within the spectrum of M1 (classical) to M2 (alternative) activation. Recently, we demonstrated that HCV infection leads to monocyte differentiation into polarized MΦs that mediate stellate cell activation via TGF-ß. In this study, we aimed to identify the viral factor(s) that mediate monocyte-to-MΦ differentiation. We performed coculture experiments using healthy monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA. Coculture of monocytes with exosome-packaged HCV, cell-free HCV, or HCV ssRNA induced differentiation into MΦs with high M2 surface marker expression and production of pro- and anti-inflammatory cytokines. The HCV ssRNA-induced monocyte activation and differentiation into MΦs could be prevented by TLR7 or TLR8 knockdown. Furthermore, TLR7 or TLR8 stimulation, independent of HCV, caused monocyte differentiation and M2 MΦ polarization. In vivo, in chronic HCV-infected patients, we found increased expression of TLR7/8 in circulating monocytes that was associated with increased intracellular expression of procollagen. Furthermore, knockdown of TLR8 completely attenuated collagen expression in monocytes exposed to HCV, and knockdown of TLR7 partially attenuated this expression, suggesting roles for TLR7/8 in induction of fibrocytes in HCV infection. We identified TLR7/8 as mediators of monocyte differentiation and M2 MΦ polarization during HCV infection. Further, we demonstrated that HCV ssRNA and other TLR7/8 ligands promote MΦ polarization and generation of circulating fibrocytes.

Early Endoscopy Is Associated with Better Clinical Outcomes in Patients Hospitalized with Ischemic Bowel Disease.

BACKGROUND AND AIMS: Providing diagnostic and therapeutic interventions, lower gastrointestinal endoscopy is a salient investigative modality for ischemic bowel disease (IB). As studies on the role of endoscopic timing on the outcomes of IB are lacking, we sought to clarify this association. METHODS: After identifying 18-to-90-year-old patients with a primary diagnosis of IB from the 2012-2014 Healthcare Cost and Utilization Project-Nationwide Inpatient Sample, we grouped them based on timing of endoscopy into three: early (n = 9268), late (n = 3515), and no endoscopy (n = 18,452). We explored the determinants of receiving early endoscopy, the impact of endoscopic timing on outcomes (mortality and 13 others), and the impact of the type of endoscopy (colonoscopy vs. sigmoidoscopy) on these outcomes among the early group (SAS 9.4). RESULTS: Less likely to receive early endoscopy were Blacks compared to Whites (adjusted odds ratio [aOR] 0.81 95% CI [0.70-0.94]), and individuals on Medicaid, Medicare, and uninsured compared to the privately insured group (aOR 0.80 [0.71-0.91], 0.70 [0.58-0.84], and 0.68 [0.56-0.83]). Compared to the late and no endoscopy groups, patients with early endoscopy had less mortality (aOR 0.53 [0.35-0.80] and 0.09 [0.07-0.12]), shorter length of stay (LOS, 4.64 [4.43-4.87] days vs. 8.87 [8.40-9.37] and 6.62 [6.52-7.13] days), lower total hospital cost (THC, $41,055 [$37,995-$44,361] vs. $72,598 [$66,768-$78,937] and $68,737 [$64,028-$73,793]), and better outcomes. Similarly, among those who received early endoscopy, colonoscopy had better outcomes than sigmoidoscopy for mortality, THC, LOS, and adverse events. CONCLUSION: Early endoscopy, especially colonoscopy, is associated with better clinical outcomes and decreased healthcare utilization in IB. Unfortunately, there are disparities against Blacks, and non-privately insured individuals in receiving early endoscopy.

Cancer-Related Pain Is an Independent Predictor of In-Hospital Opioid Overdose: A Propensity-Matched Analysis.

BACKGROUND: About 50% of patients with cancer who have undergone surgery suffer from cancer-related pain (CP). The use of opioids for postoperative pain management presents the potential for overdose, especially among these patients. OBJECTIVE: The primary objective of this study was to determine the association between CP and postoperative opioid overdose among inpatients who had undergone major elective procedures. The secondary objective was to assess the relationship between CP and inpatient mortality, total hospital charge, and length of stay in this population. METHODS: Data of adults 18 years and older from the National Inpatient Sample (NIS) were analyzed. Variables were identified using ICD-9 codes. Propensity-matched regression models were employed in evaluating the association between CP and outcomes of interest. RESULTS: Among 4,085,355 selected patients, 0.8% (N = 2,665) had CP, whereas 99.92% (N = 4,082,690) had no diagnosis of CP. We matched patients with CP (N = 2,665) and no CP (N = 13,325) in a 1:5 ratio. We found higher odds of opioid overdose (adjusted odds ratio [aOR] = 4.82, 95% confidence interval [CI] = 2.68-8.67, P < 0.0001) and inpatient mortality (aOR = 1.39, 95% CI = 1.11-1.74, P = 0.0043) in patients with CP vs no CP. Also, patients with CP were more likely to stay longer in the hospital (12.76 days vs 7.88 days) with higher total hospital charges ($140,220 vs $88,316). CONCLUSIONS: CP is an independent risk factor for opioid overdose, increased length of stay, and increased total hospital charges.

Abnormal neutrophil traps and impaired efferocytosis contribute to liver injury and sepsis severity after binge alcohol use.

BACKGROUND & AIMS: Neutrophil extracellular traps (NETs) are an important strategy utilized by neutrophils to immobilize and kill invading microorganisms. Herein, we studied NET formation and the process of neutrophil cell death (NETosis), as well as the clearance of NETs by macrophages (MΦ) (efferocytosis) in acute sepsis following binge drinking. METHODS: Healthy volunteers consumed 2 ml of vodka/kg body weight, before blood endotoxin and 16 s rDNA were measured. Peripheral neutrophils were isolated and exposed to alcohol followed by phorbol 12-myristate 13-acetate (PMA) stimulation. Mice were treated with three alcohol binges and intraperitoneal lipopolysaccharide (LPS) to assess the dynamics of NET formation and efferocytosis. In vivo, anti-Ly6G antibody (IA8) was used for neutrophil depletion. RESULTS: Inducers of NETs (endotoxin and bacterial DNA) significantly increased in the circulation after binge alcohol drinking in humans. Ex vivo, alcohol alone increased NET formation, but upon PMA stimulation alcohol attenuated NET formation. Binge alcohol in mice resulted in a biphasic response to LPS. Initially, binge alcohol reduced LPS-induced NET formation and resulted in a diffuse distribution of neutrophils in the liver compared to alcohol-naïve mice. Moreover, indicators of NET formation including citrullinated histone H3, neutrophil elastase, and neutrophil myeloperoxidase were decreased at an early time point after LPS challenge in mice receiving binge alcohol, suggesting decreased NET formation. However, in the efferocytosis phase (15 h after LPS) citrullinated histone-H3 was increased in the liver in alcohol binge mice, suggesting decreased clearance of NETs. In vitro alcohol treatment reduced efferocytosis and phagocytosis of NETotic neutrophils and promoted expression of CD206 on MΦ. Finally, depletion of neutrophils prior to binge alcohol ameliorated LPS-induced systemic inflammation and liver injury in mice. CONCLUSIONS: Dysfunctional NETosis and efferocytosis following binge drinking exacerbate liver injury associated with sepsis. LAY SUMMARY: Disease severity in alcoholic liver disease (ALD) is associated with a significant presence of neutrophils (a type of immune cell) in the liver. It remains unknown how alcohol affects the capacity of neutrophils to control infection, a major hallmark of ALD. We found that binge alcohol drinking impaired important strategies used by neutrophils to contain and resolve infection, resulting in increased liver injury during ALD.