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Rationale: Patients with obsessive-compulsive disorder (OCD) have been found to show exaggerated error responses and prediction error learning signals in a variety of EEG and fMRI tasks, with data converging on the anterior cingulate cortex as a key locus of dysfunction. Considerable evidence has linked prediction error processing to dopaminergic function., Objective: In this study, we investigate potential dopaminergic dysfunction during reward processing in the context of OCD., Methods: We studied OCD patients (n = 18) and controls (n = 18) whilst they learned probabilistic associations between abstract stimuli and monetary rewards in the fMRI scanner involving administration (on separate visits) of a dopamine receptor agonist, pramipexole 0.5 mg; a dopamine receptor antagonist, amisulpride 400 mg; and placebo. We fitted a Q-learning computational model to fMRI prediction error responses; group differences were examined in anterior cingulate and nucleus accumbens regions of interest., Results: There were no significant group, drug, or interaction effects in the number of correct choices; computational modeling suggested a marginally significant difference in learning rates between groups (p = 0.089, partial ƞ 2  = 0.1). In the imaging results, there was a significant interaction of group by drug (p = 0.013, partial ƞ 2  = 0.13). OCD patients showed abnormally strong cingulate signaling of prediction errors during omission of an expected reward, with unexpected reduction by both pramipexole and amisulpride (p = 0.014, partial ƞ 2  = 0.26, 1-β error probability = 0.94). Exaggerated cingulate prediction error signaling to omitted reward in placebo was related to trait subjective difficulty in self-regulating behavior in OCD., Conclusions: Our data support cingulate dysfunction during reward processing in OCD, and bidirectional remediation by dopaminergic modulation, suggesting that exaggerated cingulate error signals in OCD may be of dopaminergic origin. The results help to illuminate the mechanisms through which dopamine receptor antagonists achieve therapeutic benefit in OCD. Further research is needed to disentangle the different functions of dopamine receptor agonists and antagonists during bidirectional modulation of cingulate activation.

There are reasons for thinking that obsessive-compulsive disorder (OCD) and drug dependence, although conventionally distinct diagnostic categories, might share important cognitive and neurobiological substrates. We tested this hypothesis directly by comparing brain functional connectivity measures between patients with OCD, stimulant dependent individuals (SDIs; many of whom were non-dependent users of other recreational drugs) and healthy volunteers. We measured functional connectivity between each possible pair of 506 brain regional functional MRI time series representing low frequency (0.03-0.06 Hz) spontaneous brain hemodynamics in healthy volunteers (N=18), patients with OCD (N=18) and SDIs (N=18). We used permutation tests to identify i) brain regions where strength of connectivity was significantly different in both patient groups compared to healthy volunteers; and ii) brain regions and connections which had significantly different functional connectivity between patient groups. We found that functional connectivity of right inferior and superior orbitofrontal cortex (OFC) was abnormally reduced in both disorders. Whether diagnosed as OCD or SDI, patients with higher scores on measures of compulsive symptom severity showed greater reductions of right orbitofrontal connectivity. Functional connections specifically between OFC and dorsal medial pre-motor and cingulate cortex were attenuated in both patient groups. However, patients with OCD demonstrated more severe and extensive reductions of functional connectivity compared to SDIs. OCD and stimulant dependence are not identical at the level of brain functional systems but they have some important abnormalities in common compared with healthy volunteers. Orbitofrontal connectivity may serve as a human brain systems biomarker for compulsivity across diagnostic categories., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Compulsivity is a hallmark of drug addiction and in animal models is measured by consecutive incorrect responses to a previously rewarded stimulus during reversal learning. The aim of this study was to measure behavioral and neural markers of compulsivity in stimulant-dependent individuals and to test whether these markers could be modulated by treatment with drugs targeting the dopamine system., Methods: In a randomized, double-blind, placebo-controlled, crossover design, stimulant-dependent individuals (SDIs; n = 18) and healthy volunteers (n = 18) received single doses of dopamine D(2/3) receptor antagonist (amisulpride, 400 mg) and agonist (pramipexole, 0.5 mg) drugs. To examine compulsivity and its dopaminergic modulation more generally, patients with obsessive-compulsive disorder (OCD; n = 18) were also included in the study., Results: SDIs made significantly more perseverative responses to the previously correct stimulus immediately following reversal, compared with both healthy volunteers and patients with OCD. Across all participants, the number of perseverative errors was negatively correlated with functional activation in right fronto-striato-parietal networks-in particular, the right caudate nucleus. In SDIs, perseveration-related caudate activation was abnormally reduced in the placebo condition, but the dopamine D(2/3) agonist pramipexole normalized both perseverative responding and related activation of the right caudate., Conclusions: Perseveration during reversal learning was associated specifically with stimulant dependence rather than with compulsive behaviors more generally. The beneficial effects of a dopamine agonist drug challenge on both behavior and associated brain activation in SDIs may indicate new avenues for pharmacologic treatment in stimulant dependence., (Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.)

Context: There are no effective pharmacotherapies for stimulant dependence but there are many plausible targets for development of novel therapeutics. We hypothesized that dopamine-related targets are relevant for treatment of stimulant dependence, and there will likely be individual differences in response to dopaminergic challenges., Objective: To measure behavioral and brain functional markers of drug-related attentional bias in stimulant-dependent individuals studied repeatedly after short-term dosing with dopamine D(2)/D(3) receptor antagonist and agonist challenges., Design: Randomized, double-blind, placebo-controlled, parallel-groups, crossover design using pharmacological functional magnetic resonance imaging., Setting: Clinical research unit (GlaxoSmithKline) and local community in Cambridge, England., Participants: Stimulant-dependent individuals (n = 18) and healthy volunteers (n = 18)., Interventions: Amisulpride (400 mg), pramipexole dihydrochloride (0.5 mg), or placebo were administered in counterbalanced order at each of 3 repeated testing sessions., Main Outcome Measures: Attentional bias for stimulant-related words was measured during functional magnetic resonance imaging by a drug-word Stroop paradigm; trait impulsivity and compulsivity of dependence were assessed at baseline by questionnaire., Results: Drug users demonstrated significant attentional bias for drug-related words, which was correlated with greater activation of the left prefrontal and right cerebellar cortex. Attentional bias was greater in people with highly compulsive patterns of stimulant abuse; the effects of dopaminergic challenges on attentional interference and related frontocerebellar activation were different between high- and low-compulsivity subgroups., Conclusions: Greater attentional bias for and greater prefrontal activation by stimulant-related words constitute a candidate neurocognitive marker for dependence. Individual differences in compulsivity of stimulant dependence had significant effects on attentional bias, its brain functional representation, and its short-term modulation by dopaminergic challenges.

Hepatic encephalopathy (HE) constitutes a neuropsychiatric syndrome which remains a major clinical problem in patients with cirrhosis. In the severest form of HE, cirrhotic patients may develop varying degrees of confusion and coma. Ammonia has been regarded as the key precipitating factor in HE, and astrocytes have been the most commonly affected cells neuropathologically. Although the evidence base supporting a pivotal role of ammonia is robust, in everyday clinical practice a consistent correlation between the concentration of ammonia in the blood and the manifest symptoms of HE is not observed. More recently the synergistic role of inflammation and infection in modulating the cerebral effects of ammonia has been shown to be important. Furthermore, it has been recognized that infection impairs brain function both in the presence and absence of liver disease. Thus it could be postulated that in the presence of ammonia, the brain is sensitized to a systemic inflammatory stimulus and is able to elicit an inflammatory response involving both proinflammatory and neurotransmitter pathways. Ammonia is not only directly toxic to astrocytes but induces neutrophil dysfunction with the release of reactive oxygen species, which contribute to oxidative stress and systemic inflammation. This may further exacerbate the cerebral effects of ammonia and potentially reduce the capacity of the neutrophil to fight microbial attack, thus inducing a vicious circle. This evidence supports the neutrophil in addition to ammonia as being culpable in the pathogenesis of HE, making the neutrophil a target for future anti-inflammatory therapeutic strategies in addition to ammonia lowering therapies.

Optimisation of a series of oxazole diketopiperazines has led to the discovery of a very potent and selective oxytocin antagonist GSK221149A. GSK221149A has been shown to inhibit oxytocin-induced uterine contractions in the anaesthetised rat.

A short, efficient, and highly stereoselective synthesis of a series of (3R,6R,7R)-2,5-diketopiperazine oxytocin antagonists and their pharmacokinetics in rat and dog is described. Prediction of the estimated human oral absorption (EHOA) using measured lipophilicity (CHI log D) and calculated size (cMR) has allowed us to rank various 2,5-diketopiperazine templates and enabled us to focus effort on those templates with the greatest chance of high bioavailability in humans. This rapidly led to the 2',4'-difluorophenyl-dimethylamide 25 and the benzofuran 4 with high levels of potency (pK(i)) and good bioavailability in the rat and dog. Dimethylamide 25 is more potent (>20-fold) than 4 in vivo and has a high degree of selectivity toward the vasopressin receptors, >10,000 for hV1a/hV1b and approximately 500 for hV2. It has a good Cyp450 profile with no time dependent inhibition and was negative in the genotoxicity screens with a satisfactory oral safety profile in rats.

A short stereoselective synthesis of a series of chiral 7-aryl-2,5-diketopiperazines oxytocin antagonists is described. Varying the functionality and substitution pattern of substituents in the 7-aryl ring and varying the chirality of this exocyclic ring have produced potent oxytocin antagonists (pK(i) > 8.5). SAR and pharmacokinetic profiling of this series of (3R,6R,7R)-2,5-diketopiperazines together with the introduction of an ortho F group in the 7-aryl ring to improve rat pK has culminated in the 2',4'-difluorophenyldiketopiperazine derivative 37, a highly potent oxytocin antagonist against the human oxytocin receptor (pK(i) = 8.9) that has >1000-fold selectivity over all three vasopressin receptors V1a, V2, and V1b. It has good bioavailability (46%) in the rat and moderate bioavailability (13-31%) in the dog and is more active in vivo in the rat than atosiban (rat DR(10) = 0.44 mg/kg iv).

Individuals with substance use disorder (SUD) tend to have attention bias to drug and negative emotions, which leads to drug craving and relapse. This study examines attentional bias from the time dimension, and adopts the rapid sequence visual presentation (RSVP) paradigm to study the attentional blink effect of individuals with SUD towards different types of negative words. A total of 55 males with SUD were recruited from a compulsory drug rehabilitation center in Jiangxi Province. The results indicated that the following: (1) The accuracy of T2 recognition when T1 was correctly recognized (T2|T1) increased with the increase of the time interval, indicating that the attentional blink was successfully induced. (2) When T1 was addictive vocabulary, compared with the neutral vocabulary, the attentional blink effect of males with SUD was enhanced. When T2 was negative addiction vocabulary or negative vocabulary, compared with the neutral vocabulary, the attentional blink of males with SUD was weakened. The current research results not only find that males with SUD have an attention bias towards addiction clues from the time characteristics of the attention process, but also it is of great significance to guide the rehabilitation centers to improve the craving and relapse of males with SUD by reducing the appearance of negative addictive information. [ABSTRACT FROM AUTHOR]

In the last 20 years, functional magnetic resonance imaging (fMRI) has been extensively used to investigate system-level abnormalities in the brain of patients with obsessive-compulsive disorder (OCD). In this chapter, we start by reviewing the studies assessing regional brain differences between patients with OCD and healthy controls in task-based fMRI. Specifically, we review studies on executive functioning and emotional processing, protocols in which these patients have been described to show alterations at the behavioral level, as well as research using symptom provocation protocols. Next, we review studies on brain connectivity alterations, focusing on resting-state studies evaluating disruptions in fronto-subcortical functional connectivity and in cortical networks. Likewise, we also review research on effective connectivity, which, different from functional connectivity, allows for ascertaining the directionality of inter-regional connectivity alterations. We conclude by reviewing the most significant findings on a topic of translational impact, such as the use of different fMRI measurements to predict response across a variety of treatment approaches. Overall, results suggest that there exists a pattern of regions, involving, but not limited to, different nodes of the cortico-striatal-thalamo-cortical circuits, showing robust evidence of functional alteration across studies, although the nature of the alterations critically depends on the specific tasks and their particular demands. Moreover, such findings have been, to date, poorly translated into clinical practice. It is suggested that this may be partially accounted for by the difficulty to integrate into a common framework results obtained under a wide variety of analysis approaches., (© 2021. Springer Nature Switzerland AG.)

Cirrhosis is the common end-stage of chronic liver diseases of different etiology. The altered bile acids metabolism in the cirrhotic liver and the increase in the blood-brain barrier permeability, along with the progressive dysbiosis of intestinal microbiota, contribute to gut immunity changes, from compromised antimicrobial host defense to pro-inflammatory adaptive responses. In turn, these changes elicit a disruption in the epithelial and gut vascular barriers, promoting the increased access of potential pathogenic microbial antigens to portal circulation, further aggravating liver disease. After summarizing the key aspects of gut immunity during homeostasis, this review is intended to update the contribution of liver and brain metabolites in shaping the intestinal immune status and, in turn, to understand how the loss of homeostasis in the gutassociated lymphoid tissue, as present in cirrhosis, cooperates in the advanced chronic liver disease progression. Finally, several therapeutic approaches targeting the intestinal homeostasis in cirrhosis are discussed. [ABSTRACT FROM AUTHOR]

Obsessive-compulsive disorder (OCD) and pathological gambling (PG) are accompanied by deficits in behavioural flexibility. In reinforcement learning, this inflexibility can reflect asymmetric learning from outcomes above and below expectations. In alternative frameworks, it reflects perseveration independent of learning. Here, we examine evidence for asymmetric reward-learning in OCD and PG by leveraging model-based functional magnetic resonance imaging (fMRI). Compared with healthy controls (HC), OCD patients exhibited a lower learning rate for worse-than-expected outcomes, which was associated with the attenuated encoding of negative reward prediction errors in the dorsomedial prefrontal cortex and the dorsal striatum. PG patients showed higher and lower learning rates for better- and worse-than-expected outcomes, respectively, accompanied by higher encoding of positive reward prediction errors in the anterior insula than HC. Perseveration did not differ considerably between the patient groups and HC. These findings elucidate the neural computations of reward-learning that are altered in OCD and PG, providing a potential account of behavioural inflexibility in those mental disorders. A brain imaging study reveals that obsessive-compulsive disorder and problem gambling are associated with distinct patterns of learning from positive and negative reward prediction errors, providing a neurocomputational account of abnormal inflexible behaviors in those disorders. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is one of the major complications of liver disease and significantly affects the quality of life (QOL) of patients. HE is common and frequently relapses in cirrhotic patients. The management of HE is supportive, and precipitating conditions should be eliminated. Most drugs used to treat HE are conventional and include nonabsorbable disaccharides such as lactulose, and antibiotics such as rifaximin. However, their therapeutic efficacy is still suboptimal, and novel therapeutic agents are urgently needed. In addition, the optimal management and diagnosis of minimal HE/covert HE are under debate. In this review, we focus on novel pathogenetic mechanisms such as central nervous system clearance, and emerging therapeutic targets of HE, such as fecal material transplantation. We also discuss different classifications and etiologies of HE., Competing Interests: Conflicts of interest: Dr. Hui-Chun Huang, Dr. Ching-Chih Chang, Dr. Yi-Hsiang Huang, Dr. Ming-Chih Hou, and Dr. Fa-Yauh Lee, editorial board members at Journal of the Chinese Medical Association , have no roles in the peer review process of or decision to publish this article. The other authors declare that they have no conflicts of interest related to the subject matter or materials discussed in this article., (Copyright © 2023, the Chinese Medical Association.)

Dopaminergic mechanisms are a plausible treatment target for patients with clinical depression but are relatively underexplored in conventional antidepressant medications. There is continuing interest in the potential antidepressant effects of the dopamine receptor agonist, pramipexole, with data from both case series and controlled trials indicating that this agent may produce benefit for patients with difficult-to-treat depression. Pramipexole's therapeutic utility in depression is likely to be expressed through alterations in reward mechanisms which are strongly influenced by dopamine pathways and are known to function abnormally in depressed patients. Our work in healthy participants using brain imaging in conjunction with computational modelling suggests that repeated pramipexole facilitates reward learning by inhibiting value decay. This mechanism needs to be confirmed in larger clinical trials in depressed patients. Such studies will also allow assessment of whether baseline performance in reward learning in depression predicts therapeutic response to pramipexole treatment., (© 2023. The Author(s), under exclusive license to Springer Nature Switzerland AG.)

Liver fibrosis staging is a key element driving the prognosis of patients with chronic liver disease. Currently, biopsy is the only technique capable of diagnosing liver fibrosis in patients with alcohol‐related liver disease (ArLD) and nonalcoholic fatty liver disease (NAFLD) unequivocally. Noninvasive (e.g. plasma‐based) biomarker assays are attractive tools to diagnose and stage disease, yet must prove that they are reliable and sensitive to be used clinically. Here, we demonstrate proton nuclear magnetic resonance as a method to rapidly quantify the endogenous concentration of ammonium ions from human plasma extracts and show their ability to report upon early and advanced stages of ArLD and NAFLD. We show that, irrespective of the disease etiology, ammonium concentration is a more robust and informative marker of fibrosis stage than current clinically assessed blood hepatic biomarkers. Subject to validation in larger cohorts, the study indicates that the method can provide accurate and rapid staging of ArLD and NAFLD without the need for an invasive biopsy. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a challenging complication after transjugular intrahepatic portosystemic shunt (TIPS) placement. Despite recent advances, much is still uncertain regarding risk factors, preventative measures, and the management of HE after TIPS placement. Appropriate patient selection and pre-procedural risk stratification remain areas of focus. In this manuscript, we discuss the current state of research related to HE after TIPS placement, including information regarding risk stratification, complication prevention, and treatment options. [ABSTRACT FROM AUTHOR]

Purpose: To develop and assess machine learning (ML) models' ability to predict post-procedural hepatic encephalopathy (HE) following transjugular intrahepatic portosystemic shunt (TIPS) placement., Materials and Methods: In this retrospective study, 327 patients who underwent TIPS for hepatic cirrhosis between 2005 and 2019 were analyzed. Thirty features (8 clinical, 10 laboratory, 12 procedural) were collected, and HE development regardless of severity was recorded one month follow-up. Univariate statistical analysis was performed with numeric and categoric data, as appropriate. Feature selection is used with a sequential feature selection model with fivefold cross-validation (CV). Three ML models were developed using support vector machine (SVM), logistic regression (LR) and CatBoost, algorithms. Performances were evaluated with nested fivefold-CV technique., Results: Post-procedural HE was observed in 105 (32%) patients. Patients with variceal bleeding (p = 0.008) and high post-porto-systemic pressure gradient (p = 0.004) had a significantly increased likelihood of developing HE. Also, patients having only one indication of bleeding or ascites were significantly unlikely to develop HE as well as Budd-Chiari disease (p = 0.03). The feature selection algorithm selected 7 features. Accuracy ratios for the SVM, LR and CatBoost, models were 74%, 75%, and 73%, with area under the curve (AUC) values of 0.82, 0.83, and 0.83, respectively., Conclusion: ML models can aid identifying patients at risk of developing HE after TIPS placement, providing an additional tool for patient selection and management., (© 2023. Springer Science+Business Media, LLC, part of Springer Nature and the Cardiovascular and Interventional Radiological Society of Europe (CIRSE).)

Background: The occurrence of overt hepatic encephalopathy (OHE) is associated with increased mortality. HE is commonly precipitated by infection, but whether HE predisposes to new infection is unclear. This study aimed to test if OHE predisposes to de novo infection during hospitalisation and its association with short‐term mortality. Aims and Methods: Seven hundred and fifty‐nine consecutive patients were identified at two institutions from prospectively maintained clinical databases of cirrhotic patients admitted with acute decompensation (AD). Infection and HE data were collected on the day of admission, and the occurrence of de novo infections was assessed for 28 days after admission. EASL‐CLIF organ failure criteria were used to determine the presence of organ failures. Multivariable analysis using the logistic regression model was used to assess predictors of 28‐day mortality and de novo infection. Results: Patients were divided into four groups; no baseline OHE or infection (n = 352); OHE with no baseline Infection (n = 221); no OHE but baseline infection (n = 100) and OHE with baseline infection (n = 86). On multivariate analyses, OHE (OR, 1.532 [95% CI, 1.061–2.300, P = 0.024]), and admission to ITU (OR, 2.303 [95% CI, 1.508–3.517, P < 0.001]) were independent risk factors for de novo infection. 28‐day mortality was 25.3%, 60.2%, 55.0% and 72.1% in the 4‐groups respectively. Age, INR and creatinine were independently predictive of mortality. The presence of overt HE, infection, coagulation, kidney, circulatory, respiratory and liver failures were significantly associated with higher mortality. Conclusion: OHE is an independent risk factor for de novo infection in cirrhotic patients with AD. [ABSTRACT FROM AUTHOR]

Copyright of Summa, Animali da Compagnia is the property of Point Veterinaire Italie s.r.l. and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Background Drug-induced alterations to the dopamine system in stimulant use disorder (SUD) are hypothesized to impair reinforcement learning (RL). Computational modeling enables the investigation of the latent processes of RL in SUD patients, which could elucidate the nature of their impairments. Methods We investigated RL in 44 SUD patients and 41 healthy control participants using a probabilistic RL task that assesses learning from reward and punishment separately. In an independent sample, we determined the modulatory role of dopamine in RL following a single dose of the dopamine D2/3 receptor antagonist amisulpride (400 mg) and the agonist pramipexole (0.5 mg) in a randomised, double-blind, placebo-controlled, crossover design. We analyzed task performance using computational modelling and hypothesized that RL impairments in SUD patients would be differentially modulated by a dopamine D2/3 receptor antagonist and agonist. Results Computational analyses in both samples revealed significantly reduced learning rates from punishment in SUD patients compared with healthy controls, whilst their reward learning rates were not measurably impaired. In addition, the dopaminergic receptor agents modulated RL parameters differentially in both groups. Both amisulpride and pramipexole impaired RL parameters in healthy participants, but ameliorated learning from punishment in SUD patients. Conclusion Our findings suggest that RL impairments seen in SUD patients are associated with altered dopamine function. [ABSTRACT FROM AUTHOR]

Obsessive compulsive disorder (OCD) can manifest as a debilitating disease with high degrees of co-morbidity as well as clinical and etiological heterogenity. However, the underlying pathophysiology is not clearly understood. Computational psychiatry is an emerging field in which behavior and its neural correlates are quantitatively analyzed and computational models are developed to improve understanding of disorders by comparing model predictions to observations. The aim is to more precisely understand psychiatric illnesses. Such computational and theoretical approaches may also enable more personalized treatments. Yet, these methodological approaches are not self-evident for clinicians with a traditional medical background. In this mini-review, we summarize a selection of computational OCD models and computational analysis frameworks, while also considering the model predictions from a perspective of possible personalized treatment. The reviewed computational approaches used dynamical systems frameworks or machine learning methods for modeling, analyzing and classifying patient data. Bayesian interpretations of probability for model selection were also included. The computational dissection of the underlying pathology is expected to narrow the explanatory gap between the phenomenological nosology and the neuropathophysiological background of this heterogeneous disorder. It may also contribute to develop biologically grounded and more informed dimensional taxonomies of psychopathology. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a debilitating and life-threatening disease. Results from acute or chronic liver failure and is characterized by abnormal cerebral and neurological alterations. This study aimed at investigating the effect of allicin, the major functional component in freshly crushed garlic extract, on thioacetamide (TAA)-induced HE in rats. Induction of HE by a single dose of TAA (300 mg/kg; I.P.) was associated with a marked elevation in the serum levels of alanine aminotransferase, aspartate aminotransferase, bilirubin, albumin, total protein, blood urea nitrogen and serum ammonia besides reduction in the serum level of albumin. Moreover, it was accompanied with an increase in the hepatic and brain levels of inflammatory mediators; TNF-α and IL-1β as well as elevation of the hepatic and brain levels of oxidative stress biomarkers; reduced glutathione and lipid peroxidation evidenced by malondialdeyde. Oral administration of allicin (50, 100 and 200 mg/kg; P.O.) for 6 days prior to TAA injection restored the serum liver function, hepatic and brain levels of inflammatory mediators as well as oxidative stress biomarkers in a dose-dependent manner. From our results, it can be concluded that allicin has a protective effect on TAA-induced HE in rats in a dose-dependent manner due to its powerful antioxidant and anti-inflammatory properties. [ABSTRACT FROM AUTHOR]

Purpose: Hepatic encephalopathy (HE) is described as impaired brain function induced by liver failure. Ammonia is the most suspected chemical involved in brain injury during HE. Although the precise mechanism of HE is not clear, several studies mentioned the role of oxidative stress in ammonia neurotoxicity. In animal models, the use of some compounds with antioxidant properties was reported to reduce the neurotoxic effects of ammonia, improve energy metabolism, and ameliorate the HE symptoms. Citicoline is a principal intermediate in the biosynthesis pathway of phosphatidylcholine that acts as neurovascular protection and repair effects. Various studies mentioned the neuroprotective and antioxidative effects of citicoline in the central nervous system. This study aims to investigate the potential protective effects of citicoline therapeutic in an animal model of HE. Materials and Methods: Mice received acetaminophen (APAP,1g/kg, i. p.) and then treated with citicoline (500 mg/kg, i.p) one and two hours after APAP. Animals were monitored for locomotor activity and blood and brain ammonia levels. Moreover, markers of oxidative stress were assessed in the brain tissue. Results: The result of the study revealed that plasma and brain ammonia and the liver injury markers increased, and locomotor activity impaired in the APAP-treated animals. Besides, an increase in markers of oxidative stress was evident in the brain of the APAP-treated mice. It was found that citicoline supplementation enhanced the animal's locomotor activity and improved brain tissue markers of oxidative stress. Conclusion: These data propose citicoline as a potential protective agent in HE. The effects of citicoline on oxidative stress markers could play a fundamental role in its neuroprotective properties during HE. [ABSTRACT FROM AUTHOR]

Background and Purpose: In hepatic encephalopathy (HE), osmotic stressors promoting brain edema result in a compensatory drop in the astrocyte metabolite myo-inositol (mI). Identifying differences between nonalcoholic steatohepatitis (NASH) with and without HE and healthy controls using proton magnetic resonance spectroscopy (MRS) and evaluating hypoalbuminemia and hyperammonemia as osmotic stressors that predict the reduction of mI allow further understanding of mechanisms that promote brain edema in HE. The aim of this study was to assess brain edema in HE using characteristic MRS markers and serum albumin.Methods: We evaluated between group differences among 19 NASH cirrhosis without HE (Crhs-HE) (age = 63 ± 8.7), 9 NASH cirrhosis with HE (Crhs+HE) (age = 63 ± 9.2), and 16 controls (age = 57.8 ± 11.7) using 1 H MRS. Glutamine (Gln/tCr) and serum albumin were evaluated as predictors of myo-inositol (mI/tCr) using linear regression. Statistical significance was set at P < .05 with adjustment for multiple comparisons.Results: Brain mI/tCr was decreased, and Gln/tCr increased in Crhs+HE compared to Crhs-HE and controls in both brain regions (P < .001 for all). Evaluated together as joint predictors, serum albumin but not Gln/tCr significantly predicted mI/tCr in GM (P = .02 and P = .2, respectively) and PWM (P = .01 and P = .1, respectively).Conclusion: Low mI/tCr and increased Gln/tCr were characteristics of Crhs+HE. Low serum albumin was the strongest predictor of brain osmotic stress indicated by reduced mI/tCr, with no residual independent association seen for brain Gln/tCr concentration. This suggests that hypoalbuminemia in chronic liver disease may promote brain edema in HE. [ABSTRACT FROM AUTHOR]

Background: The aim of the present study was to investigate whether portal level of high‐mobility group protein B1 (HMGB1) is associated with hepatic encephalopathy (HE) after transjugular intrahepatic portosystemic shunt (TIPS). Methods: We enrolled 127 consecutive patients who underwent TIPS and collected portal and peripheral blood samples in our department from December 2017 to May 2019. HMGB1 levels were determined using enzyme‐linked immunosorbent assay kits. HMGB1 and other HE related parameters were estimated by competing risk analysis, receiver operating characteristic (ROC) analysis and Kaplan–Meier analysis. Results: Patients with HE after TIPS were older (P =.019) and had higher portal HMGB1 level (P =.038) than those without. Univariate competing risk analysis: age (sHR 1.025, P =.026), hepatorenal syndrome (sHR 3.149, P =.010), model for end‐of‐stage liver disease (MELD) score (sHR 1.055, P =.024), prior HE (sHR 4.029, P =.0005), portal HMGB1 before TIPS (sHR 1.177, P =.001) reached statistical significance. Multivariate analysis: age (sHR 1.025, P =.037), MELD score (sHR 1.062, P =.011), prior HE (sHR 2.492, P =.030) and portal HMGB1 level before TIPS (sHR 1.217, P =.0002) were significantly different. ROC analyses and Kaplan–Meier curve showed portal HMGB1 level changes before and after TIPS (ΔHMGB1) had good predictive value in the cut‐off 0.012 ng/mL (AUC = 0.748, P <.001, Sensitivity = 0.743, Specificity = 0.655). Conclusions: Portal HMGB1 may be a therapeutic target for post‐TIPS HE. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) may occur in patients with liver failure. The most critical pathophysiologic mechanism of HE is cerebral edema following systemic hyperammonemia. The dysfunctional liver cannot eliminate circulatory ammonia, so its plasma and brain levels rise sharply. Astrocytes, the only cells that are responsible for ammonia detoxification in the brain, are dynamic cells with unique phenotypic properties that enable them to respond to small changes in their environment. Any pathological changes in astrocytes may cause neurological disturbances such as HE. Astrocyte swelling is the leading cause of cerebral edema, which may cause brain herniation and death by increasing intracranial pressure. Various factors may have a role in astrocyte swelling. However, the exact molecular mechanism of astrocyte swelling is not fully understood. This article discusses the possible mechanisms of astrocyte swelling which related to hyperammonia, including the possible roles of molecules like glutamine, lactate, aquaporin-4 water channel, 18 KDa translocator protein, glial fibrillary acidic protein, alanine, glutathione, toll-like receptor 4, epidermal growth factor receptor, glutamate, and manganese, as well as inflammation, oxidative stress, mitochondrial permeability transition, ATP depletion, and astrocyte senescence. All these agents and factors may be targeted in therapeutic approaches to HE. [ABSTRACT FROM AUTHOR]

Disturbances in social cognitive processes such as the ability to infer others' mental states importantly contribute to social and functional impairments in psychiatric disorders. Yet, despite established social, emotional, and cognitive problems, the role of social cognition in obsessive-compulsive disorder is largely overlooked. The current review provides a first comprehensive overview of social (neuro)cognitive disturbances in adult patients with obsessive-compulsive disorder. Results of our review indicate various social cognitive alterations. Patients with obsessive-compulsive disorder show deficits in the recognition of affective social cues, specifically facial expressions of disgust, and more general deficits in theory of mind/mentalizing. Additionally, patients show heightened affective reactions and altered neural responding to emotions of self and others, as well as poor emotion regulation skills, which may contribute to poor social functioning of patients. However, the discrepancies in findings and scarcity of studies make it difficult to draw firm conclusions with regard to the specificity of social cognitive disturbances. The review offers directions for future research and highlights the need to investigate obsessive-compulsive disorder from an interactive social neurocognitive perspective in addition to the prevalent passive spectator perspective to advance our understanding of this intricate and burdensome disorder. [ABSTRACT FROM AUTHOR]

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Rationale: Drug addiction has been suggested to develop through drug-induced changes in learning and memory processes. Whilst the initiation of drug use is typically goal-directed and hedonically motivated, over time, drug-taking may develop into a stimulus-driven habit, characterised by persistent use of the drug irrespective of the consequences. Converging lines of evidence suggest that stimulant drugs facilitate the transition of goal-directed into habitual drug-taking, but their contribution to goal-directed learning is less clear. Computational modelling may provide an elegant means for elucidating changes during instrumental learning that may explain enhanced habit formation. Objectives: We used formal reinforcement learning algorithms to deconstruct the process of appetitive instrumental learning and to explore potential associations between goal-directed and habitual actions in patients with cocaine use disorder (CUD). Methods: We re-analysed appetitive instrumental learning data in 55 healthy control volunteers and 70 CUD patients by applying a reinforcement learning model within a hierarchical Bayesian framework. We used a regression model to determine the influence of learning parameters and variations in brain structure on subsequent habit formation. Results: Poor instrumental learning performance in CUD patients was largely determined by difficulties with learning from feedback, as reflected by a significantly reduced learning rate. Subsequent formation of habitual response patterns was partly explained by group status and individual variation in reinforcement sensitivity. White matter integrity within goal-directed networks was only associated with performance parameters in controls but not in CUD patients. Conclusions: Our data indicate that impairments in reinforcement learning are insufficient to account for enhanced habitual responding in CUD. [ABSTRACT FROM AUTHOR]

Rationale: Disorders of compulsivity such as stimulant use disorder (SUD) and obsessive-compulsive disorder (OCD) are characterised by deficits in behavioural flexibility, some of which have been captured using probabilistic reversal learning (PRL) paradigms. Objectives: This study used computational modelling to characterise the reinforcement learning processes underlying patterns of PRL behaviour observed in SUD and OCD and to show how the dopamine D2/3 receptor agonist pramipexole and the D2/3 antagonist amisulpride affected these responses. Methods: We applied a hierarchical Bayesian method to PRL data across three groups: individuals with SUD, OCD, and healthy controls. Participants completed three sessions where they received placebo, pramipexole, and amisulpride, in a double-blind placebo-controlled, randomised design. We compared seven models using a bridge sampling estimate of the marginal likelihood. Results: Stimulus-bound perseveration, a measure of the degree to which participants responded to the same stimulus as before irrespective of outcome, was significantly increased in SUD, but decreased in OCD, compared to controls (on placebo). Individuals with SUD also exhibited reduced reward-driven learning, whilst both the SUD and OCD groups showed increased learning from punishment (nonreward). Pramipexole and amisulpride had similar effects on the control and OCD groups; both increased punishment-driven learning. These D2/3-modulating drugs affected the SUD group differently, remediating reward-driven learning and reducing aspects of perseverative behaviour, amongst other effects. Conclusions: We provide a parsimonious computational account of how perseverative tendencies and reward- and punishment-driven learning differentially contribute to PRL in SUD and OCD. D2/3 agents modulated these processes and remediated deficits in SUD in particular, which may inform therapeutic effects. [ABSTRACT FROM AUTHOR]

Systemic inflammation and ammonia (hyperammonemia) act synergistically in the pathogenesis of hepatic encephalopathy (HE), the neurobehavioral sequelae of advanced liver disease. In cirrhotic patients, we have recently observed elevated levels of circulating neuronal tight junction (TJ) protein, zonula occludens 1 (ZO-1), reflective of a change to blood–brain barrier (BBB) integrity. Moreover, ZO-1 levels positively correlated with hyperammonemia, although any potential relationship remains unclear. Using a carbon tetrachloride (CCl4)–induced mouse model of cirrhosis, we primarily looked to explore the relationship between neuronal TJ protein expression and hyperammonemia. Secondarily, we assessed the potential role of a natural antioxidant, resveratrol, on neuronal TJ protein expression and hyperammonemia. Over 12 weeks, male Swiss mice were randomized (n = 8/group) to either naïve controls or induced cirrhosis, using two doses of intraperitoneal CCl4 (0.5 ml/kg/week). After 12 weeks, naïve and cirrhotic mice were randomized to receive either 2 weeks of par-oral resveratrol (10 mg/kg). Plasma samples were analyzed for ammonia, liver biochemistry (ALT, AST, albumin, and bilirubin), and pro-inflammatory cytokines (TNF-α and IL-1β), and brain tissue for brain water content, TJ protein expression (e.g., ZO-1, claudin 5, and occludin), and tissue oxidative stress and inflammatory markers (NF-κB and iNOS) using western blotting. Compared to naïve mice, cirrhosis significantly increased circulating ammonia, brain water, ALT, AST, TNF-α, IL-1β, 4HNE, NF-κB, and iNOS levels, with a concomitant reduction in all TJ proteins (P < 0.05, respectively). In cirrhotic mice, resveratrol treatment ameliorated these changes significantly (P < 0.05, respectively). Our findings provide evidence for a causal association between hyperammonemia and inflammation in cirrhosis linked to TJ protein alterations, BBB disruption, and HE predilection. Moreover, this is the first report of a potential role for resveratrol as a novel therapeutic approach to managing neurological sequelae complicating cirrhosis. [ABSTRACT FROM AUTHOR]

Background: Proline is a proteinogenic amino acid with multiple biological functions. Several investigations have been supposed that cellular proline accumulation is a stress response mechanism. This amino acid acts as an osmoregulator, scavenges free radical species, boosts cellular antioxidant defense mechanisms, protects mitochondria, and promotes energy production. The current study was designed to investigate the effect of proline treatment on the liver in bile duct ligated (BDL) rats as an animal model of cholestasis/cirrhosis. Methods: BDL rats were supplemented with proline-containing drinking water (0.25% and 0.5% w:v), and samples were collected at scheduled time intervals (3, 7, 14, 28, and 42 days after BDL surgery). Results: Drastic elevation in the serum level of liver injury biomarkers and significant tissue histopathological changes were evident in BDL rats. Markers of oxidative stress were also higher in the liver of BDL animals. It was found that proline supplementation attenuated BDL-induced alteration in serum biomarkers of liver injury, mitigated liver histopathological changes, and alleviated markers of oxidative stress at the early stage of BDL operation (3, 7, and 14 days after BDL surgery). Conclusions: The hepatoprotection provided by proline in BDL animals might be associated with its ability to attenuate oxidative stress and its consequences. [ABSTRACT FROM AUTHOR]

AbstractThe aim of this study was to explore the effect of lamotrigine (LTG) on blood ammonia level in patients with epilepsy and identify risk factors affecting blood ammonia level. This study included 91 epilepsy patients who were treated with LTG at Department of Neurology, Zhongshan Hospital, Xiamen University from January 2011 to April 2016, and were followed up for 3 years. Blood samples were taken during the interictal state and analyzed for blood LTG and ammonia levels. Total of 46.1% of the samples exceeded the median blood ammonia level, and 2.1% of patients had hyperammonemia. Blood ammonia level was positively correlated with LTG blood concentration. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils affected blood ammonia level. Blood ammonia level was significantly correlated with plasma concentration of LTG. LTG combined with valproic acid therapy, seizure within 1 year, and elevated neutrophils may be risk factors for elevated blood ammonia level in epilepsy patients treated with LTG., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

Hyperammonaemia is a common complication of liver disease in dogs. High concentrations of ammonia can be detrimental to dogs with liver disease for several reasons, notably by causing hepatic encephalopathy (HE) which describes the wide range of neurological abnormalities ranging from altered behaviour to seizures that are well recognised complications in dogs with hepatic disorders. In human patients with liver disease, hyperammonaemia has also been linked to the development of other systemic complications such as dysregulation of the innate immune system. In contrast, the effects of hyperammonaemia on the canine innate immune system is currently unknown. The aim of this study was to investigate the effects of ammonia on the oxidative burst activity of canine polymorphonuclear cells in vitro. Blood obtained from healthy dogs (n = 8) was incubated with escalating concentrations of ammonia ranging from 0 to 250 μM, and the percentage of cells experiencing an oxidative burst was evaluated using a commercial kit (Phagoburst™) and flow cytometry. The spontaneous oxidative burst was evaluated without stimulation and also following stimulation with E coli. The pH of the blood was also measured at the differing ammonia concentrations. There was an increase in the percentage of cells experiencing a spontaneous oxidative burst from ammonia concentrations of 125 μM (p = <0.05) and above (p = <0.01), with a 4.9 fold increase at 200 μM (p = < 0.001). In those cells stimulated with E coli, incubation with increasing ammonia concentrations did not result in a significant difference in oxidative burst from baseline (p = 0.953). There was no statistically significant difference between the pH of the blood at the various ammonia concentrations (p = 0.2) suggesting that the difference in spontaneous oxidative burst was due to the ammonia rather than simply a change in pH conditions. In summary, the spontaneous oxidative burst of neutrophils was significantly increased from baseline. This supports a potential role of ammonia in contributing to innate immune system dysfunction in dogs with liver disease, and may present a future therapeutic target. [ABSTRACT FROM AUTHOR]

The syndrome of decreased immunity caused by cirrhosis is a combination of different immunological mechanisms and reactions which result from an advanced stage of the liver disease. The synthesis of proteins of the acute phase becomes impaired, there develop different deficiencies of the complement system, and there ensues a decrease of receptors that are meant to recognize antigens. The negative changes become apparent in the field of cell responses, e.g. there are changes in the amounts of generated monocytes and macrophages, and their phagocytic capabilities and chemotaxic reactions are impacted as well. The humoral response results in distorted synthesis of particular antigen categories. The risk of detrimental immunoresponses with the end result of endotoxemia is not rarely coupled with both local and global infections. The combination of the aforesaid immunodeficiencies worsens the healing chances of cirrhosis sufferers and more often than not it increases the mortality of the affected patients. [ABSTRACT FROM AUTHOR]

The present study was designed to investigate the mechanisms involved in blood-brain barrier (BBB) permeability in bile duct ligation (BDL) model of chronic hepatic encephalopathy (HE). Four weeks after BDL surgery, a significant increase was observed in serum bilirubin levels. Masson trichrome staining revealed severe hepatic fibrosis in the BDL rats. 99mTc-mebrofenin retention was increased in the liver of BDL rats suggesting impaired hepatobiliary transport. An increase in permeability to sodium fluorescein, Evans blue, and fluorescein isothiocyanate (FITC)-dextran along with increase in water and electrolyte content was observed in brain regions of BDL rats suggesting disrupted BBB. Increased brain water content can be attributed to increase in aquaporin-4 mRNA and protein expression in BDL rats. Matrix metalloproteinase-9 (MMP-9) mRNA and protein expression was increased in brain regions of BDL rats. Additionally, mRNA and protein expression of tissue inhibitor of matrix metalloproteinases (TIMPs) was also increased in different regions of brain. A significant decrease in mRNA expression and protein levels of tight junction proteins, viz., occludin, claudin-5, and zona occluden-1 (ZO-1) was observed in different brain regions of BDL rats. VCAM-1 mRNA and protein expression was also found to be significantly upregulated in different brain regions of BDL animals. The findings from the study suggest that increased BBB permeability in HE involves activation of MMP-9 and loss of tight junction proteins. [ABSTRACT FROM AUTHOR]

Aim of the study: Hepatic encephalopathy and hyperammonemia is a clinical complication associated with liver cirrhosis. The brain is the target organ for ammonia toxicity. Ammonia-induced brain injury is related to oxidative stress, locomotor activity dysfunction, and cognitive deficit, which could lead to permanent brain injury, coma and death if not appropriately managed. There is no promising pharmacological intervention against cirrhosisassociated brain injury. Taurine (TAU) is one of the most abundant amino acids in the human body. Several physiological and pharmacological roles have been attributed to TAU. TAU may act as an antioxidant and is an excellent neuroprotective agent. This study aimed to evaluate the effect of TAU supplementation on cirrhosisassociated locomotor activity disturbances and oxidative stress in the brain. Material and methods: Rats underwent bile duct ligation (BDL) surgery, and plasma and brain ammonia level, plasma biochemical parameters, and rats' locomotor function were monitored. Furthermore, brain tissue markers of oxidative stress were assessed. Results: It was found that plasma and brain ammonia was increased, and markers of liver injury were significantly elevated in the cirrhotic group. Impaired locomotor activity was also evident in BDL rats. Moreover, an increase in brain tissue markers of oxidative stress was detected in the brain of cirrhotic animals. It was found that TAU supplementation (50, 100, and 200 mg/kg, gavage) alleviated brain tissue markers of oxidative stress and improved animals' locomotor activity. Conclusions: These data suggest that TAU is a potential protective agent against cirrhosis-associated brain injury. [ABSTRACT FROM AUTHOR]

Introduction Delirium, which is prevalent in postcardiac surgical patients, is an acute brain dysfunction characterised by disturbances in attention, awareness and cognition not explained by a pre-existing neurocognitive disorder. The pathophysiology of delirium remains poorly understood. However, basic science and clinical studies suggest that sleep disturbance may be a modifiable risk factor for the development of delirium. Dexmedetomidine is a α-2A adrenergic receptor agonist medication that patterns the activity of various arousal nuclei similar to sleep. A single night-time loading dose of dexmedetomidine promotes non-rapid eye movement sleep stages N2 and N3 sleep. This trial hypothesises dexmedetomidine-induced sleep as pre-emptive therapy for postoperative delirium. Methods and analysis The MINDDS (Minimizing ICU Neurological Dysfunction with Dexmedetomidine-induced Sleep) trial is a 370-patient block-randomised, placebocontrolled, double-blinded, single-site, parallel-arm superiority trial. Patients over 60 years old, undergoing cardiac surgery with planned cardiopulmonary bypass, will be randomised to receive a sleep-inducing dose of dexmedetomidine or placebo. The primary outcome is the incidence of delirium on postoperative day 1, assessed with the Confusion Assessment Method by staff blinded to the treatment assignment. To ensure that the study is appropriately powered for the primary outcome measure, patients will be recruited and randomised into the study until 370 patients receive the study intervention on postoperative day 0. Secondary outcomes will be evaluated by in-person assessments and medical record review for in-hospital end points, and by telephone interview for 30-day, 90-day and 180-day end points. All trial outcomes will be evaluated using an intention-to-treat analysis plan. Hypothesis testing will be performed using a two-sided significance level (type I error) of α=0.05. Sensitivity analyses using the actual treatment received will be performed and compared with the intention-to-treat analysis results. Additional sensitivity analyses will assess the potential impact of missing data due to loss of followup. Ethics and dissemination The Partners Human Research Committee approved the MINDDS trial. Recruitment began in March 2017. Dissemination plans include presentations at scientific conferences, scientific publications and popular media. [ABSTRACT FROM AUTHOR]

Hepatic encephalopathy (HE) is a serious neuropsychiatric complication of cirrhosis and/or porto-systemic shunting. The clinical symptoms are widely variable, extending from subtle impairment in mental state to coma. The utility of categorizing the severity of HE accurately and efficiently serves not only to provide practical functional information about the current clinical status of the patient but also gives valuable prognostic information. In the past 20-30 years, there has been rapid progress in understanding the pathophysiological basis of HE; however, the lack of direct correlation between pathogenic factors and the severity of HE make it difficult to select appropriate therapy for HE patients. In this review, we will discuss the classification system and its limitations, the neuropsychometric assessments and their challenges, as well as the present knowledge on the pathophysiological mechanisms. Despite the many prevalent hypotheses around the pathogenesis of the disease, most treatments focus on targeting and lowering the accumulation of ammonia as well as inflammation. However, treatment of minimal HE remains a huge unmet need and a big concerted effort is needed to better define this condition to allow the development of new therapies. We review the currently available therapies and future approaches to treat HE as well as the scientific and clinical data that support their effectiveness. [ABSTRACT FROM AUTHOR]

Background Mortality from chronic liver disease is rising exponentially. The liver is intimately linked to the gut via the portal vein, and exposure to gut microbiota and their metabolites translocating across the gut lumen may impact upon both the healthy and diseased liver. Modulation of gut microbiota could prove to be a potential therapeutic target. Aim To characterise the changes in the gut microbiome that occur in chronic liver disease and to assess the impact of manipulation of the microbiome on the liver. Methods We conducted a PubMed search using search terms including 'microbiome', 'liver' and 'cirrhosis' as well as 'non-alcoholic fatty liver disease', 'steatohepatitis', 'alcohol' and 'primary sclerosing cholangitis'. Relevant articles were also selected from references of articles and review of the ClinicalTrials.gov website. Results Reduced bacterial diversity, alcohol sensitivity and the development of gut dysbiosis are seen in several chronic liver diseases, including non-alcoholic fatty liver disease, alcohol-related liver disease and primary sclerosing cholangitis. Perturbations in gut commensals could lead to deficient priming of the immune system predisposing the development of immune-mediated diseases. Furthermore, transfer of stool from an animal with the metabolic syndrome may induce steatosis in a healthy counterpart. Patients with cirrhosis develop dysbiosis, small bowel bacterial overgrowth and increased gut wall permeability, allowing bacterial translocation and uptake of endotoxin inducing hepatic and systemic inflammation. Conclusions Manipulation of the gut microbiota with diet, probiotics or faecal microbiota transplantation to promote the growth of 'healthy' bacteria may ameliorate the dysbiosis and alter prognosis. [ABSTRACT FROM AUTHOR]