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Objective This study was performed to investigate the role of probiotics (Clostridium butyricum combined with Bifidobacterium infantis) in the treatment of minimal hepatic encephalopathy (MHE) in patients with hepatitis B virus (HBV)-induced liver cirrhosis. Methods Sixty-seven consecutive patients with HBV-induced cirrhosis without overt hepatic encephalopathy were screened using the number connection test and digit symbol test. The patients were randomized to receive probiotics (n = 30) or no probiotics (n = 37) for 3 months. At the end of the trial, changes in cognition, intestinal microbiota, venous ammonia, and intestinal mucosal barriers were analyzed using recommended systems biology techniques. Results The patients’ cognition was significantly improved after probiotic treatment. The predominant bacteria (Clostridium cluster I and Bifidobacterium) were significantly enriched in the probiotics-treated group, while Enterococcus and Enterobacteriaceae were significantly decreased. Probiotic treatment was also associated with an obvious reduction in venous ammonia. Additionally, the parameters of the intestinal mucosal barrier were obviously improved after probiotic treatment, which might have contributed to the improved cognition and the decreased ammonia levels. Conclusion Treatment with probiotics containing C. butyricum and B. infantis represents a new adjuvant therapy for the management of MHE in patients with HBV-induced cirrhosis.

A timely look at the ethical, legal, and policy issues surrounding brain injury and collision sports. American tackle football is an industry like any other. And like many industries, it sells a product that is dangerous to those who use it—or, in this case, those who play it. In Tackle Football and Traumatic Brain Injuries, Daniel S. Goldberg explores the connections among traumatic brain injury, collision sports, and the industry's continuing efforts to manufacture doubt. Focusing especially on youths and adolescents—the most vulnerable population that comprises over 99% of tackle football players in the US—Goldberg addresses the ethical and social implications of their participation in tackle football. Goldberg discusses the true scope of the danger and the costs to society and individuals of caring for injured participants. If these risks were to become widespread public knowledge, the profitability and perhaps even the viability of American football would be at risk. As the tackle football industry has consistently worked to mask the health hazards involved in playing football, it has used a particular tool that has proved highly effective in achieving this subterfuge: the manufacture of doubt. Goldberg advocates for using public health laws as a tool for countering these efforts at obfuscation, and he outlines specific policy proposals intended to address the population health and ethical problems presented by tackle football. The book draws on public health ethics, public health law, and the histories of occupational and public health to assess the limits of parental choice to expose their children to risks of injury. Should kids play tackle football at all—and who decides if they should? Goldberg offers practical answers to these critical legal, ethical, and social questions. Chris Nowinski, former Harvard football player and WWE wrestler, provides a timely and insider's perspective on these critical issues in the foreword.

Hepatic encephalopathy (HE) represents a dysfunctional gut-liver-brain axis in cirrhosis which can negatively impact outcomes. This altered gut-brain relationship has been treated using gut-selective antibiotics such as rifaximin, that improve cognitive function in HE, especially its subclinical form, minimal HE (MHE). However, the precise mechanism of the action of rifaximin in MHE is unclear. We hypothesized that modulation of gut microbiota and their end-products by rifaximin would affect the gut-brain axis and improve cognitive performance in cirrhosis. Aim To perform a systems biology analysis of the microbiome, metabolome and cognitive change after rifaximin in MHE. Twenty cirrhotics with MHE underwent cognitive testing, endotoxin analysis, urine/serum metabolomics (GC and LC-MS) and fecal microbiome assessment (multi-tagged pyrosequencing) at baseline and 8 weeks post-rifaximin 550 mg BID. Changes in cognition, endotoxin, serum/urine metabolites (and microbiome were analyzed using recommended systems biology techniques. Specifically, correlation networks between microbiota and metabolome were analyzed before and after rifaximin. There was a significant improvement in cognition(six of seven tests improved, p<0.01) and endotoxemia (0.55 to 0.48 Eu/ml, p = 0.02) after rifaximin. There was a significant increase in serum saturated (myristic, caprylic, palmitic, palmitoleic, oleic and eicosanoic) and unsaturated (linoleic, linolenic, gamma-linolenic and arachnidonic) fatty acids post-rifaximin. No significant microbial change apart from a modest decrease in Veillonellaceae and increase in Eubacteriaceae was observed. Rifaximin resulted in a significant reduction in network connectivity and clustering on the correlation networks. The networks centered on Enterobacteriaceae, Porphyromonadaceae and Bacteroidaceae indicated a shift from pathogenic to beneficial metabolite linkages and better cognition while those centered on autochthonous taxa remained similar. Rifaximin is associated with improved cognitive function and endotoxemia in MHE, which is accompanied by alteration of gut bacterial linkages with metabolites without significant change in microbial abundance. ClinicalTrials.gov NCT01069133.

The brain dysfunction associated with liver failure can have diverse manifestations. The main pathogenesis is metabolic derangement of cell function and brain edema. Prompt recognition and treatment may reverse, at least partially, some of the abnormalities. When the liver fails, brain function changes. Acute-on-chronic liver failure is manifested initially as abnormal behavior and compromised cognition. In the absence of preexisting disease, acute, severe liver failure may cause the brain to swell, with patients becoming comatose and losing brain function altogether. Hepatic encephalopathy in patients with chronic liver disease is potentially reversible and manageable, but new, acute (fulminant) hepatic encephalopathy with rapidly rising blood ammonia levels is more difficult to control because of diffuse brain edema and structural brain-stem injury. Although the onset of hepatic encephalopathy can rarely be pinpointed clinically, it is a clinical landmark in . . .

Ammonia levels are used to assess hepatic encephalopathy, but their levels are highly variable in clinical practice. We studied factors associated with variation in ammonia values in cirrhotic patients without previous hepatic encephalopathy and healthy volunteers (HVs). Ammonia increased by 12% and 18% at 1 and 2 hour, respectively, after a protein meal in 64 cirrhotic patients (P < 0.001). In 237 HVs, ammonia levels varied significantly between sites (P < 0.0001). New site-specific ammonia upper limits based on HV levels using a strict analysis protocol differed from routinely used values. Correlation between paired fresh samples was high (r = 0.83) but modest between fresh and frozen samples (r = 0.62). Sample handling, processing, and protein intake impact ammonia levels across sites.

Sepsis is a life-threatening clinical condition caused by a dysregulated host response to infection. Sepsis-associated encephalopathy (SAE) is a common but poorly understood neurological complication of sepsis, which is associated with increased morbidity and mortality. SAE clinical presentation may range from mild confusion and delirium to severe cognitive impairment and deep coma. Important mechanisms associated with SAE include excessive microglial activation, impaired endothelial barrier function, and blood-brain barrier (BBB) dysfunction. Endotoxemia and pro-inflammatory cytokines produced systemically during sepsis lead to microglial and brain endothelial cell activation, tight junction downregulation, and increased leukocyte recruitment. The resulting neuroinflammation and BBB dysfunction exacerbate SAE pathology and aggravate sepsis-induced brain dysfunction. In this mini-review, recent literature surrounding some of the mediators of BBB dysfunction during sepsis is summarized. Modulation of microglial activation, endothelial cell dysfunction, and the consequent prevention of BBB permeability represent relevant therapeutic targets that may significantly impact SAE outcomes.

The correct sentence should read “Time from PRES onset to control of causative factor > 30 hours.” (2013) Correction: Determinants of Recovery from Severe Posterior Reversible Encephalopathy Syndrome.

Background Hepatic encephalopathy (HE) is considered reversible regarding mental status but may not be cognitively in single-center studies. Aim To evaluate persistence of learning impairment in prior HE compared to those who never experienced HE (no-HE) in a multicenter study. Methods A total of 174 outpatient cirrhotics from three centers (94 Virginia, 30 Ohio, and 50 Rome; 36 prior HE) underwent psychometric hepatic encephalopathy score (PHES) and inhibitory control (ICT) testing at baseline and then at least 7 days apart. ICT learning (change in 2nd half lures compared to 1st half) was compared between patient groups at both visits. Change in the PHES individual sub-tests and total score between visits was compared in both groups. US versus Italian trends were also analyzed. Results HE patients had worse PHES and ICT results compared to no-HE patients at baseline. Significant improvement (1st half 7.1 vs. 2nd half 6.2, p  < 0.0001) was observed in no-HE, but not in HE (1st half 7.9 vs. 2nd half 7.8, p  = 0.1) at baseline. At retesting (median 20 days later), no-HE patients continued with significant learning (1st half 6.0 vs. 2nd half 5.4, p  < 0.0001), while HE patients again did not improve (1st half 7.8 vs. 2nd half 6.9, p  = 0.37). Between visits, no-HE patients improved significantly on four PHES sub-tests and overall score, while HE patients only improved on two sub-tests with similar overall PHES score. Trends were similar between US and Italian subjects. Conclusion In this multicenter study, prior HE patients showed persistent significant learning impairment compared to those without prior HE, despite adequate medical therapy. This persistent change should increase efforts to reduce the first HE episode.

INTRODUCTION:Critically ill patients with cirrhosis admitted to the intensive care unit (ICU) are usually on broad-spectrum antibiotics because of suspected infection or as a hospital protocol. It is unclear if additional rifaximin has any synergistic effect with broad-spectrum antibiotics in ICU patients with acute overt hepatic encephalopathy (HE).METHODS:In this double-blind trial, patients with overt HE admitted to ICU were randomized to receive antibiotics (ab) alone or antibiotics with rifaximin (ab + r). Resolution (or 2 grade reduction) of HE, time to resolution of HE, in-hospital mortality, nosocomial infection, and changes in endotoxin levels were compared between the 2 groups. A subgroup analysis of patients with decompensated cirrhosis and acute-on-chronic liver failure was performed.RESULTS:Baseline characteristics and severity scores were similar among both groups (92 in each group). Carbapenems and cephalosporin with beta-lactamase inhibitors were the most commonly used ab. On Kaplan-Meier analysis, 44.6% (41/92; 95% confidence interval [CI], 32-70.5) in ab-only arm and 46.7% (43/92; 95% CI, 33.8-63) in ab + r arm achieved the primary objective (P = 0.84).Time to achieve the primary objective (3.65 ± 1.82 days and 4.11 ± 2.01 days; P = 0.27) and in-hospital mortality were similar among both groups (62% vs 50%; P = 0.13). Seven percent and 13% in the ab and ab + r groups developed nosocomial infections (P = 0.21). Endotoxin levels were unaffected by rifaximin. Rifaximin led to lower in-hospital mortality (hazard ratio: 0.39 [95% CI, 0.2-0.76]) in patients with decompensated cirrhosis but not in patients with acute-on-chronic liver failure (hazard ratio: 0.99 [95% CI, 0.6-1.63]) because of reduced nosocomial infections.DISCUSSION:Reversal of overt HE in those on ab was comparable with those on ab + r.