Predictors of do-not-resuscitate order utilization in decompensated cirrhosis hospitalized patients: A nationwide inpatient cohort study.

INTRODUCTION AND OBJECTIVES: Decompensated cirrhosis carries high inpatient morbidity and mortality. Consequently, advance care planning is an integral aspect of medical care in this patient population. Our study aims to identify do-not-resuscitate (DNR) order utilization and demographic disparities in decompensated cirrhosis patients. PATIENTS OR MATERIALS AND METHODS: Nationwide Inpatient Sample was used to extract the cohort of patients from January 1st, 2016 to December 31st, 2017, based on the most comprehensive and recent data. The first cohort included hospitalized patients with decompensated cirrhosis. The second cohort included patients with decompensated cirrhosis with at least one contraindication for liver transplantation. RESULTS: A cohort of 585,859 decompensated cirrhosis patients was utilized. DNR orders were present in 14.2% of hospitalized patients. DNR utilization rate among patients with relative contraindication for liver transplantation was 15.0%. After adjusting for co-morbid conditions, disease severity, and inpatient mortality, African-American and Hispanic patient populations had significantly lower DNR utilization rates. There were regional, and hospital-level differences noted. Moreover, advanced age, advanced stage of decompensated cirrhosis, inpatient mortality, and relative contraindications for liver transplantation (metastatic neoplasms, dementia, alcohol misuse, severe cardiopulmonary disease, medical non-adherence) were independently associated with increased DNR utilization rates. CONCLUSIONS: The rate of DNR utilization in patients with relative contraindications for liver transplantation was similar to patients without any relative contraindications. Moreover, there were significant demographic and hospital-level predictors of DNR utilization. This information can guide resource allocation in educating patients and their families regarding prognosis and outcome expectations.

MicroRNA-7 Regulates the Function of Mitochondrial Permeability Transition Pore by Targeting VDAC1 Expression.

Mitochondrial dysfunction is one of the major contributors to neurodegenerative disorders including Parkinson disease. The mitochondrial permeability transition pore is a protein complex located on the mitochondrial membrane. Under cellular stress, the pore opens, increasing the release of pro-apoptotic proteins, and ultimately resulting in cell death. MicroRNA-7 (miR-7) is a small non-coding RNA that has been found to exhibit a protective role in the cellular models of Parkinson disease. In the present study, miR-7 was predicted to regulate the function of mitochondria, according to gene ontology analysis of proteins that are down-regulated by miR-7. Indeed, miR-7 overexpression inhibited mitochondrial fragmentation, mitochondrial depolarization, cytochrome c release, reactive oxygen species generation, and release of mitochondrial calcium in response to 1-methyl-4-phenylpyridinium (MPP(+)) in human neuroblastoma SH-SY5Y cells. In addition, several of these findings were confirmed in mouse primary neurons. Among the mitochondrial proteins identified by gene ontology analysis, the expression of voltage-dependent anion channel 1 (VDAC1), a constituent of the mitochondrial permeability transition pore, was down-regulated by miR-7 through targeting 3'-untranslated region of VDAC1 mRNA. Similar to miR-7 overexpression, knockdown of VDAC1 also led to a decrease in intracellular reactive oxygen species generation and subsequent cellular protection against MPP(+). Notably, overexpression of VDAC1 without the 3'-UTR significantly abolished the protective effects of miR-7 against MPP(+)-induced cytotoxicity and mitochondrial dysfunction, suggesting that the protective effect of miR-7 is partly exerted through promoting mitochondrial function by targeting VDAC1 expression. These findings point to a novel mechanism by which miR-7 accomplishes neuroprotection by improving mitochondrial health.

MicroRNA-7 Promotes Glycolysis to Protect against 1-Methyl-4-phenylpyridinium-induced Cell Death.

Parkinson disease is associated with decreased activity of the mitochondrial electron transport chain. This defect can be recapitulated in vitro by challenging dopaminergic cells with 1-methyl-4-phenylpyridinium (MPP(+)), a neurotoxin that inhibits complex I of electron transport chain. Consequently, oxidative phosphorylation is blocked, and cells become dependent on glycolysis for ATP production. Therefore, increasing the rate of glycolysis might help cells to produce more ATP to meet their energy demands. In the present study, we show that microRNA-7, a non-coding RNA that protects dopaminergic neuronal cells against MPP(+)-induced cell death, promotes glycolysis in dopaminergic SH-SY5Y and differentiated human neural progenitor ReNcell VM cells, as evidenced by increased ATP production, glucose consumption, and lactic acid production. Through a series of experiments, we demonstrate that targeted repression of RelA by microRNA-7, as well as subsequent increase in the neuronal glucose transporter 3 (Glut3), underlies this glycolysis-promoting effect. Consistently, silencing Glut3 expression diminishes the protective effect of microRNA-7 against MPP(+). Further, microRNA-7 fails to prevent MPP(+)-induced cell death when SH-SY5Y cells are cultured in a low glucose medium, as well as when differentiated ReNcell VM cells or primary mouse neurons are treated with the hexokinase inhibitor, 2-deoxy-d-glucose, indicating that a functional glycolytic pathway is required for this protective effect. In conclusion, microRNA-7, by down-regulating RelA, augments Glut3 expression, promotes glycolysis, and subsequently prevents MPP(+)-induced cell death. This protective effect of microRNA-7 could be exploited to correct the defects in oxidative phosphorylation in Parkinson disease.

MicroRNA-7 protects against 1-methyl-4-phenylpyridinium-induced cell death by targeting RelA.

Parkinson's disease (PD) is characterized by the progressive loss of dopaminergic neurons in the substantia nigra. Mitochondrial complex I impairment in PD is modeled in vitro by the susceptibility of dopaminergic neurons to the complex I inhibitor 1-methyl-4-phenylpyridinium (MPP+). In the present study, we demonstrate that microRNA-7 (miR-7), which is expressed in tyrosine hydroxylase-positive nigral neurons in mice and humans, protects cells from MPP+-induced toxicity in dopaminergic SH-SY5Y cells, differentiated human neural progenitor ReNcell VM cells, and primary mouse neurons. RelA, a component of nuclear factor-κB (NF-κB), was identified to be downregulated by miR-7 using quantitative proteomic analysis. Through a series of validation experiments, it was confirmed that RelA mRNA is a target of miR-7 and is required for cell death following MPP+ exposure. Further, RelA mediates MPP+-induced suppression of NF-κB activity, which is essential for MPP+-induced cell death. Accordingly, the protective effect of miR-7 is exerted through relieving NF-κB suppression by reducing RelA expression. These findings provide a novel mechanism by which NF-κB suppression, rather than activation, underlies the cell death mechanism following MPP+ toxicity, have implications for the pathogenesis of PD, and suggest miR-7 as a therapeutic target for this disease.

Wilson's Disease: An Analysis of Health Care Use and Cost Burden of Commercially Insured Adults in the United States.

The economic and health care use burdens of Wilson's disease (WD) are unknown. In this study, we aimed to quantify this health care resource use and economic burden. We performed a retrospective case-control analysis of individuals in the Truven Health MarketScan Commercial Claims database (2007-2017). Using propensity scores, 424 WD cases were matched 1:1 to chronic liver disease (CLD) controls without WD. Total and service-specific parameters, expressed in monthly averages, were quantified for the 6-month pre-WD diagnosis versus the 12-month period after diagnosis. Wilcoxon signed-rank tests and McNemar tests were used to examine incremental differences in burden between cases and controls. Adjusted multivariable generalized linear regression models were used to compare health care burdens. Relative to the 6-month pre-WD diagnosis, the 12 months after diagnosis had more claims per patient (2.87 vs. 3.35; P < 0.0001) and increased per patient health care costs (US $2,089 vs. US $3,887; P < 0.0001). WD cases incurred US $1,908 more in total unadjusted costs compared to controls in the 12-month postindex date monthly averages. The increase in claims was primarily due to outpatient visits (1.62 vs. 1.82) and pharmaceutical claims (1.11 vs. 1.37). Cases also had higher health care costs for inpatient admissions (US $559 vs. US $1,264), outpatient visits (US $770 vs. US $1,037), and pharmaceutical claims (US $686 vs. US $1,489). Conclusion: WD is associated with significant health care cost and use burdens driven by increased inpatient admissions, outpatient visits, and pharmaceutical claims.

The impact of acute kidney injury on mortality and clinical outcomes in patients with alcoholic cirrhosis in the USA.

INTRODUCTION: Acute kidney injury (AKI) is associated with increased morbidity and mortality in patients with chronic liver disease. Although the impact of AKI on patients with liver disease has been established, its impact on alcoholic cirrhosis has not been studied. METHODS: Our study utilized data from the National Inpatient Sample for the year 2016 for all patients with a diagnosis of alcoholic cirrhosis and AKI. Primary outcomes were mortality, length of stay (LOS) and hospitalization cost were compared. Secondary outcomes were complications of cirrhosis and its impact on mortality. Multivariate logistic regression analysis and propensity-score matching were used to compare the two groups. RESULTS: A total of 29 906 patients were included and 6733 (22.5%) had AKI. Propensity-matched multivariate analysis demonstrates that AKI was associated with a significant increase risk of mortality [odds ratio (OR): 8.09; 95% confidence interval (CI), 6.68-9.79; P < 0.0001]. AKI prolonged the hospital stay by 3.68 days (95% CI, 3.42-3.93; P < 0.0001) and increased total hospital charges by $50 284 (95% CI, 45 829-54 739; P < 0.0001). AKI increased the risk of complications of cirrhosis, including hepatorenal syndrome (OR: 19.15; 95% CI, 16.1-22.76), ascites (OR: 2.27; 95% CI, 2.11-2.44), hepatic encephalopathy (OR: 2.54; 95% CI, 1.87-3.47) and portal hypertension (OR: 1.08; 95% CI, 1.01-1.16). CONCLUSION: AKI in alcoholic cirrhosis significantly increases the risk of mortality, hospitalizations costs and LOS. Further studies are needed on addressing renal failure and treatment options for patients with alcoholic cirrhosis.

Acute kidney injury and hepatorenal syndrome in cirrhosis.

Acute kidney injury (AKI) in cirrhosis, including hepatorenal syndrome (HRS), is a common and serious complication in cirrhotic patients, leading to significant morbidity and mortality. AKI is separated into two categories, non-HRS AKI and HRS-AKI. The most recent definition and diagnostic criteria of AKI in cirrhosis and HRS have helped diagnose and prognosticate the disease. The pathophysiology behind non-HRS-AKI and HRS is more complicated than once theorized and involves more processes than just splanchnic vasodilation. The common biomarkers clinicians use to assess kidney injury have significant limitations in cirrhosis patients; novel biomarkers being studied have shown promise but require further studies in clinical settings and animal models. The overall management of non-HRS AKI and HRS-AKI requires a systematic approach. Although pharmacological treatments have shown mortality benefit, the ideal HRS treatment option is liver transplantation with or without simultaneous kidney transplantation. Further research is required to optimize pharmacologic and nonpharmacologic approaches to treatment. This article reviews the current guidelines and recommendations of AKI in cirrhosis.

Timing of endoscopic retrograde cholangiopancreatography in acute biliary pancreatitis without cholangitis: a nationwide inpatient cohort study.

BACKGROUND: The timing of endoscopic retrograde cholangiopancreatography (ERCP) in patients with acute biliary pancreatitis without cholangitis is unclear. We accessed a national database to analyze the outcomes of urgent (<24 h) and early (24-72 h) ERCP in this cohort. METHODS: The cohort was extracted from the Nationwide Inpatient Sample database. Hospital ERCP volumes were generated using unique hospital identifiers. Multivariate regression modeling was used to analyze the predictors of urgent vs. early ERCP use, and to determine various outcome variables between the 2 cohorts. RESULTS: Overall, 105,433 admissions were evaluated. There was a significant rise in urgent ERCP performed over the study period. Older patients, males, patients with comorbidities, African American and Hispanic patient populations were less likely to receive urgent ERCP. High ERCP volume hospitals, teaching hospitals, and hospitals in the Midwest and West were more likely to perform urgent ERCP. There were no differences in mortality rates or complication rates between the 2 cohorts. However, there were significant differences in length of stay and healthcare cost analysis. CONCLUSIONS: The increasing use of urgent ERCP did not result in a clinically significant benefit in terms of mortality, length of stay, or healthcare cost analysis. The use of urgent ERCP is also not uniform across various demographic and hospital cohorts. Urgent ERCP may be over-utilized, and it may be reasonable to perform ERCP in this patient population based on the physician's suspicion about the severity of disease.

MicroRNA-7 facilitates the degradation of alpha-synuclein and its aggregates by promoting autophagy.

Alpha-Synuclein (α-Syn) is an important protein in the pathogenesis of Parkinson disease (PD) as it accumulates as fibrillar inclusions in affected brain regions including dopaminergic neurons in the substantia nigra. Elevated levels of α-Syn seem to be crucial in mediating its toxicity. Thus, detailed information regarding the regulatory mechanism of α-Syn expression in several layers such as transcription, post-transcription and post-translation is needed in order to devise therapeutic interventions for PD. Previously, we reported that expression of α-Syn is repressed by microRNA-7 (miR-7) through its effect on the 3'-untranslated region (UTR) of α-Syn mRNA. Here, we show that miR-7 also accelerates the clearance of α-Syn and its aggregates by promoting autophagy in differentiated ReNcell VM cells. Further, miR-7 facilitates the degradation of pre-formed fibrils of α-Syn transported from outside the cells. This additional mechanism for reducing α-Syn levels show miR-7 to be an important molecular target for PD and other alpha-synucleinopathies.

MicroRNA-7 activates Nrf2 pathway by targeting Keap1 expression.

Nuclear factor E2-related factor 2 (Nrf2) is a key transcription factor that regulates the expression of a number of antioxidant and detoxifying genes that provide cellular protection against various stressors including reactive oxygen species (ROS). Nrf2 activity is tightly regulated by a cytoplasmic inhibitory protein called Kelch-like ECH-associated protein 1 (Keap1). The mechanism that controls Keap1 expression, however, remains poorly understood. In the present study, we demonstrate that microRNA-7 (miR-7), which is highly expressed in the brain, represses Keap1 expression by targeting the 3'-untranslated region (UTR) of its mRNA in human neuroblastoma cells, SH-SY5Y. Subsequently, this event results in an increased Nrf2 activity, as evidenced by an increase in the expression of its transcriptional targets, heme oxygenase 1 (HO-1) and glutamate-cysteine ligase modifier subunit (GCLM), and an enhanced nuclear localization of Nrf2. In addition, miR-7 decreases the intracellular hydroperoxides level and increases the level of reduced form of glutathione, indicative of oxidative stress relief. We also demonstrate that targeted repression of Keap1 and activation of Nrf2 pathway, in part, underlies the protective effects of miR-7 against 1-methyl-4-phenylpyridinium (MPP+)-induced toxicity in SH-SY5Y and differentiated human neural progenitor cells, ReNcell VM. These findings point to a new mechanism by which miR-7 exerts cytoprotective effects by regulating the Nrf2 pathway.

Inhibition of miR-34b and miR-34c enhances α-synuclein expression in Parkinson's disease.

Mounting evidence suggests that microRNA (miR) dysregulation contributes to neurodegenerative disorders including Parkinson's disease (PD). MiR-34b and miR-34c have been previously shown to be down-regulated in the brains of patients with PD. Here, we demonstrate that miR-34b and miR-34c repress the expression of α-synuclein (α-syn), a key protein in PD pathogenesis. Inhibition of miR-34b and miR-34c expression in human dopaminergic SH-SY5Y cells increased α-syn levels and stimulated aggregate formation. Additionally, a single nucleotide polymorphism (SNP) in the 3'-UTR of α-syn was found to lower the miR-34b-mediated repression of the protein. Our results suggest that down-regulation of miR-34b and miR-34c in the brain, as well as an SNP in the 3'-UTR of α-syn can increase α-syn expression, possibly contributing to PD pathogenesis.