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This narrative review briefly describes the mammalian circadian timing system, the specific features of the liver clock, also by comparison with other peripheral clocks, the role of the liver clock in the preparation to food intake, and its relationship with energy metabolism. It then goes on to provide a chronobiological perspective of the pathophysiology and management of several types of liver disease, with particular focus on metabolic-associated fatty liver disease (MAFLD), decompensated cirrhosis and liver transplantation. Finally, it provides some insight into the potential contribution of circadian principles and circadian hygiene practices in preventing MAFLD, improving the prognosis of advanced liver disease and modulating liver transplantation outcomes.

The aims of the present study were to obtain sleep quality and sleep timing information in a group of university students, and to evaluate the effects of a circadian hygiene education initiative. All students of the University of Padova (approximately 64,000) were contacted by e-mail (major campaigns in October 2019 and October 2020) and directed to an ad hoc website for collection of demographics and sleep quality/timing information. Participants (n=5740) received one of two sets of circadian hygiene advice (“A regular life” or “Bright days and dark nights”). Every month, they were then asked how easy it had been to comply, and provided with the advice again. At any even month from joining, they completed the sleep quality/timing questionnaires again. Information on academic performance was obtained post hoc, together with representative samples of lecture (n=5972) and exam (n=1800) timings, plus lecture attendances (n=25,302). 52% of students had poor sleep quality and 82% showed signs of sleep deprivation. Those who joined in October 2020, after several months of lockdown and distance learning, had better sleep quality, less sleep deprivation and later sleep habits. The “Bright days and dark nights” advice resulted in earlier get-up time/midsleep compared to the “A regular life” advice. Significant changes in most sleep quality and sleep timing variables were observed in both advice groups over time, also in relation to pandemic-related events characterising 2020. Early-chronotype students had better academic performances compared to their later chronotype counterparts. In a multivariate model, sleep quality, chronotype and study subject were independent predictors of academic performance. Taken together, these results underlie the importance of designing circadian-friendly university timetables.

Chronobiology is not routinely taught to biology or medical students in most European countries. Here we present the results of the chronobiology practicals of a group of students of the University of Padova, with a view to highlight some interesting features of this group, and to share a potentially interesting cross-faculty teaching experience. Thirty-eight students (17 males; 22.9 ± 1.6 yrs) completed a set of self-administered electronic sleep quality [Pittsburgh Sleep Quality Index (PSQI)], chronotype and sleepiness [Epworth Sleepiness Scale (ESS)] questionnaires. They then went on to complete sleep diaries for two weeks. Sixteen also wore an actigraph, 8 wore wireless sensors for skin temperature, and 8 underwent a course of chronotherapy aimed at anticipating their sleep-wake timing. Analyses were performed as practicals, together with the students. Average PSQI score was 5.4 ± 1.9, with 15 (39%) students being poor sleepers. Average ESS score was 6.5 ± 3.3, with 3 (8%) students exhibiting excessive daytime sleepiness. Seven classified themselves as definitely/moderately morning, 25 as intermediates, 6 as moderately/definitely evening. Students went to bed/fell asleep significantly later on weekends, it took them less to fall asleep and they woke up/got up significantly later. Diary-reported sleep onset time coincided with the expected decrease in proximal skin temperature. Finally, during chronotherapy they took significantly less time to fall asleep. In conclusion, significant abnormalities in the sleep-wake patterns of a small group of university students were observed, and the students seemed to benefit from chronotherapy. We had a positive impression of our teaching experience, and the chronobiology courses obtained excellent student feedback.

Background & Aims: Golexanolone is a novel small molecule GABA-A receptor-modulating steroid antagonist under development for the treatment of cognitive and vigilance disorders caused by allosteric over-activation of GABA-A receptors by neurosteroids. It restored spatial learning and motor coordination in animal models of hepatic encephalopathy (HE) and mitigated the effects of intravenous allopregnanolone in healthy adults in a dose-dependent fashion. Herein, we report data on the safety, pharmacokinetics (PK) and efficacy of golexanolone in adult patients with cirrhosis. Methods: Following single/multiple ascending dose studies, adults with Child-Pugh A/B cirrhosis and abnormal continuous reaction time (CRT) on screening were randomized to 3 weeks dosing with golexanolone (10, 40 or 80 mg BID) or placebo. CRT, psychometric hepatic encephalopathy score (PHES), animal naming test (ANT), Epworth sleepiness scale (ESS) and electroencephalogram (mean dominant frequency [MDF]; delta+theta/alpha+beta ratio [DT/AB]) were obtained at baseline, 10, and 21 days. Results: Golexanolone exhibited satisfactory safety and PK. Baseline characteristics were similar between the 12 and 33 patients randomized to placebo or golexanolone, respectively. By prespecified analyses, golexanolone was associated with directionally favourable changes vs. placebo in ESS (p = 0.047), MDF (p = 0.142) and DT/AB (p = 0.021). All patients also showed directionally favourable changes in CRT, PHES and ANT, but with no statistical difference between golexanolone and placebo. Post hoc analyses taking into account the variability and improvement in CRT, PHES and ANT observed between screening and baseline suggested an efficacy signal by cognitive measures as well. Conclusion: Golexanolone was well tolerated and associated with improvement in cognitive performance. These results implicate GABA-A receptor-modulating neurosteroids in the pathogenesis of HE and support the therapeutic potential of golexanolone. Lay summary: Many patients with cirrhosis experience subtle but disabling cognitive problems, including sleepiness and poor attention span, that impair their ability to be gainfully employed or carry out activities of daily living. This pilot study tested the hypothesis that these problems with cognition, for which there is no approved treatment, might be improved by an experimental drug, golexanolone, designed to normalize the function of receptors which inhibit brain function. The results of this study suggest that golexanolone is well tolerated and may improve cognition, as reflected by measures of sleepiness, attention span and brain wave activity, paving the way for future larger studies of this promising experimental drug. (C) 2021 The Author(s). Published by Elsevier B.V. on behalf of European Association for the Study of the Liver. Funding Agencies|Umecrine Cognition AB

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.

Objective This study sought to investigate how glycemia and ketonemia variations during two ketogenic diet protocols affect appetite, executive functions, and mood in young women with overweight. Methods Fifty healthy young females with overweight were randomly assigned to (1) a ketogenic diet without any restriction on energy intake, (2) a commercial energy-restricted ketogenic Mediterranean diet, and (3) an energy-restricted Mediterranean diet for 10 days. A visual analogue scale was used to test appetite, and one mood test and two cognitive tasks (working memory and inhibition control) were performed. Moreover, body composition, fasting blood glucose, and β-hydroxybutyrate (BHB) were measured. Results A positive correlation was found between glycemia and appetite (P = 0.019), unfullness score (P = 0.001), and desire to eat (P = 0.030) (pre- and postdiet levels). Postdiet BHB levels showed a positive correlation with fullness score (P = 0.002) and a negative correlation with appetite (P = 0.022) and desire to eat (P = 0.009). A positive correlation was found between prediet levels of glycemia and reaction times in the go-trials of the executive function test (P = 0.018). Postdiet BHB level showed a negative correlation with the accuracy of the no-go trials (P = 0.027). Conclusions Ketogenic diets, compared with a Mediterranean diet, have a greater effect in terms of appetite reduction but might affect inhibition functions.

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.

Sleep and circadian rhythm disorders are common amongst medical inpatients. They are caused by a mixture of factors, including noise, loss of habitual daily routines, and abnormal exposure to light, which tends to be insufficient in the day and too high at night. The aim of the present study was to test the efficacy of morning light therapy plus night short-wavelength filter glasses on sleep quality/timing, and sleepiness/mood over the daytime hours, in a group of well-characterized medical inpatients. Thirty-three inpatients were enrolled and randomized (2:1) to either treatment (n = 22; 13 males, 48.3 ± 13.3 years) or standard of care (n = 11; 8 males, 56.9 ± 12.9 years). On admission, all underwent a baseline assessment of sleep quality/timing and diurnal preference. During hospitalization they underwent monitoring of sleep quality/timing (sleep diaries and actigraphy), plus hourly assessment of sleepiness/mood during the daytime hours on one, standard day of hospitalization. Patients in the treatment arm were administered bright light through glasses immediately after awakening, and wore short-wavelength filter glasses in the evening hours. Treated and untreated patients were comparable in terms of demographics, disease severity/comorbidity, diurnal preference and pre-admission sleep quality/timing. During hospitalization, sleep diaries documented a trend for a lower number of night awakenings in treated compared to untreated patients (1.6 ± 0.8 vs. 2.4 ± 1.3, p = 0.057). Actigraphy documented significantly earlier day mode in treated compared to untreated patients (06:39 ± 00:35 vs. 07:44 ± 00:40, p = 0.008). Sleepiness during a standard day of hospitalization, recorded between 09:30 and 21:30, showed physiological variation in treated compared to untreated patients, who exhibited a more blunted profile. The level of sleepiness reported by treated patients was lower over the 09:30–14:30 interval, i.e., soon after light administration (interaction effect: F = 2.661; p = 0.026). Mood levels were generally higher in treated patients, with statistically significant differences over the 09:30–14:30 time interval, i.e., soon after light administration (treatment: F = 5.692, p = 0.026). In conclusion, treatment with morning bright light and short-wavelength filter glasses in the evening, which was well tolerated, showed positive results in terms of sleepiness/mood over the morning hours and a trend for decreased night awakenings.

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.

Background & aims The occurrence of overt hepatic encephalopathy (HE) marks a significant progression in the natural history of liver disease. The aims of the present study were: 1) to describe a large cohort of patients with cirrhosis in terms of neuropsychological/neurophysiological HE indices, and 2) to test if the severity of liver disease and/or any such indices [Psychometric Hepatic Encephalopathy Score (PHES), Scan test, electroencephalography (EEG)] predicted mortality/HE risk in a subgroup of such cohort. Method 461 patients with cirrhosis (59±10 years; 345 males) were included; information on previous overt HE episodes was available in 407. Follow up information on mortality/HE-related hospitalization in 134/127, respectively. Information on previous overt HE episodes and both mortality and HE-related hospitalization over the follow up in 124. Results Patients with a history of overt HE (60%) had poorer liver function, worse neuropsychiatric indices, higher ammonia levels and higher prevalence of portal-systemic shunt. The risk of HE-related hospitalization over the follow up was higher in patients with higher MELD score and worse Scan performance. Mortality was higher in those with higher MELD. Amongst patients without a history of overt HE, those with worse PHES had higher HE risk. Amongst patients with a history, those with higher MELD, better PHES and worse Scan performance had higher HE risk. Conclusions In patients without previous overt HE episodes, neuropsychological and neurophysiological tests predict HE, while in those with previous overt HE episodes, HE development largely depends on the severity of liver dysfunction.

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.

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.

To examine the relationship between electroencephalographic (EEG) activity and hypoglycemia unawareness, we investigated early parameters of vigilance and awareness of various symptom categories in response to hypoglycemia in intensively treated type 1 diabetic (T1DM) patients with different degrees of hypoglycemia unawareness. Hypoglycemia was induced with a hyperinsulinemic-hypoglycemic clamp in six T1DM patients with a history of hypoglycemia unawareness previous severe hypoglycemic coma (SH) and in six T1DM patients without (C) history of hypoglycemia unawareness previous severe hypoglycemic coma. Cognitive function tests (four choice reaction time), counterregulatory responses (adrenaline), and symptomatic responses were evaluated at euglycemia (90 mg/dl) and during step-wise plasma glucose reduction (68, 58 and 49 mg/dl). EEG activity was recorded continuously throughout the study and analyzed by spectral analysis. Cognitive function deteriorated significantly at a glucose threshold of 55 ± 1 mg/dl in both groups (p = ns) during hypoglycemia, while the glucose threshold for autonomic symptoms was significantly lower in SH patients than in C patients (49 ± 1 vs. 54 ± 1 mg/dl, p

The aim of the present study was to develop a Polygenic Score–based model for molecular chronotype assessment. Questionnaire-based phenotypical chronotype assessment was used as a reference. In total, 54 extremely morning/morning (MM/M; 35 females, 39.7 ± 3.8 years) and 44 extremely evening/evening (EE/E; 20 females, 27.3 ± 7.7 years) individuals donated a buccal DNA sample for genotyping by sequencing of the entire genetic variability of 19 target genes known to be involved in circadian rhythmicity and/or sleep duration. Targeted genotyping was performed using the single primer enrichment technology and a specifically designed panel of 5526 primers. Among 2868 high-quality polymorphisms, a cross-validation approach lead to the identification of 83 chronotype predictive variants, including previously known and also novel chronotype-associated polymorphisms. A large (35 single-nucleotide polymorphisms [SNPs]) and also a small (13 SNPs) panel were obtained, both with an estimated predictive validity of approximately 80%. Potential mechanistic hypotheses for the role of some of the newly identified variants in modulating chronotype are formulated. Once validated in independent populations encompassing the whole range of chronotypes, the identified panels might become useful within the setting of both circadian public health initiatives and precision medicine.