Digital therapeutics have developed rapidly in recent years, providing a new method for disease management. The burden of liver diseases in China is heavy, and there are obvious problems in disease management. This paper expounds on the definition and classification of digital therapeutics, introduces their application in liver disease treatment and management in detail, and analyzes their development prospects in the field of liver diseases and future challenges.Graphical abstract available for this article.

Sarcopenia is highly prevalent in patients with liver cirrhosis and is associated with adverse clinical outcomes, including HE. Androgen receptor agonists, androgen receptor agonists, can address these conditions through multimodal mechanisms of action; however, their safety and efficacy in patients with cirrhosis have not been well established.

In this multicenter, double-blind, phase 2 trial, men with sarcopenia and cirrhosis awaiting liver transplant were randomized 1:1 to receive either oral Androgen Receptor Agonist LPCN 1148 or placebo for 24 weeks (NCT04874350). The primary end point was the change from baseline to 24 weeks in skeletal muscle index measured by a CT scan of the L3 region, analyzed with a prespecified modified intent-to-treat population. The secondary end point was the number of overt HE events. Twenty-nine participants (mean age=59 y, MELD=17) received at least 1 dose of LPCN 1148 (n=15) or placebo (n=14). Baseline characteristics were similar between groups. Primary end point analysis demonstrated an increase in L3-skeletal muscle index measured by a CT scan of the L3 region in the LPCN 1148 group (n=15) compared to placebo (n=10), with a mean group difference of 4.4 cm 2 /m 2 (95% CI: 1.3-7.4 cm 2 /m 2 , p =0.007). Participants in LPCN 1148 experienced fewer episodes of overt HE (Common Terminology Criteria for Adverse Events grade ≥2; p =0.02) than placebo. The number and severity of treatment-emergent adverse events were similar between arms.

LPCN 1148 treatment improved sarcopenia and reduced the number of overt HE episodes in men with cirrhosis and sarcopenia awaiting liver transplant. These findings support additional research on the efficacy of LPCN 1148 in treating sarcopenia and preventing HE recurrence.

Covert hepatic encephalopathy (CHE) is a subtle yet significant neurological complication of liver diseases, especially in patients with cirrhosis. Although it lacks overt clinical signs, CHE severely impacts quality of life, increases accident risks, and has serious prognostic implications. It is characterized by neurocognitive symptoms detectable only through specialized neuropsychometric tests. CHE affects 30%-80% of cirrhotic patients and represents the early stage of hepatic encephalopathy, which is a predictor of mortality. Early diagnosis is essential to improve patient outcomes. The Psychometric Hepatic Encephalopathy Score (PHES) is the gold standard for diagnosing CHE, but it is time-consuming and requires specialized training. Other tests, like the Animal Naming Test (ANT), are simpler and more practical for screening minimal hepatic encephalopathy (MHE), though they lack specificity. The Stroop test shows promise as a quicker and reliable diagnostic tool, but still has limitations. Recent innovations include a smartphone-based self-screening method developed by Dobbermann et al., combining three digital tests: the Tip Test, Number Connection Test, and Modified Stroop Test. This approach correlates well with PHES, is independent of language skills, and is accessible for a diverse patient population, including those with color vision deficiencies. This tool offers a rapid and reliable way to screen for CHE even in home settings, potentially improving early detection and intervention. In conclusion, CHE is an underrecognized but critical condition that requires greater clinical attention. Current diagnostic tools have limitations, highlighting the need for more effective, practical methods. A multidisciplinary approach involving hepatologists, neurologists, and neuropsychologists is crucial to improve the diagnosis and management of CHE, ultimately enhancing patient outcomes.

Cognitive impairment in cirrhosis is driven by multiple influencers. Those with cognitive impairment have greater traffic accidents and violations. While the presence of minimal hepatic encephalopathy has been associated with poor driving skills, studies show conflicting results and variable associations with regard to accidents.

In a prospective study of stable outpatients with cirrhosis without a recent history of overt hepatic encephalopathy (OHE) (<3 months), we assessed, the overall practice of driving, recent (<1 month) self-reported accidents, and factors associated with driving accidents.

Of 433 patients, 147 (33.9%) [age, 55 (46-61) years, 97.9% males, 29.9% alcohol-related, 13.6% prior OHE, MELD 11 (10-16), lactulose use 45.5%, rifaximin use 23.1%] reported recent driving (≤1 month), of whom 22 (14.9%) had recent driving accidents. Those with reported accidents had a higher history of prior OHE (31.8 vs. 10.5%, P  < 0.05) and lower sodium [131 (129-134) vs. 134 (132-138), P  < 0.05]. Psychometric hepatic encephalopathy score (PHES) [-5.5 (-4 to -9), vs. -4 (-3 to -7), P  = 0.10], alcohol as an etiology (22.7 vs. 31.2%, P  = 0.68), MELD [12.5 (10-17) vs. 11 (9.7-16), P  = 0.36], animal naming test [18 (16-23) vs. 18 (15-22), P  = 0.35], outpatient fasting ammonia [93 (63.7-121.5) vs. 81 (67.2-96.2), P  = 0.43] were similar. On univariate analysis, prior OHE, sodium levels and PHES [odds ratio (OR): 0.87 (0.75-1.0), P  = 0.09], and animal naming test [OR: 0.89 (0.76-1.04), P  = 0.10)] showed a trend of association, while on multivariable analysis only prior OHE [adjusted OR: 3.48 (1.07-10.74), P  = 0.03] and sodium levels [adjusted OR: 0.89 (0.79-0.99), P  = 0.03] were associated with recent driving accidents [model AUC (prior OHE + Na≤130), 0.70 (0.62-0.77)].

In stable outpatients with cirrhosis, a remote history of OHE and hyponatremia are most strongly associated with recent driving accidents.

Covert hepatic encephalopathy (CHE) can worsen the quality of life and prognosis of patients with cirrhosis. We analyzed the risk factors of CHE and identified patients at high risk for overt hepatic encephalopathy (HE) who would benefit from therapeutic interventions. We included 145 patients without a history of or treatment for overt HE. Patients were divided into the CHE and no-CHE groups (n = 91 and 54, respectively). CHE had a score above the age-based cutoff value of one of the neuropsychological tests, such as the Stroop and number connection tests. CHE prevalence was 62.8% (n = 91). Compared with the no-CHE group, the CHE group had significantly lower serum zinc and albumin levels. Multiple logistic regression analysis identified serum zinc levels at a cutoff value of 74 µg/dL. Subclinical zinc deficiency showed a diagnostic performance of 55.6% sensitivity and 81.5% specificity for CHE. Blood ammonia levels and liver functional reserves were not predictive of CHE. Compared with patients with zinc levels < 74 µg/dL (n = 102), those with ≥74 µg/dL (n = 43) had significantly lower CHE prevalence and better hepatic functional reserve. Subclinical zinc deficiency was associated with CHE occurrence in patients with cirrhosis without a history of or treatment for overt HE. Measurement of zinc levels facilitates early detection of CHE by neuropsychological testing.

Objectives: Water polo players ought to possess various physical capacities and well-developed cognitive functions that reflect the requirements of their specific playing position. Therefore, the objective of this study was to compare the cognitive performance, anthropometric characteristics and specific swimming capacities of youth water polo players in different playing positions. Methods: The present cross-sectional study involved 106 youth water polo players. The subjects were recruited as part of a project for talent identification and selection for the Croatian National Water Polo Team. Testing included anthropometric measurements, specific swimming capacities and cognitive performance (Stroop test). Results: Among the 106 youth water polo players, there were 15 goalkeepers (14.2%), 21 center-defenders (19.8%), 17 center-forwards (16.0%), 34 drivers (32.1%) and 19 wings (17.9%), with the mean age of 14.14 ± 0.38 years. The wings performed faster than center-forwards in both StroopOff time (wings: 57.14 ± 10.04 s vs. center-forwards: 67.03 ± 9.72 s, p = 0.016) and StroopOn time (wings: 66.18 ± 15.86 s vs. center-forwards: 80.24 ± 15.64 s, p = 0.019). Conclusions: In conclusion, this study demonstrated significant differences between different playing positions in youth water polo players, specifically between center-forwards and wings. They performed faster than center-forwards in all tested variables of the Stroop test, measures of psychomotor ability, response inhibition and motor speed, as well as in specific swimming capacities measured in the 50 m crawl and the 400 m crawl. The results of this study provide a valuable foundation for establishing developmental recommendations for different playing positions, aimed at improving player's performance. These recommendations should take into account anthropometric characteristics, specific functional swimming capacities and cognitive functions that influence players' game intelligence, which can be enhanced through properly designed training programs.

Background: Trends in global ageing underscore the rising burden of age-related cognitive decline and concomitant cardiometabolic diseases, including type 2 diabetes mellitus (T2DM). Carnosine, a naturally occurring dipeptide with anti-inflammatory, antioxidant and anti-glycating properties, has shown promise in animal models and limited human studies for improving cognitive function, insulin resistance and T2DM, but its therapeutic effects on cognition remain unclear. The aim of this study is to assess the effects of carnosine on cognitive function in individuals with prediabetes or well-controlled T2DM. Methods: This is a secondary analysis of a double-blind randomised controlled trial (RCT), whereby 49 adults with prediabetes or early-stage well-controlled T2DM were randomised to receive 2 g of carnosine or identical placebo daily for 14 weeks. At baseline and follow-up, cognitive function was assessed as a secondary outcome using the Digit-Symbol Substitution Test, Stroop test, Trail Making Tests A & B, and the Cambridge Automated Neuropsychological Test Battery (CANTAB). Results: In total, 42 adults (23 males and 19 females) completed the trial. There were no differences in participant anthropometry or cognitive functioning between carnosine and placebo groups at baseline (all p > 0.1). After the 14-week supplementation period, there were no differences between carnosine and placebo groups in change and follow-up values for any cognitive measures including Stroop, Digit Symbol Substitution Sest, Trail Making A/B or CANTAB (all p > 0.05). Adjustments for baseline cognitive scores, diabetic status, level of education, age or interaction effects with participants' sex did not change the results. Conclusions: Carnosine supplementation did not improve cognitive measures in individuals with prediabetes or T2DM in this study. While larger trials may provide further insights, alternative factors-such as the relatively young and healthy profile of our cohort-may have contributed to the lack of observed effect. Future research should examine individuals with existing cognitive impairment or those at higher risk of cognitive decline to better define the therapeutic potential of carnosine in this context.

Minimal hepatic encephalopathy is a common and prognostically severe complication of cirrhosis with a significant impact on the quality of life. Detailed diagnostic work-up of minimal hepatic encephalopathy is time-consuming and difficult to integrate into daily clinical routine.

We aimed to develop a new, simple, and easy-applicable smartphone-based self-assessment method for screening of minimal hepatic encephalopathy.

92 patients with cirrhosis and 20 healthy controls were recruited to perform 3 different short digital tests on smartphones (Tip test (TT), number connection test (dNCT) and modified Stroop test (ST)). Results were correlated with the Psychometric Hepatic Encephalopathy Score (PHES) as the presumed gold standard for minimal hepatic encephalopathy. The impact of age, gender, education, CHILD and MELD scores was further investigated.

All 3 digital tests showed good correlation with PHES (TT r = -0.76, dNCT r = -0.58, and ST r = -0.65; all p < 0.001). Digital tests were performed significantly faster (TT median 41s (IQR 36-51s); dNCT median 21s (IQR 8-16s); ST median 76s (IQR 55-99s) than PHES (median 322s; IQR 261-434s); There were significant differences between age groups and different levels of education (p < 0.05). AUC for TT was 0.835 (95% confidence interval 0.747-0.922, p < 0.001) and highest among all digital tests.

All 3 digital tests proved to be suitable for screening of minimal hepatic encephalopathy. TT showed the highest correlation with reference PHES and was not affected by language skills or color blindness, and, thus, might represent a new and fast method for minimal hepatic encephalopathy detection. Intra-individually adjusted smartphone-based thresholds might further eliminate the influence of age, gender, educational level or training, to refine early app-based alerts in case of cognitive deterioration in cirrhotic patients.

With progress in basic and clinical research on hepatic encephalopathy in cirrhosis worldwide, the Chinese Society of Hepatology of the Chinese Medical Association has invited experts in relevant fields to revise the 2018 "Chinese Guidelines on the Management of Hepatic Encephalopathy in Cirrhosis." The updated guidelines provide recommendations for the clinical diagnosis, treatment, and both primary and secondary prevention of hepatic encephalopathy in cirrhosis.

Jiang et al explored the diagnostic capabilities of EncephalApp, a smartphone-based Stroop Test, in patients with nonalcoholic liver disease. The study included 160 patients with nonalcoholic cirrhosis and utilized the psychometric hepatic encephalopathy score as a benchmark for diagnosing minimal encephalopathy. The identified optimal cutoff times were > 101.93 seconds for the "off" time and > 205.86 seconds for the combined "on + off" time, demonstrating sensitivities of 0.84 and 0.90, and specificities of 0.77 and 0.71, respectively. The findings suggest the necessity of employing different cutoffs for patients with alcoholic vs nonalcoholic liver cirrhosis, reflecting the distinct pathophysiologies underlying each condition. Additionally, alcohol consumption itself may influence Stroop test outcomes. Therefore, it is reasonable to establish separate benchmarks for alcoholic and nonalcoholic cirrhotic patients. Further validation in larger patient cohorts with clinical outcomes is essential. The demand for noninvasive liver disease assessments remains high in clinical practice.

Background/Objective: Recently, there has been an increasing need to implement the diagnosis of the presence of covert hepatic encephalopathy (CHE) in patients with cirrhosis. The aim of this study was to identify novel factors associated with CHE in clinical practice. Methods: This retrospective study enrolled a total of 402 patients with cirrhosis at 17 institutions. The Stroop test was performed to diagnose CHE at each center. Results: The patients comprised 233 males and 169 females, with a median age of 69 (IQR, 61-75) years. The median albumin and 25(OH)D3 levels were 3.9 (3.5-4.3) g/dL and 15.4 (11.0-21.0) ng/mL, respectively. This cohort included 181 patients with esophageal varices (EV). Multivariate analysis revealed that low 25(OH)D3 (p < 0.05) and EV (p < 0.05) were independent risk factors for CHE. When limited to only laboratory factors, low albumin (p < 0.01) and low 25(OH)D3 (p < 0.05) were independent factors for CHE. The optimal cut-off values of albumin and 25(OH)D3 for predicting CHE were 3.7 g/dL and 16.5 ng/mL, respectively. The prevalence of CHE was 59.2% for 25(OH)D3 < 16.5 ng/mL and EV, 53.8% for albumin < 3.7 g/dL and 25(OH)D3 < 16.5 ng/mL, and 66.7% for albumin < 3.7 g/dL, EV, and 25(OH)D3 < 16.5 ng/mL. Conclusions: Low 25(OH)D3 and albumin levels, and the EV were positively associated with CHE in patients with cirrhosis. Specifically, the prevalence of CHE increased with a decrease in 25(OH)D3 levels. Patients with such risk factors should be actively and carefully examined for the presence of CHE.

Laboratory studies have demonstrated that manual dexterity decreases with increasing cold, which may adversely affect performance. Dexterity may be impaired by cooling of the hand, cooling of the lower motor neurons, and cognitive impairment. Wetsuits are commonly used in open-water swimming and are mandated in some situations. This study investigates the effects of cold-water wetsuited swimming on dexterity.

Five male and 4 female trained swimmers were recruited for this cohort crossover study. Following dual-energy X-ray absorptiometry scans to determine body composition, they swam in a freshwater lake on 7 occasions with water temperatures between 24.5 °C and 8.4 °C. Dexterity was measured preswim and postswim with a "nut-washer-bolt assembly time test" and cognition with a Stroop test. Core and peripheral body temperatures were continuously monitored. Effects were analyzed by linear mixed-model regression.

Pre-post swim difference in time to complete the nut-bolt assembly increased as water temperatures decreased (1.0 s, 95% CI, 0.5-1.5 per 1 °C, P < .0001; R2 = .456), to a maximum of 14.7 seconds (95% CI, 3.3-26.0). This represented a 47.5% increase in assembly time from 24.5 °C to 8.4 °C, which we consider to be of practical significance. Decreased dexterity was associated with decreased forearm and scapular temperature and decreased cognitive function. Body composition did not affect dexterity, cognitive function, or body temperature during swims. Water temperature did not affect swim speed.

Despite the use of wetsuits, manual dexterity decreased with cold-water swimming. Swimmers, triathletes, and event organizers should consider the implications for safety, performance, and equipment utilization.

In chronic diseases, there have been issues with low levels of participant adherence and retention during well-supported lifestyle behaviour change interventional studies. Theoretically informed, the objective was to explore the types of challenges participants are experiencing to inform future designs.

We conducted an exploratory descriptive study in an adult cirrhosis population after the first 4-6 weeks of a 12-week semi-supervised nutrition and exercise online program.

Participants in the parent feasibility study, assessing the nutrition and exercise intervention (Heal-Me), were eligible for this nested study. Heal-Me is a multimodal program that is tailorable to a participant's abilities through regular interaction with the study's registered dietician and exercise specialist. Interviews (~60 min) with participants were recorded then analysed descriptively, guided by the capability, opportunity and motivational behaviour change model.

The 20 participants preferred the expert-led group online nutrition and exercise classes over independent activities such as protein tracking and the exercise videos. Social gamification (e.g., weekly polls on favourite things like movies or sports teams) contributed to the group experience. All except one person required program tailoring to address preferences, abilities and new onset health events. Findings led to the inclusion of 4 behaviour change techniques to the initial 17, whereas 2 others were expanded.

While program tailoring, awareness of cirrhosis nutrition and regular interactions with staff influenced participant retention and adherence in the first 4-6 weeks of the online program.

There is a growing global burden of liver disease with the current management for complications of liver cirrhosis being reactive as opposed to proactive, affecting outcomes. Management can often be suboptimal in overburdened health-care systems with considerable socioeconomic and geographical disparity existing, which was exacerbated by the COVID-19 pandemic, highlighting the need for sustainable care pathways to be delivered remotely. To this end, digital health care could be the key and, in this Review, we highlight the principal studies that have explored the use of digital technology in the management of cirrhosis complications. While digital health care is a somewhat new field, considerable advances have been made in various domains, particularly in the development of remote monitoring and risk modelling. We aim to provide a balanced perspective of the opportunities for and barriers to the integration of digital technology into established liver-care pathways. Lastly, we reflect on the current acceptability of digital health care and the required future directions to ensure the digital transformation of hepatology is a success.

According to the latest clinical guidelines, minimal hepatic encephalopathy (MHE) is diagnosed by using a single test for which the center has experience and local norms. Nowadays, several tests are available. Here we describe the most frequently used tests: Psychometric Hepatic Encephalopathy Score (PHES), Continuous Reaction Time (CRT), Inhibitory Control Test (ICT), Stroop test, Animal Naming Test (ANT), critical flicker frequency (CFF) and electroencephalography (EEG) using characteristics such as: creation specificity, neurocognitive domains, computerized vs. pencil and paper, translatability, time to perform, learning effect, affecting factors, local norms, copyright, medical equipment and need for specific training. After that we briefly address comparison of the results of different tests or test combinations. Such information may prove useful to anyone new to the field of minimal hepatic encephalopathy.

Current guidelines recommend the assessment for minimal HE in patients with liver cirrhosis. Various efforts were made to find tools that simplify the diagnosis. Here, we compare the 6 most frequently used tests for their validity and their predictive value for overt hepatic encephalopathy (oHE), rehospitalization, and death.

One hundred thirty-two patients with cirrhosis underwent the Portosystemic Encephalopathy-Syndrome-Test yielding the psychometric hepatic encephalopathy score (PHES), Animal Naming Test (ANT), Critical Flicker Frequency (CFF), Inhibitory Control Test (ICT), EncephalApp (Stroop), and Continuous Reaction Time Test (CRT). Patients were monitored for 365 days regarding oHE development, rehospitalization, and death. Twenty-three patients showed clinical signs of HE grade 1-2 at baseline. Of the remaining 109 neurologically unimpaired patients, 35.8% had abnormal PHES and 44% abnormal CRT. Percentage of abnormal Stroop (79.8% vs. 52.3%), ANT (19.3% vs. 51.4%), ICT (28.4% vs. 36.7%), and CFF results (18.3% vs. 25.7%) changed significantly when adjusted norms were used for evaluation instead of fixed cutoffs. All test results correlated significantly with each other ( p <0.05), except for CFF. During follow-up, 24 patients developed oHE, 58 were readmitted to the hospital, and 20 died. Abnormal PHES results were linked to oHE development in the multivariable model. No other adjusted test demonstrated predictive value for any of the investigated endpoints.

Where applicable, the diagnosis of minimal HE should be made based on adjusted norm values for the tests, exclusively. The minimal HE tests cannot be equated with one another and have an overall limited value in predicting clinical outcomes.

Minimal hepatic encephalopathy (MHE) has a substantial impact on the clinical outcomes and quality of life (QOL) of patients with cirrhosis. However, timely diagnosis and intervention are challenging due to sophisticated diagnostic methods. In this study, 673 healthy controls and 905 patients with cirrhosis were screened, and 660 healthy controls and 757 patients with cirrhosis, divided into the test (292 patients) and validation (465 patients) cohort, were analyzed after screening. A diagnostic model of the Stroop test (Stroop-CN) was constructed by multivariate linear regression based on the results of healthy controls. The prevalence of MHE and the comparison results with psychometric hepatic encephalopathy score through the Stroop-CN model were stable in the test and validation cohorts. Moreover, the prevalence of MHE remained significantly higher in patients with worse disease conditions marked as high Child-Pugh grades and the Model for End-stage Liver Disease and Sodium (MELD-Na) scores in the test and validation cohort. The EuroQol 5-D questionnaire revealed that patients with MHE had a worse QOL than those without MHE both in the test and validation cohort. In conclusion, an easy and practical Stroop-CN model for MHE diagnosis based on the EncephalApp is established. It is found that a considerable number of Chinese patients with cirrhosis experience MHE, which significantly impacts their QOL.

This pilot study evaluated the impact of using a 3D printed model of the patient's bronchovascular lung anatomy on the mental workload and fatigue of surgeons during full thoracoscopic segmentectomy.

We performed a feasibility pilot study of a prospective randomized controlled trial with 2 parallel arms. All included patients underwent digital 3D visual reconstruction of their bronchovascular anatomy and were randomized into the following two groups: Digital arm (only a virtual 3D model was available) and Digital + Object arm (both virtual and printed 3D models were available). The primary end-point was the surgeons' mental workload measured using the National Aeronautics and Space Administration-Task Load Index (NASA-TLX) score.

Between October 28, 2020 and October 05, 2021, we successively investigated all anatomic segmentectomies performed via thoracoscopy in the Thoracic Department of the Montsouris Mutualiste Institute, except for S6 segmentectomies and S4+5 left bi-segmentectomies.

We assessed 102 patients for anatomical segmentectomy. Among the, 40 were randomly assigned, and 34 were deemed analysable, with 17 patients included in each arm.

Comparison of the two groups, each comprising 17 patients, revealed no statistically significant difference in primary or secondary end-points. The consultation of the visual digital model was significantly less frequent when a 3D printed model was available (6 versus 54 consultations, p = 0.001). Notably, both arms exhibited high NASA-TLX scores, particularly in terms of mental demand, temporal demand, and effort scores.

In our pilot study, 3D printed models and digital 3D reconstructions for pre-operative planning had an equivalent effect on thoracoscopic anatomic segmentectomy for experienced surgeons. The originality of this study lies in its focus on the impact of 3D printing of bronchovascular anatomy on surgeons, rather than solely on the surgical procedure.

Minimal hepatic encephalopathy (MHE) is a pervasive frequent complication of cirrhosis of any etiology. The diagnosis of MHE is difficult as the standard neurologic examination is essentially within normal limits. None of the symptoms and signs of overt HE is present in a patient with MHE, such as confusion, disorientation, or asterixis. Progress has been made in diagnostic tools for detection of attention and cognitive deficits at the point of care of MHE. The development of MHE significantly impacts quality of life and activities of daily life in affected patients including driving motor vehicles and machine operation.

This study aimed to analyze the validity and reliability of a smartphone app (i.e., Encephalapp Stroop) to measure cognitive performance. Ten physically active individuals (mean age: 25.2 ± 4.3 years) participated in three laboratory visits. In a randomized sequence, subjects completed cognitive assessments using the app and a computer separately. The response times from 100 measurements for congruent and incongruent stimuli were compared between the two devices (app and computer) using the intraclass correlation coefficient, Pearson product-moment correlation coefficient (r), Cronbach's alpha (α), and Bland-Altman plots. There was excellent agreement between the computerized Stroop and the app version for response times for congruent (ICC = 0.806, p < 0.001; Bland-Altman bias = 41.3 ± 56.4 ms, p < 0.001) and incongruent stimuli (ICC = 0.755, p < 0.001; Bland-Altman bias = 76.4 ± 75.1 ms, p < 0.001). In comparison to the computerized version, the app demonstrated a moderate correlation for response times of congruent (r = 0.678, p < 0.001) and incongruent (r = 0.623, p < 0.001) stimuli. The results of the present study indicate that the response times of congruent and incongruent stimuli can be easily, accurately, and reliably evaluated using a mobile app.

Sarcopenia is associated with adverse outcomes in cirrhosis. Branched-chain amino acids (BCAA) target several pathways that lead to muscle loss in this population.

We aimed to evaluate the impact of BCAA supplementation on sarcopenia measures in patients with cirrhosis.

We conducted a 12-month double-blinded, randomised, controlled trial of BCAA supplementation (30 g daily) compared to an equicaloric, equi-nitrogenous whey protein in volunteers with cirrhosis and reduced muscle strength. The primary endpoint was an increase in grip strength and upper limb lean mass measured on DEXA. Mean-adjusted differences (MAD, 95% CI) between groups at 6 and 12 months are reported as treatment effect using a linear mixed model for repeated measures.

A total of 150 volunteers entered the trial (74 BCAA, 76 control), with a median age of 58 years [IQR 48; 63] and MELD of 14 [12; 17]. At 12 months, 57% in the BCAA arm and 61% in the control arm met the primary endpoint (p = 0.80). No significant between-group difference was found in grip strength (MAD -0.15 kg [-0.37; 0.06], p = 0.29) or upper limb lean mass (1.7 kg [-0.2; 3.6], p = 0.22) at 12 months. No significant differences in other body composition parameters, physical performance, frailty, rates of hospitalisation or mortality were found between the BCAA and the control group. Fatigue improved across the entire cohort, without significant between-group differences. 15% of volunteers reported side effects, with distaste higher in the BCAA arm (p = 0.045).

BCAA supplementation did not improve measures of muscle strength, mass or performance or physical frailty compared to a whey protein supplement in a randomised controlled setting. ACTRN12618000802202.

Morbidities indicated for hospital-at-home (HAH) treatment include infectious diseases and exacerbations of chronic conditions. Electrolyte disturbances are not included per se. However, their rate is high. We aimed to describe our experience via the monitoring and treatment of such patients.

This was a retrospective analysis of patients in the setting of telemedicine-controlled HAH treatment. We collected data from the electronic medical records of patients who presented electrolyte disturbances.

For 14 months, we treated 267 patients in total in HAH settings, with a mean age of 72.2 + 16.4, 44.2% for males. In total, 261 (97.75%) patients were flagged with electrolyte disturbances, of whom 149 had true electrolyte disturbances. Furthermore, 67 cases (44.96%) had hyponatremia, 9 (6.04%) had hypernatremia after correction for hyperglycemia, 20 (13.42%) had hypokalemia and 27 (18.12%) had hyperkalemia after the exclusion of hemolytic samples. Ten (6.09%) patients had hypocalcemia and two (1.34%) had hypercalcemia corrected to albumin levels. Thirteen (8.72%) patients had hypomagnesemia and one (0.67%) had hypermagnesemia. Patients with electrolyte disturbances suffered from more chronic kidney disease (24.2% vs. 12.2%; p = 0.03) and malignancy (6.3% vs. 0.6%; p = 0.006), and were more often treated with diuretics (12.6% vs. 4.1%; p = 0.016). No patient died or suffered from clinically significant cardiac arrhythmias.

The extent of electrolyte disturbances amongst HAH treatment patients is high. The monitoring and treatment of such patients can be conducted safely in this setting.

Nutrition and exercise are the mainstay of therapy for the prevention and treatment of frailty in cirrhosis. This pilot study assessed feasibility of the online delivery of an app-based semi-supervised nutrition and exercise intervention in this population.

The 11-week pilot recruited adults with cirrhosis who owned internet-connected devices. Patients were encouraged to participate in exercise sessions 3× per week including a combination of online group exercise (weekly) and home-based follow-along exercise (biweekly). They also participated in group nutrition classes (five sessions) and one-to-one exercise and nutrition check-ins delivered through the app. Primary outcome measures pertained to program feasibility: recruitment, retention, adherence, and satisfaction. Exploratory measures included physical performance (liver frailty index [LFI], 6-minute walk test [6MWT]), health behaviour domains, and quality of life.

Twenty three patients completed baseline measures. Of these, 18 (72%) completed end of study measures (mean MELD-Na, 9.2; female, 44.4%). Over 70% of participants fulfilled 75% or more of the feasibility criteria. Satisfaction with the program was high (mean, 89%). Exercise program modifications were required for 17 patients to accommodate health events or abilities. Exploratory evaluation showed improvement in the LFI and the 6MWT by -0.58-units (95% CI: -0.91 to -0.25) and 46.0 m (95% CI: 22.7-69.3) respectively without changes in quality of life or health behaviour domains.

Outcomes demonstrate feasibility of the app-based delivery of programming with promising exploratory impact on efficacy for physical performance. Findings can guide the design of a large-scale app-based randomized controlled trials in cirrhosis.

Data regarding the prevalence and phenotype of cognitive impairment in non-alcoholic fatty liver disease (NAFLD) are limited.

We assessed the prevalence and nature of cognitive deficits in people with NAFLD and assessed whether liver fibrosis, an important determinant of outcomes in NAFLD, is associated with worse cognitive performance.

We performed a prospective cross-sectional study. Patients with NAFLD underwent liver fibrosis assessment with transient elastography and the following assessments: Cognitive Change Index, Eight-Item Informant Interview to Differentiate Aging and Dementia Questionnaire (AD8), Montreal Cognitive Assessment (MoCA), EncephalApp minimal hepatic encephalopathy test and a limited National Institutes of Health Toolbox battery (Flanker Inhibitory Control and Attention Test, Pattern Comparison Test and Auditory Verbal Learning Test). We used multiple linear regression models to examine the association between liver fibrosis and cognitive measures while adjusting for relevant covariates.

We included 69 participants with mean age 50.4 years (SD 14.4); 62% were women. The median liver stiffness was 5.0 kilopascals (IQR 4.0-6.9), and 25% had liver fibrosis (≥7.0 kilopascals). Cognitive deficits were common in people with NAFLD; 41% had subjective cognitive impairment, 13% had an AD8 >2, 32% had MoCA <26 and 12% had encephalopathy detected on the EncephalApp test. In adjusted models, people with liver fibrosis had modestly worse performance only on the Flanker Inhibitory Control and Attention Task (β=-0.3; 95% CI -0.6 to -0.1).

Cognitive deficits are common in people with NAFLD, among whom liver fibrosis was modestly associated with worse inhibitory control and attention.

The neurotoxic effects of ozone exposure are related to neuroinflammation and increases in reactive oxygen species (ROS). This study aimed to assess inflammation, Brain-Derived Neurotrophic Factor (BDNF), and cognition in healthy male cyclists following polyphenol supplementation and exercise in an ozone-polluted environment. Ten male cyclists initially completed a maximal incremental test and maximal effort 4 km time trial in ambient air. Cyclists then completed two trials in an ozone-polluted environment (0.25 ppm) following 7 days of supplementation with either polyphenol (POLY) or placebo (PL). Experimental trials consisted of a three-stage submaximal test followed by a 4 km time trial. Blood samples were drawn pre- and post-exercise, and analyzed for BDNF, interleukin 6 (IL-6), interleukin 10 (IL-10) and tumor necrosis factor (TNF-α). The Stroop test and serial subtraction task were performed before ozone exposure and again after the 4 km TT. Serum BDNF increased post-exercise (p < 0.0001), and positive differences were observed post-exercise in the ozone POLY group relative to PL (p = 0.013). Plasma IL-6 increased post-exercise (p = 0.0015), and TNF-α increased post-ozone exposure (p = 0.0018). There were no differences in Stroop or serial subtraction tasks pre- or post-exercise. Exercise increases BDNF in ozone.

Chronic liver disease and cirrhosis is a significant cause of healthcare utilization and patient morbidity and mortality worldwide. Smartphone applications have high uptake in most communities and therefore have great potential to provide remote support solutions to this patient population. The aim of this scoping review was therefore to provide a comprehensive overview using narrative synthesis on the use of smartphone-application-based digital interventions in cirrhotic populations.

PRISMA guidelines were followed, with two independent researchers identifying 10 relevant studies. Patients studied were predominantly those with decompensated cirrhosis, and hepatic encephalopathy was the most common complication studied.

Smartphones were the most common platform used, but training periods, prior to commencement of the study, were rarely offered. Patient engagement rates with the technology were reported only in three studies, but all reported high (>50%) rates of engagement. Only one study examined the clinical effects of their digital intervention, with a 38% reduction in readmission rate reported.

Overall, the use of smartphone apps in cirrhosis is in an early phase of development and evaluation but preliminary studies suggest significant potential as an adjunct to routine medical care. Further high-quality studies of well-designed digital interventions are needed to advance this promising early experience.

We examined the effect of amount of muscle mass involved in moderate-intensity continuous physical exercise on executive function. To this end, fifty-five participants completed two acute physical exercise sessions on an airbike ergometer using the upper and lower limbs simultaneously and only the upper limbs, and a resting control session in a randomized order. The physical exercise session lasted 30 min and was performed at moderate intensity (between 64 %-76 % of maximal heart rate evaluated in graded maximal exercise testing). Participants took the Stroop test (congruent and incongruent trials) before and after the sessions to assess executive performance. For the congruent trial, both physical exercise interventions improved executive function performance (pre vs. post, p-value = 0.002 and 0.003 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). Furthermore, executive function performance was higher after the physical exercise interventions than after the control session (p-value = 0.002 and 0.004 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). For the incongruent trial, both physical exercise interventions also improved executive function performance (pre vs. post, p-value < 0.001 for physical exercise with upper limbs and physical exercise with upper and lower limbs, respectively). However, there were no significant differences after both physical exercise interventions and resting control session (p-value = 0.175). Executive function (congruent trial) was positively impacted by acute aerobic physical exercise regardless of the amount of muscle mass involved (upper limbs or upper plus lower limbs). Therefore, we recommend aerobic physical exercise with less or more muscle mass involved to improve cognitive function.

Background: Covert hepatic encephalopathy (CHE) is underdiagnosed and is difficult to detect. The EncephalApp Stroop test is validated for its screening. The aim of the study was to define Tunisian norms for the test based on healthy controls norms and to estimate the prevalence of CHE in cirrhotic Tunisian patients. Methods: A prospective, multicenter, cross-sectional study was conducted. Ambulatory or hospitalized cirrhotic patients aged 40 years and over were recruited at 11 centers. Healthy subjects aged 40 years and over were recruited at 8 centers. We used a translated Arabic version of the streamlined EncephalApp Stroop test. The task has two components: "Off" and "On" state depending on the discordance or concordance of the stimuli. Results: 142 patients were included. The mean age was 57.26 years [40-86]. 40 (28.17%) of cirrhotic patients who were included were diagnosed as having a minimal hepatic encephalopathy or CHE. Among the ineligible patients, 22 had overt hepatic encephalopathy. If we consider these patients, the overall prevalence rate of CHE was around 24.39% in cirrhotic patients. It was more frequent in women (34.21% vs 25.96%), and in patients whose level of school education is between 6 and 13 years. Its prevalence does not appear to be affected by gender, MELD score, etiology of cirrhosis and age group of patients, as these variables were independent with respective p according to the chi-square test 0.413; 0.736; 0.663 and 0.1. The stroop times (On / Off and On + Off) correlated significantly with each other, are associated significantly and positively with age (respective Pearson coefficients: 0.578; 0.567 and 0.6). The more the age increases, the more the stroop response times increases (p > 10 -3). Conclusions: EncephalApp Stroop test was an efficient screening tool for CHE in Tunisian cirrhotic patients.

Sarcopenia in cirrhosis is associated with poor outcomes. While transjugular intrahepatic portosystemic shunt (TIPS) insertion improves radiological measures of muscle mass, its impact on muscle function, performance and frailty has not been evaluated.

Patients with cirrhosis referred for TIPS were prospectively recruited and followed for 6 months. L3 CT scans were used to calculate skeletal muscle and adipose tissue parameters. Handgrip strength, Liver Frailty Index and short physical performance battery were serially monitored. Dietary intake, insulin resistance, insulin-like growth factor (IGF)-1, and immune function using QuantiFERON Monitor (QFM) were measured.

Twelve patients completed the study with a mean age of 58 ± 9 years and model for end-stage liver disease score of 16 ± 5. At 6 months post-TIPS, skeletal muscle area increased from 139.33 cm 2  ± 22.72 to 154.64 ± 27.42 ( P  = 0.012). Significant increases were observed in the subcutaneous fat area ( P  = 0.0076) and intermuscular adipose tissue ( P  = 0.041), but not muscle attenuation or visceral fat. Despite marked changes in muscle mass, no improvements were observed in handgrip strength, frailty, or physical performance. At 6 months post-TIPS, IGF-1 ( P  = 0.0076) and QFM ( P  = 0.006) increased compared to baseline. Nutritional intake, hepatic encephalopathy measures, insulin resistance and liver biochemistry were not significantly impacted.

Muscle mass increased following TIPS insertion as did IGF-1, a known driver of muscle anabolism. The lack of improvement in muscle function was unexpected and may relate to impairment in muscle quality and the effects of hyperammonaemia on muscle contractile function. Improvements in QFM, a marker of immune function, may suggest a reduction in infection susceptibility in this at-risk population and requires further evaluation.

For patients with chronic liver disease (CLD), telemedicine is emerging as a useful tool to prevent liver decompensation or hospitalization, allowing access to and the decentralization of care, even for patients with limited resources. However, research and attendant evidence are still lacking; thus, this review aims to systematically explore the topic of telemonitoring for CLD to describe the currently used tools and clinical outcomes. The review was conducted by using key terms on PubMed/EMBASE and searching for observational studies or clinical trials (according to PRISMA recommendations) that were published between 6 April 2013 and 6 April 2023 to keep the technological framework limited to the last 10 years. The studies were described and grouped according to the aim of telemonitoring, the underlying disease, and the tools adopted to achieve remote monitoring. A total of 32 articles met the inclusion criteria. Of these, 11 articles report the successful use of a telehealth program to support and improve access to care in the management of HCV-related cirrhosis, eight articles examine the efficacy of telemedicine for remote monitoring interventions to prevent or decrease the risk of decompensation in high-risk patients, and five articles examine improvements in the physical performance and quality of life of cirrhotic patients through telehealth rehabilitation programs. Four studies were completed during the recent COVID-19 pandemic. Telehealth has the potential to provide and expand treatment access and reduce barriers to care for the most disadvantaged patients and might be able to reduce the need for hospital readmission for CLD, though most practice to test feasibility is still in the pilot stage.

It remains challenging to identify covert hepatic encephalopathy and predict progression to overt hepatic encephalopathy. Psychometric testing is a widely used diagnostic modality, but it is often inaccurate and difficult to implement in diverse populations, making it a less than ideal assessment. Alternatively, by using easily accessible data from the electronic health record, simple clinical assessment tools, and patient-reported outcomes, we may be better able to predict hepatic encephalopathy across multiple populations. Furthermore, incorporation of patient-reported outcomes into our diagnostic toolset not only aids detection of covert hepatic encephalopathy and prediction of overt hepatic encephalopathy, but also allows us to target therapies and track their impact. Herein, we outline a potential algorithm based on these easily integrated tools to promote patient risk-stratification and early therapeutic intervention.

Patients with decompensated cirrhosis present frequent hospitalisations with a relevant clinical and socio-economic impact. This study aims to characterise unscheduled readmissions up to 1-year follow-up and identify predictors of 30-day readmission after an index hospitalisation for acute decompensation (AD).

We performed a secondary analysis of a prospectively collected cohort of patients admitted for AD. Laboratory and clinical data at admission and at discharge were collected. Timing and causes of unscheduled readmissions and mortality were recorded up to 1 year.

A total of 329 patients with AD were included in the analysis. Acute-on-chronic liver failure was diagnosed in 19% of patients at admission or developed in an additional 9% of patients during the index hospitalisation. During the 1-year follow-up, 182 patients (55%) were rehospitalised and 98 (30%) more than once. The most frequent causes of readmission were hepatic encephalopathy (36%), ascites (22%), and infection (21%). Cumulative incidence of readmission was 20% at 30 days, 39% at 90 days, and 63% at 1 year. Fifty-four patients were readmitted for emergent liver-related causes within 30 days. Early readmission was associated with a higher 1-year mortality (47 vs. 32%, p = 0.037). Multivariable Cox regression analysis showed that haemoglobin (Hb) ≤8.7 g/dl (hazard ratio 2.63 [95% CI 1.38-5.02], p = 0.003) and model for end-stage liver disease-sodium score (MELD-Na) >16 at discharge (hazard ratio 2.23 [95% CI 1.27-3.93], p = 0.005), were independent predictors of early readmission. In patients with MELD-Na >16 at discharge, the presence of Hb ≤8.7 g/dl doubles the risk of early rehospitalisation (44% vs. 22%, p = 0.02).

Besides MELD-Na, a low Hb level (Hb ≤8.7 g/dl) at discharge emerged as a new risk factor for early readmission, contributing to identification of patients who require closer surveillance after discharge.

Patients with decompensated cirrhosis face frequent hospitalisations. In the present study, type and causes of readmissions were analysed during 1-year follow-up in patients discharged after the index hospitalisation for an acute decompensation of the disease. Early (30-day) liver-related readmission was associated with higher 1-year mortality. The model for end-stage liver disease-sodium score and low haemoglobin at discharge were identified as independent risk factors for early readmissions. Haemoglobin emerged as a new easy-to-use parameter associated with early readmission warranting further investigation.