Overt Hepatic Encephalopathy: More Than Meets the Eye.

INTRODUCTION: We aimed to assess the reliability of a qualitative approach to overt hepatic encephalopathy (OHE) diagnosis compared with the semiquantitative, and recommended one. METHODS: The above 2 methods were compared in 411 outpatients (71% males, 60 ± 10 years, model for end-stage liver disease 13.5 ± 5.0). RESULTS: Of the 73 patients with OHE on quantitative assessment, 19 (26%) were missed on qualitative assessment, with no difference in the likelihood of the physician missing grades II or III. Sixty-eight (20%) of the 270 patients with no OHE on quantitative assessment were wrongly qualified as having OHE. DISCUSSION: Qualitative clinical evaluation of OHE is not reliable, and recommendations should be followed.

Minimal hepatic encephalopathy is associated with a higher risk of overt hepatic encephalopathy and poorer survival.

BACKGROUND AND AIMS: Minimal hepatic encephalopathy (MHE) is a frequent complication in patients with liver cirrhosis. Its impact on predicting the development of overt hepatic encephalopathy (OHE) and survival has not been studied in large multicenter studies. METHODS: Data from patients recruited at eight centers across Europe and the United States were analyzed. MHE was detected using the psychometric hepatic encephalopathy score (PHES). A subset was also tested with the simplified animal naming test (S-ANT1). Patients were followed for OHE development and death/liver transplantation (LTx). RESULTS: A total of 1462 patients with a median model of end-stage liver disease of 11 were included (Child-Pugh (CP) stages: A 47%/B 41%/C 12%). Median follow-up time was 19 months, during which 336 (23%) patients developed an OHE episode and 464 (32%) reached the composite end point of death/LTx (369 deaths, 95 LTx). In multivariable analyses, MHE (defined by PHES) was associated with the development of OHE (subdistribution hazard ratio 1.74, p < 0.001) and poorer LTx-free survival (hazard ratio 1.53, p < 0.001) in the total cohort as well as in the subgroup of patients without a history of OHE. In subgroup analyses, MHE (defined by PHES) was associated with OHE development in patients with CP B, whereas there was no association in patients with CP A or C. In the subgroup of patients with available S-ANT1, MHE (defined by S-ANT1) was independently associated with OHE development. Combined testing (PHES+S-ANT1) was superior to single testing for predicting OHE and poorer LTx-free survival. CONCLUSIONS: This large multicenter study demonstrates that screening for MHE is a useful tool for predicting OHE and poorer survival.

Personalising circadian hygiene educational initiatives aimed at university students-"He who has ears to hear, let him hear".

The aim of the present study was to characterise "early drop-outs" (n = 3185) out of a group of university students (n = 7766) engaged in an ongoing circadian education initiative, to evaluate its efficacy and direct its developments. The initiative is aimed at improving sleep timing/quality through one of two sets of circadian hygiene advice covering the timing of sleep, meals, exercise and light exposure, and it has already been shown to have a positive effect on sleep timing. This second, interim analysis confirmed the high prevalence of disturbed night sleep and social jetlag amongst students at Padova University. Three-thousand, one-hundred and eighty-five (41.0%) students were early drop-outs. These were more commonly males (46.4 versus 37.6%; χ2 = 58, p < 0.0001), had later sleep-wake habits, more daytime sleepiness and worse night sleep quality. Chronotype distribution was also different, with a slight but significantly higher proportion of extremely evening/evening types amongst early drop-outs (χ2 = 10, p < 0.05). These results suggest that the more evening the student, the lower their likelihood of choosing/being able to follow circadian advice.

Prevalence of Minimal Hepatic Encephalopathy in Patients With Liver Cirrhosis: A Multicenter Study.

INTRODUCTION: The prevalence of minimal hepatic encephalopathy (MHE), in particular in different subgroups, remains unknown. This study aimed to analyze the prevalence of MHE in different subgroups to identify patients at high risk and to pave the way for personalized screening approaches. METHODS: In this study, data of patients recruited at 10 centers across Europe and the United States were analyzed. Only patients without clinical signs of hepatic encephalopathy were included. MHE was detected using the Psychometric Hepatic Encephalopathy Score (PHES, cut-off < or ≤-4 depending on local norms). Clinical and demographic characteristics of the patients were assessed and analyzed. RESULTS: In total, 1,868 patients with cirrhosis with a median model for end-stage liver disease (MELD) of 11 were analyzed (Child-Pugh [CP] stages: A 46%, B 42%, and C 12%). In the total cohort, MHE was detected by PHES in 650 patients (35%). After excluding patients with a history of overt hepatic encephalopathy, the prevalence of MHE was 29%. In subgroup analyses, the prevalence of MHE in patients with CP A was low (25%), whereas it was high in CP B or C (42% and 52%). In patients with a MELD score <10, the prevalence of MHE was only 25%, but it was 48% in patients with a MELD score ≥20. Standardized ammonia levels (ammonia level/upper limit of normal of each center) correlated significantly, albeit weakly with PHES (Spearman ρ = -0.16, P < 0.001). DISCUSSION: The prevalence of MHE in patients with cirrhosis was high but varied substantially between diseases stages. These data may pave the way for more individualized MHE screening approaches.

Working Memory in Patients with Varying Degree of Hepatic Encephalopathy (HE): A Pilot EEG-fNIRS Study.

It is known that patients with covert hepatic encephalopathy (CHE) exhibit working memory abnormalities, but to date there is no study comparing patients with cirrhosis with/without CHE and controls with both electrophysiological and hemodynamic data collected at the same time.Here we collected behavioral [accuracy and reaction times (RTs), electrophysiological (evoked potentials) and hemodynamic (oxygenated and deoxygenated haemoglobin) correlates of an n-back task [formed by a control (0-back) condition, a low (1-back) and a high (2-back) working memory load conditions] in patients with cirrhosis with/without CHE: (1) at baseline (n = 21, males = 15, 58±8 yrs), and by comparison with controls (n = 21, males = 15, 57±11 yrs) and (2) after a 3-month course of rifaximin (n = 18, males = 12, 61±11 yrs), and by comparison to baseline.All patients showed slower RTs (p < 0.0001) and lower P2 amplitude compared with controls (p = 0.018); moreover, patients with CHE showed reduced accuracy (p < 0.0001) compared with controls, and patients without CHE showed higher oxygenated haemoglobin in the central dorsolateral prefrontal cortex in the 2-back compared with patients with CHE. Post-rifaximin, oxygenated haemoglobin increased in the central frontopolar cortex. In addition, in patients without CHE the RTs of the 2-back became comparable to those of the 0-back and P3 showed higher amplitude.In conclusion, the presence of cirrhosis seemed to have more effects than CHE on working memory at baseline. A course of treatment with rifaximin was more beneficial to patients without CHE, who probably had more room for improvement in this complex task.

Circadian rhythms and the liver.

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 of 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 a 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 Alarm Clock Against the Sun: Trends in Google Trends Search Activity Across the Transitions to and from Daylight Saving Time.

The human circadian timing system depends on the light/dark cycle as its main cue to synchronize with the environment, and thus with solar time. However, human activities depend also on social time, i.e. the set of time conventions and restrictions dictated by society, including Daylight Saving Time (DST), which adds an hour to any degree of desynchrony between social and solar time. Here, we used Google Trends as a data source to analyze diurnal variation, if any, and the daily peak in the relative search volume of 26 Google search queries in relation to the transitions to/from DST in Italy from 2015 to 2020. Our search queries of interest fell into three categories: sleep/health-related, medication and random non sleep/health-related. After initial rhythm and phase analysis, 11 words were selected to compare the average phase of the 15 days before and after the transition to/from DST. We observed an average phase advance after the transition to DST, and a phase delay after the transition to civil time, ranging from 25 to 60 minutes. Advances or delays shorter than 60 minutes, which were primarily observed in the sleep/health-related category, may suggest that search timing for these queries is at least partially driven by the endogenous circadian rhythm. Finally, a significant trend in phase anticipation over the years was observed for virtually all words. This is most likely related to an increase in age, and thus in earlier chronotypes, amongst Google users.

Driving fatigue increases after the Spring transition to Daylight Saving Time in young male drivers: A pilot study.

The Spring transition to Daylight Saving Time (DST) has been associated with several health and road safety issues. Previous literature has focused primarily on the analysis of historical crash and hospitalization data, without investigating specific crash contributing factors, such as driving fatigue. The present study aims to uncover the effects of DST-related circadian desynchrony and sleep deprivation on driving fatigue, by means of a driving simulator experiment. Eighteen participants (all males, age range 21-30 years, mean = 24.2, SD = 2.9) completed two 50-minute trials (at one week distance, same time and same day of the week) on a monotonous highway environment, the second one taking place in the week after the Spring transition to DST. Driving fatigue was evaluated by analysing several different variables (including driving-based, physiological and subjective indices) and by comparison with a historical cohort of pertinent, matched controls who had also undergone two trials, but in the absence of any time change in between. Results showed a considerable rise in fatigue levels throughout the driving task in both trials, but with significantly poorer performance in the post-DST trial, documented by a worsening in vehicle lateral control and an increase in eyelid closure. However, participants seemed unable to perceive this decrease in their alertness, which most likely prevented them from implementing fatigue-coping strategies. These findings indicate that DST has a detrimental effect on driving fatigue in young male drivers in the week after the Spring transition, and provide valuable insights into the complex relationship between DST and road safety.

A pilot study of golexanolone, a new GABA-A receptor-modulating steroid antagonist, in patients with covert hepatic encephalopathy.

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. CLINICAL TRIAL REGISTRATION NUMBER: EudraCT 2016-003651-30.

Clinical, neuropsychological and neurophysiological indices and predictors of hepatic encephalopathy (HE).

BACKGROUND AND 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 to: 1) describe a large cohort of patients with cirrhosis in terms of neuropsychological or neurophysiological HE indices, and 2) 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: Four hundred and sixty-one 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. Among patients without a history of overt HE, those with worse PHES had higher HE risk. Among 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.

Sleep, Circadian Rhythmicity and Response to Chronotherapy in University Students: Tips from Chronobiology Practicals.

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.

The psychomotor vigilance task: Role in the diagnosis of hepatic encephalopathy and relationship with driving ability.

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 ±â€¯10 years, model for end-stage liver disease [MELD] score 13 ±â€¯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 ±â€¯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.

The influence of HE history, HE status and neuropsychological test type on learning ability in patients with cirrhosis.

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.

Predictive value of induced hyperammonaemia and neuropsychiatric profiling in relation to the occurrence of post-TIPS hepatic encephalopathy.

Hepatic encephalopathy (HE) occurs in 20-50% of patients after transjugular intrahepatic portosystemic shunt (TIPS) placement. Older age, HE history and severe liver failure have all been associated with post-TIPS HE but it remains difficult to identify patients at risk. The aim of the present pathophysiological, pilot study was to assess the role of induced hyperammonaemia and associated neuropsychological and neurophysiological changes as predictors of post-TIPS HE. Eighteen TIPS candidates with no overt HE history (56 ± 8 yrs., MELD 11 ± 3) underwent neurophysiological [Electroencephalography (EEG)], neuropsychological [Psychometric Hepatic Encephalopathy Score (PHES) and Scan tests], ammonia and sleepiness assessment at baseline and after the induction of hyperammonaemia by an oral amino acid challenge (AAC). Pre-AAC, 17% of patients had abnormal EEG, 5% abnormal PHES, and 33% abnormal Scan performance. Post-AAC, 17% had abnormal EEG, 0% abnormal PHES, and 17% abnormal Scan performance. Pre-AAC, ammonia concentrations were 201 ± 73 µg/dL and subjective sleepiness 2.5 ± 1.2 (1-9 scale). Post-AAC, patients exhibited the expected increase in ammonia/sleepiness. Six months post-TIPS, 3 patients developed an episode of HE requiring hospitalization; these showed significantly lower pre-AAC fasting ammonia concentrations compared to patients who did not develop HE (117 ± 63 vs. 227 ± 57 µg/dL p = 0.015). They also showed worse PHES/Scan performance pre-AAC, and worse Scan performance post-AAC. Findings at 12 months follow-up (n = 5 HE episodes) were comparable. In conclusion, baseline ammonia levels and both pre- and post-AAC neuropsychiatric indices hold promise in defining HE risk in TIPS candidates with no HE history.

Cognitive, neurophysiologic and metabolic sequelae of previous hypoglycemic coma revealed by hyperinsulinemic-hypoglycemic clamp in type 1 diabetic patients.

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 < 0.05, respectively). In SH patients, eye-closed resting EEG showed a correlation between the mean dominance frequency and plasma glucose (r = 0.62, p < 0.001). Theta relative power increased during controlled hypoglycemia compared to euglycemia (21.6 ± 6 vs. 15.5 ± 3% Hz p < 0.05) and was higher than in the C group (21.6 ± 6 vs. 13.8 ± 3%, p < 0.03). The cognitive task beta activity was lower in the SH group than in the C group (14.8 ± 3 Hz, vs. 22.6 ± 4 vs. p < 0.03). Controlled hypoglycemia elicits cognitive dysfunction in both C and SH patients; however, significant EEG alterations during hypoglycemia were detected mainly in patients with a history of hypoglycemia unawareness and previous severe hypoglycemic coma. These data suggest that prior episodes of hypoglycemic coma modulate brain electric activity.

Proton pump inhibitor use and risk of hepatic encephalopathy: A multicentre study.

Background & Aims: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting, and data from multicentre studies are scarce. The aim of this study was to dissect the potential association between PPI use and minimal (MHE) and overt HE (OHE). Methods: Data from patients with cirrhosis recruited at seven centres across Europe and the US were analysed. MHE was defined by the psychometric hepatic encephalopathy score (PHES). PPI use was recorded on the day of testing with PHES. Patients were followed for OHE development and death/liver transplantation. Results: A total of 1,160 patients with a median MELD of 11 were included (Child-Pugh stages: A 49%/B 39%/C 11%). PPI use was noted in 58% of patients. Median follow-up time was 18.1 months, during which 230 (20%) developed an OHE episode, and 224 (19%) reached the composite endpoint of death/liver transplantation. In multivariable analyses, PPI use was neither associated with the presence of MHE at baseline nor OHE development during follow-up. These findings were consistent in subgroup analyses of patients with Child-Pugh A or B cirrhosis and after excluding patients with a history of OHE. PPI use was also not associated with a higher risk of OHE, neither in patients with an indication for treatment nor in patients without an indication. Conclusions: PPI use is not associated with a higher risk of HE in patients with cirrhosis. Based on these findings, at present, a prescription should not be prohibited in case of a generally accepted indication. Impact and implications: Data on the association between proton pump inhibitor (PPI) use and hepatic encephalopathy (HE) are conflicting. In this study, PPI use was not associated with a higher risk of minimal HE at baseline or overt HE during follow-up in patients with cirrhosis. Based on these findings, prescription of a PPI for a generally accepted indication should not be prohibited in patients with cirrhosis.

Managing Circadian Disruption due to Hospitalization: A Pilot Randomized Controlled Trial of the CircadianCare Inpatient Management System.

The objective of the present study was to test the effects of an inpatient management system (CircadianCare) aimed at limiting the negative impact of hospitalization on sleep by enhancing circadian rhythmicity. Fifty inpatients were randomized to either CircadianCare (n = 25; 18 males, 62.4 ± 1.9 years) or standard of care (n = 25; 14 males, 64.5 ± 2.3 years). On admission, all underwent a full sleep-wake evaluation; they then completed daily sleep diaries and wore an actigraph for the whole length of hospitalization. On days 1 (T0), 7 (T1), and 14 (T2, if still hospitalized), salivary melatonin for dim light melatonin onset (DLMO) and 24-h skin temperature were recorded. In addition, environmental noise, temperature, and illuminance were monitored. Patients in the CircadianCare arm followed 1 of 3 schedules for light/dark, meal, and physical activity timings, based on their diurnal preference/habits. They wore short-wavelength-enriched light-emitting glasses for 45 min after awakening and short-wavelength light filter shades from 18:00 h until sleep onset. While the first, primary registered outcome (reduced sleep-onset latency on actigraphy or diary) was not met, based on sleep diaries, there was a trend (0.05 < p < 0.1) toward an advance in bedtime for CircadianCare compared to standard of care patients between T0 and T1. Similarly, DLMO time significantly advanced in the small group of patients for whom it could be computed on both occasions, with untreated ones starting from earlier baseline values. Patients sleeping near the window had significantly higher sleep efficiency, regardless of treatment arm. As noise fluctuation increased, so did the number of night awakenings, regardless of treatment arm. In conclusion, the CircadianCare management system showed positive results in terms of advancing sleep timing and the circadian rhythm of melatonin. Furthermore, our study identified a combination of environmental noise and lighting indices, which could be easily modulated to prevent hospitalization-related insomnia.

PHES scores have limited impact on the risk of overt HE in patients with minimal HE.

BACKGROUND: Minimal hepatic encephalopathy, defined by the portosystemic hepatic encephalopathy score (PHES), is associated with a higher risk of subsequent OHE. It remains unclear if there is a stepwise increase in OHE risk with worse PHES results. METHODS: In this multicenter study, patients with minimal hepatic encephalopathy, as defined by abnormal PHES, were followed for OHE development. RESULTS: In all, 207 patients were included. There was no stepwise increase in OHE risk with worse PHES results. CONCLUSIONS: Abnormal PHES is associated with a higher OHE risk, but we found no stepwise increase in OHE risk with worse PHES results below the established cutoff.

Toward a Molecular Approach to Chronotype Assessment.

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.