Patients With Autoimmune Hepatitis and Nonalcoholic Fatty Liver Disease: Characteristics, Treatment, and Outcomes.

GOAL: The objective of this study was to characterize an autoimmune hepatitis (AIH)/nonalcoholic fatty liver disease (NAFLD) overlap cohort, determine if they received standard of care treatment, and delineate their outcomes in comparison with patients with AIH or NAFLD alone. BACKGROUND: AIH is a relatively rare and heterogeneously presenting liver disease of unknown etiology. NAFLD is a leading cause of liver disease worldwide. AIH treatment includes steroids, which have adverse metabolic effects that can worsen NAFLD. No treatment guidelines are available to mitigate this side on AIH/NAFLD overlap patients. Few studies to date have examined these patients' characteristics, management practices, and outcomes. MATERIALS AND METHODS: A single-center, retrospective chart review study examining biopsy-proven AIH/NAFLD, AIH, and NAFLD patients. Characteristics, treatment, and 1- and 3-year outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) were evaluated. RESULTS: A total of 72 patients (36.1% AIH/NAFLD, 34.7% AIH, and 29.2% NAFLD) were included. AIH/NAFLD patients were found to be more often Hispanic/Latino, female, and with lower liver aminotransaminases, immunoglobulin G, and anti-smooth muscle antibody positivity. AIH/NAFLD patients were less likely to receive standard of care treatment. No significant differences in outcomes were seen between AIH/NAFLD and either AIH or NAFLD. CONCLUSIONS: Our study demonstrated that AIH/NAFLD patients have unique characteristics and are less likely to receive standard of care treatment compared with patients with AIH alone. Despite this, no difference in outcomes (all-cause mortality, need for liver transplantation, or decompensated cirrhosis) was seen. Given NAFLD's rising prevalence, AIH/NAFLD cases will likely increase, and may benefit from alternative treatment guidelines to prevent worsening of NAFLD.

Binge drinking alcohol and circadian misalignment in night shift nurses is associated with decreased resiliency to COVID-19 infection.

BACKGROUND: Nurses and other first responders are at high risk of exposure to the SARS-CoV2 virus, and many have developed severe COVID-19 infection. A better understanding of the factors that increase the risk of infection after exposure to the virus could help to address this. Although several risk factors such as obesity, diabetes, and hypertension have been associated with an increased risk of infection, many first responders develop severe COVID-19 without established risk factors. As inflammation and cytokine storm are the primary mechanisms in severe COVID-19, other factors that promote an inflammatory state could increase the risk of COVID-19 in exposed individuals. Alcohol misuse and shift work with subsequent misaligned circadian rhythms are known to promote a pro-inflammatory state and thus could increase susceptibility to COVID-19. To test this hypothesis, we conducted a prospective, cross-sectional observational survey-based study in nurses using the American Nursing Association network. METHOD: We used validated structured questionnaires to assess alcohol consumption (the Alcohol Use Disorders Identification Test) and circadian typology or chronotype (the Munich Chronotype Questionnaire Shift -MCTQ-Shift). RESULTS: By latent class analysis (LCA), high-risk features of alcohol misuse were associated with a later chronotype, and binge drinking was greater in night shift workers. The night shift was associated with more than double the odds of COVID-19 infection of the standard shift (OR 2.67, 95% CI: 1.18 to 6.07). Binge drinkers had twice the odds of COVID-19 infection of those with low-risk features by LCA (OR: 2.08, 95% CI: 0.75 to 5.79). CONCLUSION: Working night shifts or binge drinking may be risk factors for COVID-19 infection among nurses. Understanding the mechanisms underlying these risk factors could help to mitigate the impact of COVID-19 on our at-risk healthcare workforce.

Glycosuria and Acute Kidney Injury: A Rare Presentation of Acute Interstitial Nephritis.

Acute interstitial nephritis (AIN) is often induced by drugs and is a common cause of acute kidney injury. Clinically diagnosing AIN can often be challenging because these signs and symptoms rarely present in concert. The inflammatory pathology of AIN leads to renal tubule dysregulation, which can be clinically observed as glycosuria, eosinophilia, leukocytes or white blood cell casts, and proteinuria. We present a case of an otherwise healthy woman in her 30s with AIN presenting with acute kidney injury and glycosuria without pyuria. This patient had an atypical presentation of AIN that lacked classic diagnostic laboratory features and has been rarely reported. She had profound glycosuria in the setting of normoglycemia, which resolved following a course of corticosteroids. Glycosuria was most likely due to proximal tubule damage from AIN. This case supports previous hypotheses that drug-induced AIN can cause proximal tubule dysfunction resulting in glycosuria in the absence of other identifiable proximal tubule dysregulations. We hypothesize that resolution of AIN involves the repair and restoration of sodium-dependent glucose cotransporter function.

Pharmacological DNA Demethylation Weakens Inhibitory Synapses in the Auditory Cortex and Re-opens the Critical Period for Frequency Map Plasticity.

The critical period is a time of maximal plasticity within the cortex. The progression of the critical period is marked by experience-dependent transcriptional alterations in cortical neurons, which in turn shifts the excitatory-inhibitory balance in the brain, and accordingly reduces plasticity. Epigenetic mechanisms, such as DNA methylation, control the transcriptional state of neurons, and have been shown to be dynamically regulated during the critical period. Here we show that adult animals have a significantly higher concentration of DNA methylation than critical period animals. Pharmacological reduction of DNA methylation in adult animals re-establishes critical period auditory map plasticity. Furthermore, the reduction of DNA methylation in adult animals, reverted intrinsic characteristics of inhibitory synapses to an immature state. Our data suggest that accumulation of DNA methylation during the critical period confers a mature phenotype to cortical neurons, which in turn, facilitates the reduction in plasticity seen after the critical period.

Analysis of learning deficits in aged rats on the W-track continuous spatial alternation task.

Young and aged animals were tested on a spatial alternation task that consisted of two interleaved components: (1) an "outbound" or alternation component (working memory) and (2) an "inbound" component, requiring the animal to remember to return to a central location in space (spatial memory). In the present study, aged rats made more outbound errors throughout testing, resulting in significantly more days to reach learning criterion, as compared to young rats. Furthermore, while all animals were able to learn the hippocampus-dependent inbound component of the task, most aged animals remained just above chance on the outbound component, even after extended testing days. Aged rats may be more impaired on the outbound part of the task because it requires cooperation of both the hippocampus and mPFC, each of which is compromised with age. In addition to presenting these results, we compare one commonly used analysis (repeated measures ANOVA) and two less common hierarchical modeling techniques (hierarchical generalized linear model and state-space random effects model) to determine the best method for comparing population learning over time. We found that hierarchical modeling is the most appropriate for this task and that a state-space model better captures the behavioral responses. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Clinically Divergent Mutation Effects on the Structure and Function of the Human Cardiac Tropomyosin Overlap.

The progression of genetically inherited cardiomyopathies from an altered protein structure to clinical presentation of disease is not well understood. One of the main roadblocks to mechanistic insight remains a lack of high-resolution structural information about multiprotein complexes within the cardiac sarcomere. One example is the tropomyosin (Tm) overlap region of the thin filament that is crucial for the function of the cardiac sarcomere. To address this central question, we devised coupled experimental and computational modalities to characterize the baseline function and structure of the Tm overlap, as well as the effects of mutations causing divergent patterns of ventricular remodeling on both structure and function. Because the Tm overlap contributes to the cooperativity of myofilament activation, we hypothesized that mutations that enhance the interactions between overlap proteins result in more cooperativity, and conversely, those that weaken interaction between these elements lower cooperativity. Our results suggest that the Tm overlap region is affected differentially by dilated cardiomyopathy-associated Tm D230N and hypertrophic cardiomyopathy-associated human cardiac troponin T (cTnT) R92L. The Tm D230N mutation compacts the Tm overlap region, increasing the cooperativity of the Tm filament, contributing to a dilated cardiomyopathy phenotype. The cTnT R92L mutation causes weakened interactions closer to the N-terminal end of the overlap, resulting in decreased cooperativity. These studies demonstrate that mutations with differential phenotypes exert opposite effects on the Tm-Tn overlap, and that these effects can be directly correlated to a molecular level understanding of the structure and dynamics of the component proteins.