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The soft-bodied cephalopods including octopus, cuttlefish, and squid are broadly considered to be the most cognitively advanced group of invertebrates. Previous research has demonstrated that these large-brained molluscs possess a suite of cognitive attributes that are comparable to those found in some vertebrates, including highly developed perception, learning, and memory abilities. Cephalopods are also renowned for performing sophisticated feats of flexible behaviour, which have led to claims of complex cognition such as causal reasoning, future planning, and mental attribution. Hypotheses to explain why complex cognition might have emerged in cephalopods suggest that a combination of predation, foraging, and competitive pressures are likely to have driven cognitive complexity in this group of animals. Currently, it is difficult to gauge the extent to which cephalopod behaviours are underpinned by complex cognition because many of the recent claims are largely based on anecdotal evidence. In this review, we provide a general overview of cephalopod cognition with a particular focus on the cognitive attributes that are thought to be prerequisites for more complex cognitive abilities. We then discuss different types of behavioural flexibility exhibited by cephalopods and, using examples from other taxa, highlight that behavioural flexibility could be explained by putatively simpler mechanisms. Consequently, behavioural flexibility should not be used as evidence of complex cognition. Fortunately, the field of comparative cognition centres on designing methods to pinpoint the underlying mechanisms that drive behaviours. To illustrate the utility of the methods developed in comparative cognition research, we provide a series of experimental designs aimed at distinguishing between complex cognition and simpler alternative explanations. Finally, we discuss the advantages of using cephalopods to develop a more comprehensive reconstruction of cognitive evolution.

Funder: European Commission; FundRef: http://dx.doi.org/10.13039/501100000780; Grant(s): Marie Skłodowska-Curie Fellowship MENTALIZINGORIGINS Grant reference: 752373, Funder: FP7 Ideas: European Research Council; Grant(s): ERC Grant Agreement N 3399933, Eurasian jays have been reported to protect their caches by responding to cues about either the visual perspective or current desire of an observing conspecific, similarly to other corvids. Here, we used established paradigms to test whether these birds can – like humans – integrate multiple cues about different mental states and perform an optimal response accordingly. Across five experiments, which also include replications of previous work, we found little evidence that our jays adjusted their caching behaviour in line with the visual perspective and current desire of another agent, neither by integrating these social cues nor by responding to only one type of cue independently. These results raise questions about the reliability of the previously reported effects and highlight several key issues affecting reliability in comparative cognition research.

Vitamin E is an essential micronutrient with relevant antioxidant and anti-inflammatory properties found in plant leaves, seeds, and products derived from their processing. Familial vitamin E deficiency is a rare inherited syndrome characterized by ataxia and peripheral neuropathy with a massive decrease in plasma vitamin E (

Hepatic encephalopathy (HE) is a form of brain dysfunction that is caused by liver insufficiency and/or portal-systemic shunting. The exact nature of HE is debated; as such, conflicting uses of the term “HE” may cause inconsistencies in its detection and management. This review highlights the meaning of the term “HE” on the basis of its historical origins and current consensus. It also provides criteria for the diagnosis of the condition based on its phenotypes and risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical reporting of HE episodes is discussed.

Corvids appear to be capable of adjusting their behaviour according to another’s perspective, knowledge and desire. For example, Eurasian jays have been found to employ a variety of cache protection strategies to minimise cache loss by responding to cues about the visual perspective or current desire of an observing conspecific. However, it is not known whether these jays (or any other corvid) can integrate multiple cues about different mental states and perform the optimal response accordingly. Across five experiments, we found little evidence that our Eurasian jays responded to either the visual perspective or current desire of another agent. In Experiments 1 and 2 we investigated whether Eurasian jays can limit the risk of cache loss by responding simultaneously to cues about the desire and perspective of a potential conspecific pilferer. Building on established paradigms, we used opaque and clear barriers to manipulate the observer’s visual access to cache locations, and specific satiety to manipulate the observer’s desire towards different types of food. Across both experiments the jays’ caching pattern provided no evidence that they could integrate information about the observer’s desire and perspective. Moreover, the results were also inconsistent with the previously reported effects that jays protect their caches by responding to either the visual access or specific satiety of the observer independently. To gain further insight into these unexpected results, we conducted three more experiments. In Experiments 3 and 4, we attempted to replicate the previous finding that Eurasian jays prefer to cache behind an opaque barrier over a clear barrier when observed by a conspecific than when caching in private. In Experiment 5, we further investigated the previous finding that jays preferentially cache a type of food that had been eaten to satiety by a conspecific over a food that had not been eaten by the conspecific. Experiments 3, 4 and 5 found no significant effects in the direction of the previously reported effects, questioning their robustness. We conclude by discussing the implications of our study for the field of corvid cognition and highlight several key issues that affect the reliability of comparative cognition research.

Lacking an external shell and a rigid endoskeleton, octopuses exhibit a remarkable flexibility in their movements. Bipedal locomotion is perhaps the most iconic example in this regard. Until recently, this peculiar mode of locomotion had been observed only in two species of tropical octopuses: Amphioctopus marginatus and Abdopus aculeatus. Yet, recent evidence indicates that bipedal walking is also part of the behavioral repertoire of the common octopus, Octopus vulgaris. Here we report a further observation of a defense behavior that encompasses both postural and locomotory elements of bipedal locomotion in this cephalopod. By highlighting differences and similarities with the other recently published report, we provide preliminary considerations with regard to bipedal locomotion in the common octopus., Here we report a further observation of a defense behavior that encompasses both postural and locomotory elements of bipedal locomotion in Octopus vulgaris. Our observation complements previous reports by showing that O. vulgaris can flexibly incorporate postural and locomotory components of bipedal walking amid heterogeneous displacement sequences.

Hepatic encephalopathy (HE) is a form of brain dysfunction that is specifically caused by liver insufficiency and/or portal-systemic shunt. The exact nature of HE is debated, so that conflicting uses of the term HE may cause inconsistencies in its detection and, in turn, issues with its management. This review highlights the meaning of the term HE on the basis of both its historical origins and current consensus. It also provides criteria for the diagnosis of the condition, on the basis of its phenotypes and the risk factors for its occurrence. The procedure for differential diagnosis from other conditions which result in similar phenotypes is considered, together with precipitants and confounders. Finally, the current multidimensional approach for the correct clinical recording of HE episodes is discussed.

Previous research reported that corvids preferentially cache food in a location where no food will be available or cache more of a specific food in a location where this food will not be available. Here, we consider possible explanations for these prospective caching behaviours and directly compare two competing hypotheses. The Compensatory Caching Hypothesis suggests that birds learn to cache more of a particular food in places where that food was less frequently available in the past. In contrast, the Future Planning Hypothesis suggests that birds recall what-when-where features of specific past events to predict the future availability of food. We designed a protocol in which the two hypotheses predict different caching patterns across different caching locations such that the two explanations can be disambiguated. We formalised the hypotheses in a Bayesian model comparison and tested this protocol in two experiments with one of the previously tested species, namely Eurasian jays. Consistently across the two experiments, the observed caching pattern did not support either hypothesis; rather it was best explained by a uniform distribution of caches over the different caching locations. Future research is needed to gain more insight into the cognitive mechanism underpinning corvids’ caching for the future.

Background Spontaneous portosystemic shunts (SPSS) are common in cirrhosis. Their characterization and clinical implications remain unclear. Aims To devise a system of assessment of these shunts, and assess their clinical implications METHODS: We retrospectively studied patients with cirrhosis who underwent imaging in a liver transplant program. A novel index was computed to assess total SPSS -the diameter of a circle having an area equivalent to the sum of the areas of all the existing shunts. This 'SPSS equivalent diameter' was compared with the clinical variables. Results Among 127 patients, 70% (CI95% 62-77) had SPSS, and 57% (CI95% 62-77) had multiple SPSS. The risk for SPSS was related to the severity of cirrhosis (Child-Pugh B/C vs. A: OR 2.4 CI95% 1.1-5.4) and alcoholic aetiology (OR 2.9 CI95% 1.2-7.1). The SPSS equivalent diameter was related to a history of HE, cognitive impairment (EEG/PHES) and ammonia(p 19.5 mm was a predictor of large SPSS (AUC 0.77, CI95%:0.68-0.87, p ≤ 0.001). Conclusions The SPSS equivalent diameter, a comprehensive assessment of portosystemic shunting, was associated with severity of liver disease, hyperammonemia, and cognitive dysfunction. The diameter of the inferior vena cava was a good predictor of SPSS.

Hepatic encephalopathy (HE) is a frequent and serious complication of both chronic liver disease and acute liver failure. HE manifests as a wide spectrum of neuropsychiatric abnormalities, from subclinical changes (mild cognitive impairment) to marked disorientation, confusion and coma. The clinical and economic burden of HE is considerable, and it contributes greatly to impaired quality of life, morbidity and mortality. This review will critically discuss the latest classification of HE, as well as the pathogenesis and pathophysiological pathways underlying the neurological decline in patients with end-stage liver disease. In addition, management strategies, diagnostic approaches, currently available therapeutic options and novel treatment strategies are discussed.

Intelligence in large-brained vertebrates might have evolved through independent, yet similar processes based on comparable socioecological pressures and slow life histories. This convergent evolutionary route, however, cannot explain why cephalopods developed large brains and flexible behavioural repertoires: cephalopods have fast life histories and live in simple social environments. Here, we suggest that the loss of the external shell in cephalopods (i) caused a dramatic increase in predatory pressure, which in turn prevented the emergence of slow life histories, and (ii) allowed the exploitation of novel challenging niches, thus favouring the emergence of intelligence. By highlighting convergent and divergent aspects between cephalopods and large-brained vertebrates we illustrate how the evolution of intelligence might not be constrained to a single evolutionary route.

Working memory (WM) is a limited capacity cognitive system that temporarily holds information for processing. In the present study, we tested the effect of age, gender and cognitive reserve in terms of educational level, working and leisure time activities on an active visuospatial WM task. One-hundred thirty-four participants between 20 and 80 years old performed an n-back task with different degree of WM demanding. Reaction times (RTs) became slower and accuracy decreased with age; the former started to decline in participants that were 35 years old, the latter in participants that were 57 years old. Males were faster than females. Educational level (10 years in accuracy and 15 years in RTs) showed a positive effect on accuracy and RTs. Cognitive reserve had a positive effect on accuracy but no effect on RTs. In conclusion, age-related decline influenced earlier the speed and later the accuracy in a task that required active processes. While male was faster independently of WM demanding and age, middle school degree and an average cognitive reserve prevent errors during performance. Coherently, high school degree prevents slowing down but only in low demanding condition.

Although there have been suggestions that altered cognitive control and food reward sensitivity contribute to overeating in obese individuals, neurophysiological correlates of these mechanisms have been poorly investigated. The current study investigated event-related potentials (ERP) in 24 severely obese and 26 normal weight individuals in fasting condition, using a novel Simon task with food and object distractors. The study showed that conflict in the Simon task for the food distractor increased with hunger in both groups but was larger with respect to a neutral condition only in the obese individuals. ERP showed higher N1amplitudes in both groups for food distractor, reflecting early food processing. The P2 latency was delayed and the effect of distractors on N2 amplitude was smaller in the obese subjects, reflecting altered neural mechanisms associated with selective attention and cognitive control, all contributing hypothetically to delay response selection of these individuals faced with food distractor.

Eurasian jays (Garrulus glandarius) do not habitually use tools, yet they can be trained to solve object-dropping tasks, i.e. to insert a tool into an apparatus to release a food reward. Previous research suggests the these jays can learn a preference toward functional tools – objects allowing to obtain a food reward placed inside an apparatus – according to their density (Cheke et al., 2011). However, it is not yet known whether they can also select functional tools (tool selectivity) according to other physical properties such as size and shape, and use different kinds of tools to solve a similar task. Here we conducted three object-dropping experiments aimed at exploring these abilities in Eurasian jays. In Experiment 1, jays tended to select large stones as tools irrespective of the diameter of the apparatus. However, jays progressively developed a preference for the small tool, which was functional with both the wide and the narrow apparatuses. In Experiment 2, only vertically-oriented long stones could fit into the narrow apparatus, whereas both long and round stones were functional with the wide apparatus. Jays showed a preference for the long stone and, with the narrow apparatus, tended to achieve the correct manipulation after one or more unsuccessful attempts. In Experiment 3, jays were able to use sticks and adopt a novel technique on the same object-dropping apparatus, thus providing the first evidence that Eurasian jays can use sticks as tools. Taken together, these results indicate that Eurasian jays may have limited tool selectivity abilities but nonetheless can use different kinds of tools to solve similar tasks.

In a recent study with potential wide-reaching influence, (Edsinger and Dölen, 2018) tested, for the first time, the effect of 3, 4- methylendioxymethamphetamine (MDMA) in the cephalopod mollusk Octopus bimaculoides. In their main experiment (Experiment 2), the authors placed octopuses in the central compartment of a three- chambered arena and allowed them to freely explore the lateral chambers, one containing an object and the other containing a social stimulus (a familiar male conspecific), both isolated through a perforated plastic container. All subjects first received a pre-trial to establish a baseline for the social response toward the conspecific, and following the administration of MDMA, they were given a post-trial with the same individual. According to the authors, the results demonstrate that MDMA induces both quantitative (i.e., longer intervals spent in the social stimulus chamber) and qualitative (i.e., different behaviors) acute prosocial responses in octopus. Here we highlight fundamental flaws in the study, thus challenging the authors' conclusions.

In a recent review [1], we discussed the evolution of cephalopods with a focus on the process that may have triggered the emergence of large brains and behavioural flexibility in coleoids (octopuses, cuttlefish, and squid). We suggested that the internalization or loss of the protective shell allowed the ancestors of coleoids to colonize a wide array of new environmental niches, thereby exposing them to increased predatory pressures and fostering complex foraging strategies. These novel ecological challenges may have in turn played a key role in driving intelligence in coleoids. In their commentary, Mollo et al. question our hypothesis by arguing that coleoids must have evolved intelligence prior to losing their shell, because the opposite sequence of adaptations would have resulted in the extinction of these soft-bodied animals. According to the authors, our hypothesis might only be valid if intelligence is assumed to have evolved as a dramatic mutation across one-generation, which is not a reasonable assumption. Here we highlight that our hypothesis does not hinge on the abrupt evolution of intelligence in cephalopods, and that it concurs with some of Mollo and colleagues’ views. However, we disagree with the authors’ arguments that i) coleoid ancestors developed intelligence prior to losing their shell, and ii) the evolution of alternative defence mechanisms must precede the disappearance of the shell in molluscs.

To date urinary metabolic profiling has been applied to define a specific metabolic fingerprint of hepatocellular carcinoma on a background of cirrhosis. Its utility for the stratification of other complications of cirrhosis, such as hepatic encephalopathy (HE), remains to be established. Urinary proton nuclear magnetic resonance (1H-NMR) spectra were acquired and NMR data from 52 patients with cirrhosis (35 male; 17 female, median (range) age [60 (18–81) years]) and 17 controls were compared. A sub-set of 45 patients (33 male; 12 female, [60 (18–90) years, median model for end stage liver disease (MELD) score 11 (7–27)]) were fully characterised by West-Haven criteria, Psychometric Hepatic Encephalopathy Score (PHES) and electroencephalogram (EEG), and defined as overt HE (OHE, n = 21), covert HE (cHE, n = 7) or no HE (n = 17). Urinary proton nuclear magnetic resonance (1H-NMR) spectra were analysed by partial-least-squares discriminant analysis (PLS-DA). The results showed good discrimination between patients with cirrhosis (n = 52) and healthy controls (n = 17) (R2X = 0.66, R2Y = 0.47, Q2Y = 0.31, sensitivity-60 %, specificity-100 %) as the cirrhosis group had higher 1-methylnicotinamide with lower hippurate, acetate, phenylacetylglycine and N-methyl nicotinic acid levels. While patients with OHE could be discriminated from those with no HE, with higher histidine, citrate and creatinine levels, the best models lack robust validity (R2X = 0.65, R2Y = 0.48, Q2Y = 0.12, sensitivity-100 %, specificity-64 %) with the sample size used. Urinary 1H-NMR metabolic profiling did not discriminate patients with cHE from those without HE, nor discriminate subjects on the basis of PHES/EEG result or MELD score. In conclusion, patients with cirrhosis showed different urinary 1H-NMR metabolic profiles compared to healthy controls and those with OHE may be distinguished from those with no HE although larger studies are required. However, urinary 1H-NMR metabolic profiling did not discriminate patients with differing grades of HE or according to severity of underlying liver disease.

Electroencephalography (EEG) is useful to objectively diagnose/grade hepatic encephalopathy (HE) across its spectrum of severity. However, it requires expensive equipment, and hepatogastroenterologists are generally unfamiliar with its acquisition/interpretation. Recent technological advances have led to the development of low-cost, user-friendly EEG systems, allowing EEG acquisition also in settings with limited neurophysiological experience. The aim of this study was to assess the relationship between EEG parameters obtained from a standard-EEG system and from a commercial, low-cost wireless headset (light-EEG) in patients with cirrhosis and varying degrees of HE. Seventy-two patients (58 males, 61 ± 9 years) underwent clinical evaluation, the Psychometric Hepatic Encephalopathy Score (PHES), and EEG recording with both systems. Automated EEG parameters were calculated on two derivations. Strong correlations were observed between automated parameters obtained from the two EEG systems. Bland and Altman analysis indicated that the two systems provided comparable automated parameters, and agreement between classifications (normal versus abnormal EEG) based on standard-EEG and light-EEG was good (0.6 < κ < 0.8). Automated parameters such as the mean dominant frequency obtained from the light-EEG correlated significantly with the Model for End-Stage Liver Disease score (r = −0.39, P < 0.05), fasting venous ammonia levels (r = −0.41, P < 0.01), and PHES (r = −0.49, P < 0.001). Finally, significant differences in light-EEG parameters were observed in patients with varying degrees of HE. Conclusion: Reliable EEG parameters for HE diagnosing/grading can be obtained from a cheap, commercial, wireless headset; this may lead to more widespread use of this patient-independent tool both in routine liver practice and in the research setting. (Hepatology 2016;63:1651-1659)

Classification of cirrhosis based on clinical stages is rapid and based on five stages at present. Two other relevant events, hepatic encephalopathy (HE) and spontaneous bacterial peritonitis (SBP), can be considered in a clinical perspective but no study has implemented a seven-stage classification and confirmed its value before. In addition, long-term validation of the Model for End-Stage Liver Disease (MELD) in large cohorts of patients with cirrhosis and comparison with clinical findings are insufficient. Therefore, we performed a study to address these items. From the Chang-Gung Research Database (CGRD), 20,782 patients with cirrhosis were enrolled for an historical survival study. The MELD score, the five-stage clinical score (i.e., occurrence of esophageal varices (EV), EV bleeding, ascites, sepsis) and a novel seven-stage clinical score (i.e., occurrence of EV, EV bleeding, ascites, sepsis, HE, SBP) were compared with their Cox models by receiver operating characteristic (ROC) analysis. The addition of HE and SBP to the seven-stage model had a 5% better prediction result than the five-stage model did in the survival ROC analysis. The result showed that the seven clinical stages are associated with an increased risk for mortality. However, the predicted performances of the seven-stage model and MELD system are likely equivalent. In conclusion, the study (i) proved that clinical staging of cirrhosis based on seven items/stages had higher prognostic value than the five-stage model and (ii) confirmed the validity of the MELD criteria vs. clinical assessment.

Background & Aims Hepatic encephalopathy (HE) is a syndrome of decreased vigilance and has been associated with impaired driving ability. The aim of this study was to evaluate the psychomotor vigilance task (PVT), which is used to assess both vigilance and driving ability, in a group of patients with cirrhosis and varying degrees of HE. Methods A total of 145 patients (120 males, 59 ± 10 years, model for end-stage liver disease [MELD] score 13 ± 5) underwent the PVT; a subgroup of 117 completed a driving questionnaire and a subgroup of 106 underwent the psychometric hepatic encephalopathy score (PHES) and an electroencephalogram (EEG), based on which, plus a clinical evaluation, they were classed as being unimpaired (n = 51), or as having minimal (n = 35), or mild overt HE (n = 20). All patients were followed up for an average of 13 ± 5 months in relation to the occurrence of accidents and/or traffic offences, HE-related hospitalisations and death. Sixty-six healthy volunteers evenly distributed by sex, age and education served as a reference cohort for the PVT. Results Patients showed worse PVT performance compared with healthy volunteers, and PVT indices significantly correlated with MELD, ammonia levels, PHES and the EEG results. Significant associations were observed between neuropsychiatric performance/PVT indices and licence/driving status. PVT, PHES and EEG results all predicted HE-related hospitalisations and/or death over the follow-up period; none predicted accidents or traffic offences. However, individuals with the slowest reaction times and most lapses on the PVT were often not driving despite having a licence. When patients who had stopped driving for HE-related reasons (n = 6) were modelled as having an accident or fine over the subsequent 6 and 12 months, PVT was a predictor of accidents and traffic offences, even after correction for MELD and age. Conclusions The PVT is worthy of further study for the purposes of both HE and driving ability assessment. Lay summary Hepatic encephalopathy (HE) is a complication of advanced liver disease that can manifest as excessive sleepiness. Some patients with HE have been shown to have difficulty driving. Herein, we used a test called the Psychomotor Vigilance Task (PVT), which measures sleepiness and can also be used to assess driving competence. We showed that PVT performance is fairly stable in healthy individuals. We also showed that PVT performance parallels performance in tests which are commonly used in cirrhotic patients to measure HE. We suggest that this test is helpful in quantifying HE and identifying dangerous drivers among patients with cirrhosis.

Mather’s (2019) provocative claim that octopuses have a mind hinges on the inference that their striking behavioural flexibility is evidence of “complex” cognitive abilities. I discuss alternative explanations -- not to deny the possibility of complexity but to point out that current evidence does not allow us to draw firm conclusions. Only an agnostic approach will lead to the systematic investigation of octopus behaviour and ultimately, greater insights into the cognitive capacities of these fascinating creatures.

BACKGROUND & AIMS Learning ability may be impaired in patients with a history of overt hepatic encephalopathy (OHE). The aim of this study was to compare performance on the first/second attempt at a series of tests. METHODS Two hundred and fourteen patients with cirrhosis were enrolled. On the day of study, 41% were classed as unimpaired, 38% as having minimal HE and 21% as having mild OHE; 58% had a history of OHE. Performance was compared between two versions of the trail-making test A (TMT-A), and between the first/second half of a simple/choice reaction time (sRT and cRT), and a working memory test (ScanRT). RESULTS Both patients with and without OHE history improved in TMT-A, sRT and ScanRT. Only patients with no OHE history improved in cRT. All patients, regardless of their HE status on the day of study, improved in TMT-A and sRT. Only patients with mild OHE on the day of study improved in cRT. Only unimpaired patients improved in ScanRT. When OHE history and HE status on the day of study were tested together, only HE status had an effect. The same held true when age, the Model for End Stage Liver Disease (MELD) and educational attainment were adjusted for. CONCLUSIONS HE status on the day of study and the type of neuropsychological test had an effect on learning ability in a well-characterized group of patients with cirrhosis.

Hepatic encephalopathy is a brain dysfunction caused by liver insufficiency and/or portal-systemic shunt; it manifests as a wide spectrum of neurological or psychiatric abnormalities ranging from subclinical alterations to coma. It should be differentiated from other neurological/psychiatric disorders that can occur in patients with liver disease. Its classification needs to take into account the underlying condition, severity, course, precipitating factors, and—possibly—sensitivity to ammonia-lowering agents.

Background Liver cirrhosis is associated with reduced heart rate variability (HRV), which indicates impaired integrity of cardiovascular control in this patient population. There are several different indices for HRV quantification. The present study was designed to: 1) determine which of the HRV indices is best at predicting mortality in patients with cirrhosis; 2) verify if such ability to predict mortality is independent of the severity of hepatic failure. Methods Ten minutes electrocardiogram was recorded in 74 patients with cirrhosis. Heart rate fluctuations were quantified using statistical, geometrical and non-linear analysis. The patients were followed-up for 18 months and information was collected on the occurrence of death/liver transplantation. Results During the follow-up period, 24 patients (32%) died or were transplanted for hepatic decompensation. Cox’s regression analysis showed that SDNN (total HRV), cSDNN (corrected SDNN), SD1 (short-term HRV), SD2 (long-terms HRV) and spectral indices could predict survival in these patients. However, only SD2 and cSDNN were shown to be independent of MELD in predicting survival. The prognostic value of HRV indices was independent of age, gender, use of beta blockers, and the aetiology of liver disease. Conclusion Two HRV indices were identified that could predict mortality in patients with cirrhosis, independently of MELD. These indices are potentially useful tools for survival prediction.

Background & Aims Overt hepatic encephalopathy (HE) affects patients' quantity and quality of life and places a burden on families. There is evidence that overt HE might be prevented pharmacologically, but prophylaxis would be justified and cost effective only for patients at risk. We aimed to identify patients with cirrhosis at risk for overt HE. Methods We collected data from October 2009 through December 2012 for 216 consecutive patients with cirrhosis (based on liver biopsy, 96 patients with minimal HE), admitted to the Gastroenterology Unit at the University of Rome. Patients were followed up and evaluated for an average of 14.7 ± 11.6 months; development of overt HE was recorded. We analyzed end-stage liver disease scores, shunt placement, previous overt or minimal HE, psychometric hepatic encephalopathy score (PHES), and levels of albumin, bilirubin, creatinine, and sodium to develop a prediction model. We validated the model in 112 patients with cirrhosis seen at the University of Padua and followed up for 12 ± 9.5 months. Results During the follow-up period, 68 patients (32%) developed at least 1 episode of overt HE. Based on multivariate analysis, the development of overt HE was associated with previous HE, minimal HE (based on PHES), and level of albumin less than 3.5 g/dL (area under curve [AUC], 0.74). A model that excluded minimal HE but included albumin level and previous HE also identified patients who would develop overt HE (AUC, 0.71); this difference in AUC values was not statistically significant ( P = .104). Both models were validated in the independent group of patients (3 variables: AUC, 0.74; 95% confidence interval, 0.66–0.83; and 2 variables: AUC, 0.71; 95% confidence interval, 0.63–0.78). Conclusions We developed and validated a model to identify patients with cirrhosis at risk for overt HE based on previous HE, albumin levels, and PHES. If PHES was not available, previous HE and albumin levels still can identify patients at risk. Psychometric evaluation is essential for patients with no history of HE. These findings should aid in planning studies of pharmacologic prevention of overt HE.

Sleep-wake abnormalities in patients with cirrhosis have been traditionally associated with hepatic encephalopathy (HE). In recent years, a certain amount of work has been devoted to the study of this relationship. This has lead to a modified picture, with weakening of the association between HE and poor night sleep, and the emergence of stronger links between HE and excessive daytime sleepiness. This brief review focuses on the evidence in favor of the interpretation of HE as a sleepiness syndrome, and on the diagnostic, therapeutic and social implications of such an interpretation.

Hepatic encephalopathy (HE) is a debilitating neuropsychiatric condition often associated with acute liver failure or cirrhosis. Advanced liver diseases are characterized by a leaky gut and systemic inflammation. There is strong evidence that the pathogenesis of HE is linked to a dysbiotic gut microbiota and to harmful microbial by-products, such as ammonia, indoles, oxindoles and endotoxins. Increased concentrations of these toxic metabolites together with the inability of the diseased liver to clear such products is thought to play an important patho-ethiological role. Current first line clinical treatments target microbiota dysbiosis by decreasing the counts of pathogenic bacteria, blood endotoxemia and ammonia levels. This review will focus on the role of the gut microbiota and its metabolism in HE and advanced cirrhosis. It will critically assess data from different clinical trials measuring the efficacy of the prebiotic lactulose, the probiotic VSL#3 and the antibiotic rifaximin in treating HE and advanced cirrhosis, through gut microbiota modulation. Additionally data from Randomised Controlled Trials using pre-, pro- and synbiotic will be also considered by reporting meta-analysis studies. The large amount of existing data showed that HE is a clear example of how an altered gut microbiota homeostasis can influence and impact on physiological functions outside the intestine, with implication for host health at the systems level. Nevertheless, a strong effort should be made to increase the information on gut microbiota ecology and its metabolic function in liver diseases and HE.

Hepatic encephalopathy (HE) is a peculiar kind of brain dysfunction caused by liver insufficiency and/or portal-systemic shunting. It is related to gut-derived substances. It is a relevant cause of morbidity and hospitalisation for patients with cirrhosis. The prognosis of HE is important in terms of survival and re-hospitalisation. It is related to impaired quality of life, falls and poor driving; presents a relevant burden for caregivers and health services; and may negatively impact on patient's job and income. Proper diagnosis and classification are expected to improve HE management. Once diagnosed, the management and therapeutic options for HE are generally clear. The improvement of knowledge in recent years has also clarified which are the further aims of research in this field of medicine. Prophylaxis of overt HE should always be performed, and this is generally secondary prophylaxis. Primary prophylaxis should be done immediately after upper gastrointestinal bleeding. Great advances in the detection and treatment of mild forms of HE are expected to lead to further improvement in patient management.

To detect whether adults with type 1 diabetes mellitus (T1DM) have lower cognitive performance than healthy individuals and to detect risk factors for low cognitive performance.Twenty-six adults with T1DM and twenty-six healthy subjects matched for age, gender and educational level were compared for cognitive performance by a chronometric computerized test measuring visuo-spatial working memory (N-Back) and by two validated neuropsychological tests (Mini Mental State Examination, Animal Naming Test). Clinical data about diabetes duration, average daily insulin dosage, glycated haemoglobin, retinopathy, urine albumin-creatinine ratio, previous hypoglycaemic coma and awareness of hypoglycaemia were obtained from medical records. Basal pre-test glycemia and blood pressure were measured for each patient.No differences were found between patients (n = 26) and healthy controls (n = 26) in neuropsychological tests. Within diabetic patients, those with impaired awareness of hypoglycaemia (n = 7) or history of coma in the recent 1-3 years (n = 5) had psychomotor slowing at the N-Back test (592 ± 35 vs. 452 ± 21 ms and 619 ± 40 vs. 462 ± 19 ms, respectively; both p 0.01). The variables related to diabetic severity did not show a relationship with reaction times of the N-Back test.Psychomotor speed slowing is detectable in patients with T1DM who have a history of previous hypoglycaemic episodes or coma.