In addition to surgical technology, successful liver transplantation (LT) depends on perioperative management, which needs an effective prognostic index. Therefore, a simplified and sensitive postoperative index for adult LT should be developed.

In total, 906 patients who underwent LT were included in this cross-sectional study. Univariate analysis was used to identify the independent risk factors for recipient survival. Multivariate logistic and stepwise regression analyses were used to construct and simplify the model design. Area under the curve (AUC) and Kaplan-Meier's (K-M) analysis demonstrated superiority of the new index. The postoperative survival score (POSS) index was further simplified via restricted cubic spline (RCS) analysis. Finally, the interpretation of the long-term mortality and subgroup analyses extended the application of the POSS index.

Finally, a total of five factors (donor sex, recipient body mass index (BMI), total bilirubin (Tbil), international normalized ratio (INR) and total operative time) were identified as independent risk parameters and included in our POSS index. The AUCs of the original and simplified POSS indices were 0.764 and 0.723, respectively. Patients with high scores had poor short-term survival. Our index also functioned well in predicting long-term mortality, and it was more effective for patients with hepatitis B cirrhosis or hepatocellular carcinoma (HCC).

We constructed a simplified and effective postoperative survival scoring index to predict short-term complications and survival in adult LT patients.

Early prediction of the prognosis of viral-related cirrhosis patients after transjugular intrahepatic portosystemic shunt (TIPS) is beneficial for clinical decision-making. The aim of this study is to explore a comprehensive prognostic assessment model for evaluating the survival outcomes of patients post-TIPS.

A total of 155 patients treated with TIPS were included in the study. The data were collected from electronic records. The nutritional status of the patient is evaluated using imaging examinations measuring by the axial CT images from the L3 vertebral level. The primary endpoint was set as death within 1 year after TIPS. Multivariate Cox regression was performed to determine the factors associated with mortality.

The Cox regression analysis revealed that the lower PMFI was associated with a lower risk of all-cause mortality after TIPS (hazard ratio [HR] 1.159, 95% confidence interval [CI] 1.063-1.263, p = 0.001). Furthermore, subgroup analyses according to gender revealed the PMFI was associated with postoperative death both in male (HR 2.125, 95% CI, 1.147-3.936, p = 0.017) and female patients (HR 1.070, 95% CI, 1.001-1.144, p = 0.047). The area under the curve (AUC) for predicting death within 1 year was 0.807. The clinical impact curve analysis showed that PMFI had higher levels of risk threshold probability and a smaller gap between actual and predicted curves.

In viral-related cirrhosis patients with portal hypertension, increased muscle fat content might be a potential prognostic marker and associated with postoperative death after TIPS.

This review highlights recent advancements in liver organ allocation, specifically the transition to MELD 3.0 and the potential introduction of continuous distribution. These developments are timely, as they address the increasing need for a more efficient, equitable, and personalized system for prioritizing liver transplant candidates.

The review covers two key innovations: MELD 3.0: A refined version of the original MELD score, designed to improve the prioritization process by incorporating additional factors that offer a more accurate and urgent measure of transplant need. This approach aims to better assess the severity of liver disease and the need for transplantation. Continuous distribution: A dynamic approach that shifts away from the static allocation model. It integrates multiple donor and recipient variables - such as geographic location, organ quality, and recipient condition - into a continuous, flexible allocation process. This framework seeks to make more nuanced decisions based on a broader set of factors that reflect transplant suitability.

These innovations aim to enhance fairness and patient outcomes by refining candidate prioritization and reducing disparities in access to transplants. However, implementing these systems presents challenges, such as technical complexities and regional differences in access. Ongoing evaluation is necessary to ensure their effectiveness and equitable implementation across diverse patient populations.

Drug-induced liver injury (DILI) remains a leading cause of acute liver failure worldwide. Drugs such as isoniazid, alone or in combination with other anti-tuberculosis drugs, as well as a growing number of herbal and complementary medicines, have been implicated in most cases of acute liver failure in registry studies.

This review summarizes current knowdledge on the acute and chronic outcomes in patients with idiosyncratic DILI and discusses several of the existing prognostic models.

The reasons why some individuals progress from DILI to end-stage liver disease are still largely unknown. However, collaborative efforts over the past few decades have provided figures on the relative incidence of drug-induced acute liver failure and allowed the development of prognostic models to predict this worse outcome at the onset of the event. The outcome of chronic DILI is less well characterised due to the lack of sufficient follow-up in cohort studies, but several phenotypes of DILI can progress to chronicity, and specific drugs such as nitrofurantoin or amiodarone are classic examples of agents leading to chronic forms of DILI. Therapy for drug-induced acute liver failure and chronic DILI is mainly supportive, although some randomised clinical trials have shown beneficial effects of N-acetylcysteine and corticosteroids.

/Aims: This study aimed to evaluate the performance of the Model for End-Stage Liver Disease (MELD) 3.0 for predicting mortality and liver-related complications compared with the Child-Pugh classification, albumin-bilirubin (ALBI) grade, the MELD, and the MELD sodium (MELDNa) score.

We evaluated a multicenter retrospective cohort of incorporated patients with cirrhosis between 2013 and 2019. We conducted comparisons of the area under the receiver operating characteristic curve (AUROC) of the MELD3.0 and other models for predicting 3-month mortality. Additionally, we assessed the risk of cirrhosis-related complications according to the MELD3.0 score.

A total of 3,314 patients were included. The mean age was 55.9±11.3 years, and 70.2% of the patients were male. Within the initial 3 months, 220 patients (6.6%) died, and the MELD3.0 had the best predictive performance among the tested models, with an AUROC of 0.851, outperforming the Child-Pugh classification, ALBI grade, MELD, and MELDNa. A high MELD3.0 score was associated with an increased risk of mortality. Compared with that of the group with a MELD3.0 score <10 points, the adjusted hazard ratio of the group with a score of 10-20 points was 2.176, and that for the group with a score of ≥20 points was 4.892. Each 1-point increase in the MELD3.0 score increased the risk of cirrhosis-related complications by 1.033-fold. The risk of hepatorenal syndrome showed the highest increase, with an adjusted hazard ratio of 1.149, followed by hepatic encephalopathy and ascites.

The MELD3.0 demonstrated robust prognostic performance in predicting mortality in patients with cirrhosis. Moreover, the MELD3.0 score was linked to cirrhosis-related complications, particularly those involving kidney function, such as hepatorenal syndrome and ascites.

Alcohol-associated hepatitis (AH) is the leading cause of liver-related mortality, with severe alcohol-associated hepatitis (SAH) showing a short-term mortality rate of 20%-50% even in developed countries. Corticosteroids are the only evidence-based pharmacologic treatment, but their efficacy is limited to short-term survival, with 30%-40% of patients achieving a complete response. Early liver transplantation (LT) has been explored as a salvage therapy for steroid-refractory SAH, but its feasibility is restricted by ethical concerns and donor shortages, particularly in Japan. In the absence of LT eligibility, patients are often left with the best supportive care, underscoring the urgent need for alternative salvage therapies. Recent studies have explored selective anti-inflammatory strategies targeting proinflammatory cytokines, such as TNFα and IL-1β. However, clinical trials have yet to demonstrate sufficient efficacy to outweigh the increased risk of infection. Granulocyte colony-stimulating factor (G-CSF) therapy has been investigated for its potential to promote liver regeneration, but its efficacy remains inconsistent across populations. Neutrophil-targeted therapies, including granulocyte-monocyte/macrophage apheresis (GMA), have emerged as a novel approach. Our recent pilot study demonstrated improved survival in patients with steroid-refractory SAH treated with GMA, supporting its potential as a safe and effective anti-inflammatory therapy. This review summarizes the latest advances in the treatment of SAH and emphasizes the need for novel salvage therapies to address unmet needs in steroid-refractory cases. Further research is essential to validate these new therapies and to optimize treatment strategies to improve the long-term prognosis of SAH.

Fatigue and altered cognitive capacity are common symptoms following cirrhosis. Patients consider information about cirrhosis difficult to understand. Health literacy levels vary among persons with chronic illnesses, which can hamper participation in and adaptation to treatment, potential restrictions and recommendations. Limited health literacy might also lead to decreased autonomy.

The aim was to explore predictors of limited health literacy among adults with cirrhosis.

This cross-sectional study explored health literacy among 167 Swedish adults with cirrhosis, 94 men and 73 women with a median age of 65 years using the 'Newest Vital Sign' instrument. Predictors of limited health literacy were examined in relation to patient characteristics and cirrhosis disease events. The study is reported following the STROBE guidelines.

The prevalence of limited health literacy was 58%. Low education and covert hepatic encephalopathy were associated with limited health literacy (p < 0.05).

Limited health literacy is common among Swedish adults with cirrhosis. Both covert hepatic encephalopathy and low education might be predictors of limited health literacy. Healthcare providers should tailor their patient education based on the patient's literacy level to facilitate understanding, learning and self-management.

Post-hepatectomy liver failure (PHLF) is a severe complication following liver surgery. We aimed to develop a novel, interpretable machine learning (ML) model to predict PHLF. We enrolled 312 hepatocellular carcinoma (HCC) patients who underwent hepatectomy, and 30% of the samples were utilized for internal validation. Variable selection was performed using the least absolute shrinkage and selection operator regression in conjunction with random forest and recursive feature elimination (RF-RFE) algorithms. Subsequently, 12 distinct ML algorithms were employed to identify the optimal prediction model. The area under the receiver operating characteristic curve, calibration curves, and decision curve analysis (DCA) were utilized to assess the model's predictive accuracy. Additionally, an independent prospective validation was conducted with 62 patients. The SHapley Additive exPlanations (SHAP) analysis further explained the extreme gradient boosting (XGBoost) model. The XGBoost model exhibited the highest accuracy with AUCs of 0.983 and 0.981 in the training and validation cohorts among 12 ML models. Calibration curves and DCA confirmed the model's accuracy and clinical applicability. Compared with traditional models, the XGBoost model had a higher AUC. The prospective cohort (AUC = 0.942) further confirmed the generalization ability of the XGBoost model. SHAP identified the top three critical variables: total bilirubin (TBIL), MELD score, and ICG-R15. Moreover, the SHAP summary plot was used to illustrate the positive or negative effects of the features as influenced by XGBoost. The XGBoost model provides a good preoperative prediction of PHLF in patients with resectable HCC.

Acute-on-chronic liver failure (ACLF) represents the terminal and most lethal phase of acute decompensated cirrhosis. Systemic inflammation plays a critical role in the pathogenesis of ACLF. Systemic inflammation reaction syndrome (SIRS) is a marker of ongoing inflammation. Therefore, we aim to evaluate the relationship of sterile SIRS with hepatitis B virus (HBV)-related ACLF (HBV-ACLF).

HBV-ACLF patients with sterile SIRS who were hospitalized between December 2016 and December 2018 were retrospectively analyzed. All patients were followed up until 90 days. Risk factors associated with 90-day mortality and sterile SIRS development were assessed.

Among 151 HBV-ACLF patients without infection, 37 patients (24.5%) presented with or developed sterile SIRS. During the 90-day follow-up, 23 of the 37 patients with sterile SIRS died (62.2%), compared to 40 patients without sterile SIRS (35.1%, P  = 0.004). Univariate analysis showed that age, total bilirubin (TBIL), international normalized ratio, ammonia, presence of sterile SIRS, model for end-stage liver disease score, presence of complications, and organ failures were associated with 90-day mortality. In multivariate analyses, the presence of sterile SIRS was an independent risk factor for 90-day mortality. Among SIRS components, heart rate (HR) was the most frequently met criterion (56 patients, 37.09%). Patients who met the HR or temperature criterion had lower 90-day survival rate than those who did not (46.4 vs 65.3%, P  = 0.020; 16.7 vs 60.0%, P  = 0.020).

The presence of sterile SIRS in HBV-ACLF patients was closely associated with prognosis.

Accurate prediction of disease severity and prognosis are challenging in patients with cirrhosis. We evaluated whether the deep learning-based AI-Cirrhosis-ECG (ACE) score could detect hepatic decompensation and predict clinical outcomes in cirrhosis.

We analyzed 2,166 ECGs from 472 patients in a retrospective Mayo Clinic cohort, 420 patients in a prospective Mayo transplant cohort, and 341 patients in an external validation cohort from Hospital Clínic de Barcelona. The ACE score's performance was assessed using receiver-operating characteristic analysis for decompensation detection and competing risks Cox regression for outcome prediction.

The ACE score showed high accuracy in detecting hepatic decompensation (area under the curve 0.933, 95% CI: 0.923-0.942) with 88.0% sensitivity and 84.3% specificity at an optimal threshold of 0.25. In multivariable analysis, each 0.1-point increase in ACE score was independently associated with increased risk of liver-related death (hazard ratio [HR] 1.44, 95% CI 1.32-1.58, p <0.001). Adding ACE to model for end-stage liver disease-sodium significantly improved prediction of adverse outcomes across all cohorts (c-statistics: retrospective cohort 0.903 vs. 0.844; prospective cohort 0.779 vs. 0.735; external validation 0.744 vs. 0.732; all p <0.001).

The ACE score accurately identifies hepatic decompensation and independently predicts liver-related outcomes in cirrhosis. This non-invasive tool enhances current prognostic models and may improve risk stratification in cirrhosis management.

This study demonstrates the potential of artificial intelligence to enhance prognostication in liver disease, addressing the critical need for improved risk stratification in cirrhosis management. The AI-Cirrhosis-ECG (ACE) score, derived from widely available ECGs, shows promise as a non-invasive tool for detecting hepatic decompensation and predicting liver-related outcomes, which could significantly impact clinical decision-making and resource allocation in hepatology. These findings are particularly important for hepatologists, transplant surgeons, and patients with cirrhosis, as they offer a novel approach to complement existing prognostic models such as model for end-stage liver disease-sodium. In practical terms, the ACE score could be integrated into routine clinical assessments to provide more accurate risk predictions, potentially improving the timing of interventions, optimizing transplant listing decisions, and ultimately enhancing patient outcomes. However, further validation in diverse populations and integration with other established predictors is necessary before widespread clinical implementation.

Direct-acting antiviral (DAA) regimens for the treatment of hepatitis C virus (HCV) infection are endowed with sustained virological response (SVR) rates >95%. However, HCV cure does not completely eliminate the risk of hepatocellular carcinoma (HCC) development and liver decompensation. The present study investigated the impact of the administered DAA regimen on clinical long-time outcomes after SVR.Matched-pair survival analyses of 5802 chronically HCV infected patients from the German Hepatitis C-Registry compared the incidence of liver-related events 2.5 years after SVR in patients receiving either sofosbuvir (SOF)-based treatment or NS3/NS4A-protease inhibitor (PI)-containing DAA regimens. Hypothesis driven logistic regression analyses were performed to identify independent predictors for the occurrence of liver-related events.Matched-pair survival analyses revealed a borderline significant difference in the incidence of liver-related endpoints (except of HCC development) in patients receiving SOF-based treatment (4.1%) compared to PI-containing DAA regimens (2.6%) 2.5 years after SVR (p=0.061). Numerically, a trend towards a benefit of PI-based DAA treatment was observed (PI 65 events vs SOF 102 events). Hypothesis driven logistic regression analyses could not confirm SOF-based treatment as an independent predictor for the occurrence of liver-related events after HCV cure (p=0.072, OR=0.670).The incidence of liver-related events 2.5 years after HCV cure did not differ significantly between SOF-based DAA treatment and PI-containing regimens. However, numerically a trend towards a benefit of PI-based DAA treatment was observed. Therefore, a minor effect of the applied DAA regimen on the long-term incidence of liver-related events cannot be excluded.

We sought to develop a predictive model to preoperatively identify patients with hepatocellular carcinoma (HCC) at risk of undergoing futile upfront liver resection (LR).

Patients undergoing curative-intent LR for HCC were identified from a large multi-institutional database. Futile LR was defined by death or disease recurrence within six months postoperatively. Backward logistic regression was performed to identify factors associated with futility. Additionally, binary criteria were established for surgical candidacy, aiming to keep the likelihood of futility below 20 %.

Among 1633 patients with HCC, 264 (16.2 %) underwent futile upfront LR. Tumor burden score (TBS) (coefficient: 0.083, 95%CI: 0.067-0.099), alpha-fetoprotein (AFP) (coefficient: 0.254, 95%CI: 0.195-0.310), and albumin-bilirubin (ALBI) grade 2/3 (coefficient: 0.566, 95%CI: 0.420-0.718) were independently associated with an increased risk of futile LR. The model demonstrated strong discrimination and calibration in both derivation and validation cohorts. Low, intermediate, and high-risk groups were determined based on the risk model, each with an escalating likelihood of futility, worse histological features, and worse survival outcomes. Six distinct conditions based on AFP-adjusted-to-TBS criteria were established, all with a futility likelihood of less than 20 %. Patients fulfilling these criteria had significantly better long-term recurrence-free and overall survival. The futility risk model was made available online for wide clinical applicability: (https://altaf-pawlik-hcc-futilityofsurgery-calculator.streamlit.app/).

A preoperative risk model and AFP-adjusted-to-TBS criteria were developed and validated to predict the likelihood of futile LR among patients with HCC. This pragmatic clinical tool may assist clinicians in preoperative decision-making, helping them avoid futile surgery unlikely to offer long-term benefits.

Morphologic criteria, such as the Barcelona Clinic Liver Cancer staging system often fail to accurately predict long-term survival among patients undergoing liver resection for hepatocellular carcinoma. We sought to develop a continuous risk score that incorporates established markers of tumor biology and liver function to improve the prediction of overall survival.

Data from a multi-institutional database were used to identify patients who underwent curative-intent hepatectomy for hepatocellular carcinoma. A predictive score for overall survival was developed using weighted beta-coefficients from a multivariable Cox regression model.

Among 850 patients, 595 (70.0%) were assigned to the training cohort, and 255 (30.0%) to the test cohort. In the training cohort, multivariable analysis identified the Model of End-Stage Liver Disease (hazard ratio, 1.04; 95% confidence interval, 1.01-1.07), log-transformed alpha-fetoprotein (hazard ratio, 1.07; 95% confidence interval, 1.02-1.13), and tumor burden score (hazard ratio, 1.07; 95% confidence interval, 1.03-1.11) as independent predictors of worse overall survival. The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score, based on the Cox model, stratified patients into low-risk (n = 466, 78.3%) with a 5-year OS of 70.5% and high-risk (n = 129, 21.7%) with a 5-year OS of 47.0% (P < .001). In the test cohort, the Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score demonstrated superior discriminative accuracy (C-index: 0.72, time-dependent area under the curve 1-year: 0.80, 3-year 0.76, 5-year 0.70) compared with the Barcelona Clinic Liver Cancer staging system (C-index: 0.53, time-dependent area under the curve 1-year: 0.61, 3-year 0.55, 5-year 0.56). An online tool was made accessible at https://jk-osu.shinyapps.io/MELD_AFP_TBS/.

The Model of End-Stage Liver Disease-alpha-fetoprotein-tumor burden score provides a novel, accurate tool for prognostic stratification of patients with hepatocellular carcinoma, identifying high-risk patients who may benefit from alternative treatments to improve outcomes.

Systemic therapy represents the standard of care treatment for patients with advanced hepatocellular carcinoma (HCC). Given the increased risk of death from cirrhosis-related complications in patients with advanced liver dysfunction, pivotal phase III trials traditionally limited inclusion to patients with Child-Pugh class A, where death is more likely to be attributed to HCC progression. Therefore, Western guidelines recommend the use of systemic therapies primarily in patients with preserved liver function. However, patients with HCC and Child-Pugh class B are commonly encountered in clinical practice, but due to limited prospective evidence, there is no clear guidance on their optimal management.In this recent advances article, we discuss how the clinical course of cirrhosis can affect eligibility to treatment in the modern era of systemic therapy for HCC, elaborate on strategies to improve liver function in HCC patients by targeting cirrhosis-related and tumour-related factors and summarise the current literature on systemic therapy in HCC patients with Child-Pugh class B. Based on this information, we finally propose a clinical algorithm on how to systematically approach patients with HCC and advanced liver dysfunction in clinical practice.

Robotic-assisted hepatectomy has gained traction in hepatobiliary surgery, but its cost-effectiveness compared to traditional surgical approaches remains unclear. This study investigates clinical outcomes and financial implications of robotic-assisted liver surgery in a high-volume center, comparing it with open and laparoscopic methods. A retrospective cohort study was conducted on patients undergoing hepatectomy at Lille University Hospital in 2018 and 2021, performed by the institution's first experienced robotic hepatobiliary surgeon. Data on patient demographics, intraoperative details, postoperative outcomes, and costs were analyzed. Costs included hospital stays, surgical materials, and complications, derived from national cost studies. A total of 111 patients were included, with a rise in minimally invasive procedures from 47.5% in 2018 to 75% in 2021. Robotic-assisted hepatectomy was associated with reduced hospital stays, lower complication rates, and fewer severe morbidities compared to laparotomy. The average cost per procedure (all surgical approaches combined) decreased from €12,169 in 2018 to €8,513 in 2021, with robotic surgery offering a significant financial advantage. The total savings for the 71 patients in the 2021 cohort was €259,576, driven primarily by reduced hospitalization times and fewer complications. Robotic-assisted hepatectomy is clinically safe and cost-effective, offering substantial financial savings over traditional surgery. The reduction in postoperative complications and hospital stay durations, particularly for complex cases, highlights the advantages of robotic surgery in hepatobiliary procedures. As surgical expertise increases, robotic surgery represents a sustainable and efficient alternative in liver resection.

Phosphatidylethanol (PEth) is an ethanol metabolite used as a specific biomarker for recent alcohol consumption. We aimed to determine the proportion of patients with or at risk for metabolic dysfunction-associated steatotic liver disease (MASLD) who had PEth levels indicative of harmful alcohol consumption, and to assess associations between PEth levels and the risk of major adverse liver outcomes (MALOs).

We conducted a cohort study involving persons tested for PEth in Stockholm, Sweden between 2012 and 2020 (N=46,406), including patients with various steatotic liver disease (SLD) subtypes and individuals without SLD. Cumulative incidences of MALOs were calculated for the different groups while accounting for competing risk. Cox regression was used to evaluate the association between baseline PEth levels and the incidence of MALOs.

Among 6,377 patients with presumed MASLD, 1,294 (20%) had baseline PEth levels between 0.05 and 0.30 μmol/L (35-210 ng/ml), indicating excessive alcohol intake (MetALD), while 854 patients (13%) had values >0.30 μmol/L, indicating alcohol-related liver disease (ALD). Patients with MASLD and PEth levels between 0.05-0.30 μmol/L had similar median FIB-4 scores and cirrhosis prevalence as those with MASLD and PEth levels <0.05 μmol/L. However, patients with PEth levels between 0.05-0.30 μmol/L had higher cumulative incidences of MALOs compared to those with PEth levels <0.05 μmol/L. Elevated PEth levels were significantly linked to higher rates of MALOs in patients without cirrhosis, even after adjustments for age, sex, SLD subtype, and FIB-4 score. Patients with ALD had the highest PEth levels and worst prognosis.

PEth is a valuable alcohol biomarker for distinguishing between SLD subtypes, especially ALD, and predicts adverse outcomes in people with and without SLD.

There is controversy regarding the various proposed steatotic liver disease (SLD) subtypes, the most recent definition suggesting that patients with an elevated alcohol consumption and MASLD should be classified as having MetALD. Here, we address this challenge by classifying patients with SLD by utilizing the biomarker phosphatidylethanol (PEth), a direct and reliable biomarker for recent alcohol consumption. Our analysis of this large cohort-comprising 46,406 patients-revealed that using the objective PEth biomarker may be a valuable tool for distinguishing between MASLD and MetALD, and that PEth is strongly associated with the risk of liver outcomes in individuals with and without known SLD. Integrating PEth testing into routine diagnostic evaluations could enhance knowledge on the underlying pathophysiology in SLD, reduce the potential for misclassification, and ultimately improve patient outcomes by enabling clinicians to offer appropriate therapies. Further research is needed to validate these findings in other populations and to explore the potential integration of PEth into broader clinical guidelines for managing SLD.

Given our desire to reduce kidney transplant waiting times by utilizing more difficult-to-place ("higher-risk") DD kidneys, we wanted to better understand post-transplant renal function among 1119 adult DD recipients consecutively transplanted during 2016-2019. Stepwise linear regression of eGFR (CKD-EPI formula) at 3-, 6-, and 12-months post-transplant (considered as biomarkers for longer-term outcomes), respectively, was performed to determine the significant multivariable baseline predictors, using a type I error ≤ 0.01 to avoid spurious/weak associations. Three unfavorable characteristics were selected as highly significant in all three models: Older DonorAge (yr) (p < 0.000001), Longer StaticColdStorage Time (hr) (p < 0.000001), and Higher RecipientBMI (p ≤ 0.00003). Other significantly unfavorable characteristics included: Shorter DonorHeight (cm) (p ≤ 0.00001), Higher Natural Logarithm {Initial DonorCreatinine} (p ≤ 0.001), Longer MachinePerfusion Time (p ≤ 0.003), Greater DR Mismatches (p = 0.01), DonorHypertension (p ≤ 0.004), Recipient HIV+ (p ≤ 0.006), DCD Kidney (p = 0.002), Cerebrovascular DonorDeath (p = 0.01), and DonorDiabetes (p = 0.01). Variables not selected into any model included DonorAKI Stage (p ≥ 0.24), Any DonorAKI (p ≥ 0.04), and five KDRI components: two DonorAge splines at 18 years (p ≥ 0.52) and 50 years (p ≥ 0.28), BlackDonor (p ≥ 0.08), DonorHCV+ (p ≥ 0.06), and DonorWeight spline at 80 kg (p ≥ 0.03), indicating that DonorAKI and the weaker KDRI components have little, if any, prognostic impact on renal function during the first 12 months post-transplant. Additionally, biochemical determinations with skewed distributions such as DonorCreatinine are more accurately represented by natural logarithmic transformed values. In conclusion, one practical takeaway is that donor AKI may be ignored when evaluating DD risk.

Hepatocellular carcinoma arises in the setting of cirrhosis in most cases, requiring multidisciplinary input to define resectability. In this regard, more precise surgical management considers patient factors and anatomical states, including resection margins, tumour biology, and perioperative therapy. Together with advances in surgical techniques, this integrated approach has resulted in considerable improvements in patient morbidity and oncological outcomes. Despite this, recurrence rates in hepatocellular carcinoma remain high. As the systemic treatment landscape in hepatocellular carcinoma continues to evolve and locoregional options are increasingly used, we review current and future opportunities to individualise the surgical management of patients with hepatocellular carcinoma.

Objective: The prevalence and mortality of chronic liver disease has risen significantly. In end-stage liver disease (ESLD), the survival of patients is approximately 2 years. Despite the poor prognosis and high symptom burden, integration of palliative care in ESLD is reduced, and the majority of patients continue to die in inpatient care. We aim to assess predictors and outcomes of home palliative care, as well as factors associated with death at home in patients with ESLD. Methods: Retrospective cohort study of patients with ESLD, followed by a palliative care team between 2017 and 2022. Information regarding patient demographics, ESLD etiology, decompensations, and interventions was collected. Two-sided tests were used to identify factors associated with home palliative care. Results: We analyzed 75 patients: 44% had home palliative care and 33% died at home. ESLD patients with home palliative care were older (72.52 vs 64.45; p = 0.002), had a longer palliative care intervention time (149.97 ± 196.23 vs 43.69 ± 100.60 days; p = 0.007), higher rates of ascites or hepatic encephalopathy (χ2 = 11.024; p = 0.029), and hepatocarcinoma (90.9% vs 64.3%; p = 0.007). Patients with home palliative care had a reduction in-hospital admissions (2.61 vs 1.06; p = 0.000) and a greater probability of death at home (66.7% vs 33.3%; p = 0.000). Patients who died at home (33.3%) were older (72.20 vs 64.40; p = 0.000) and had longer palliative care intervention time (178.80 ± 211.78 vs 46.28 ± 99.67 days; p = 0.006). Conclusion: Home palliative care in ESLD differs based on demographics and disease complications, with a positive impact of homecare translated into a reduction in hospital admissions and an increased probability of death at home.

Emerging evidence suggests that rotational thromboelastometry (ROTEM) is superior to conventional haemostatic tests in the assessment and management of bleeding risk in patients with cirrhosis. Whether ROTEM may also be useful for assessing the prognosis of these patients is unknown. We aimed to explore the role of ROTEM in predicting the transplant-free survival of patients with cirrhosis.

We conducted a prospective cohort study of patients with cirrhosis at two hospitals. All patients underwent ROTEM analysis at baseline and were followed up until death, liver transplantation or the end of follow-up (28 February 2023). Univariate and multivariate Cox regression analyses were performed to explore the association between transplant-free survivals.

Between April 2018 and October 2021, 162 patients with cirrhosis were recruited and followed-up for a median of 42 months. During follow-up, 36 patients died and 7 underwent liver transplantation. On univariate analysis, maximum clot firmness (MCF) using both EXTEM and INTEM tests was significantly reduced in the death/liver transplant group compared to the survivor group (52 vs. 57, P  = 0.02; and 51 vs. 55, P  = 0.01, respectively). After adjusting for age, sex, presence of clinically significant portal hypertension, hepatocellular carcinoma, care setting, bilirubin, sodium and creatinine, only albumin (hazard ratio: 0.92, 95% CI: 0.85-0.99, P  = 0.018) and MCF EXT (hazard ratio: 0.96, 95% CI: 0.92-0.99, P  = 0.032) remained significant predictors of transplant-free survival.

ROTEM may be useful in assessing the survival of patients with cirrhosis. Further research is needed to determine the clinical utility of ROTEM parameters as prognostic markers in cirrhosis.

Increasingly, acute care surgeons have taken over the management of general surgery consult patients in the hospital, many of whom present with sepsis and/or in septic shock. In this article, we will discuss the intricacies of sepsis management for acute care surgery. The underlying tenants of sepsis management will be outlined with specific attention to the nuances associated with surgical patients. Ultimately, when a surgical problem is identified, this management will culminate with the need for specific source control - the unique aspect when a surgical as opposed to a medical disease process is the cause of sepsis. However, surgeons must also be competent in the other components of sepsis management including antimicrobial therapy and hemodynamic support. This article is designed for the surgeon or for any provider caring for patients with a potential acute care surgical problem, recognizing that different practice settings will vary with regard to resource availability for laboratory tests, invasive monitoring, diagnostics, and surgeon availability.

Biliary strictures are among the most common complications following liver transplantation (LT). If endoscopic retrograde cholangiography fails, percutaneous transhepatic biliary drainage (PTBD) may serve as an alternative approach. Description of clinical important short- and long-term outcomes as well as outcome prediction following PTBD after LT are scarce.

We analyzed outcomes of 56 liver-transplanted adults with biliary complications receiving a PTBD. We described the safety and longitudinal laboratory changes. We analyzed as endpoints, incidence of biliary complications, need for surgical biliary revision/re-LT and overall-survival at 12- and 60-months. We used simple comparison tests accordingly and performed competing risk analysis and multivariate competing risk regression as well as log-rank test and cox proportional hazard regression for further analysis.

PTBD procedures had a high technical success rate (98%) and tolerable safety profile. Multiple laboratory indicators improved during follow-up (37 patients with complete biochemical follow-up). Incidence of subsequent biliary complications was highly dependent on the nature of present biliary strictures (Anastomotic stricture (AS): adjusted SHR: 0.26, 95% CI: 0.09-0.78, p = 0.016). Need for surgical biliary revision/re-LT remained below 15%. 12-month survival was significantly better, if drainage into the small intestine was achieved at first attempt compared to completely external drainage (internal: 92.9 vs. external: 67.9%, p = 0.018). Patients with AS had a numerically higher long-term-survival and higher C-reactive-protein (CRP) and lower body-mass-index (BMI) at baseline were significantly associated with inferior short- and long-term-survival.

PTBD for biliary complications following LT had a high technical success and a tolerable safety profile. Incidence of subsequent biliary complications was highly dependent on the nature of biliary strictures and increased mortality was found in patients with higher CRP, lower BMI and failure of initial PTBD internalization.

Hepatocellular carcinoma (HCC) is the sixth common malignancy worldwide. In Egypt, the main cause of HCC is hepatitis C virus (HCV)-related cirrhosis. After the successful mass treatment program of HCV in 2018 with direct-acting antivirals (DAAs) therapy, a large percentage of patients have been treated and effectively achieved sustained virological response (SVR). Recently, some studies claimed that HCCs that developed after treatment with DAAs have more aggressive behavior. Purpose of the study is to detect the possible change of HCC pattern before and after DAAs era and its effect on overall survival (OS).

428 naïve HCC patients were divided into 2 groups: Group I HCC patients not treated with DAAs and Group II HCC patients treated with DAAs. Then we compared demographic, clinical, radiological, and laboratory characteristics between both groups.

Group II had improved liver function tests, including serum bilirubin, albumin, and international normalized ratio, than Group I (p < 0.001, p < 0.001, p < 0.001, respectively). They had a lower level of liver aminotransferases. Group II showed a larger infiltrative pattern of HCC, with a high incidence of portal vein thrombosis (p = 0.003, p < 0.001, p = 0.048, respectively). Group II received more curative or palliative treatment options, while 55 % of Group I received the best supportive care. There was no significant difference in 1-year and 2-years OS between both group, except that group II patients had better 2-year OS in subgroup BCLC stage C.

The tumor pattern has changed into a more aggressive phenotype after DAAs. DAAs have succeeded in preserving the liver condition. However, they did not demonstrate any protective effect on the OS of the patients. There is a strong need for strict screening program for early detection of HCC in the early stages, that are eligible for curative options, after HCV treatment of DAAs.

Laparoscopic liver surgery following previous resections poses significant challenges due to adhesions and altered anatomy. Hand-assisted laparoscopic liver resection (HALR) combines the tactile advantages of open surgery with minimally invasive techniques, potentially benefitting patients undergoing repeat hepatectomy. This study aims to assess the safety and efficacy of HALR for repeat hepatectomy and compare these outcomes with those of an open liver resection (OR).

A retrospective study included patients who underwent repeat hepatectomy via HALR or OR from January 2013 to December 2022. Patient characteristics and outcomes were compared before and after propensity score matching. The primary outcome was 90-day morbidity. Surgical difficulty was stratified using the Institut Mutualiste Montsouris (IMM) classification into grade I (low), grade II (intermediate), and grade III (high).

The study included 248 patients: 112 in the HALR group and 136 in the OR group. Conversion to open occurred in 2 cases (1.8%). After matching, 76 HALR patients were compared with 76 OR patients. HALR patients had a longer operative time (median: 402 vs. 277 min and p < 0.001), shorter postoperative hospital stay (median: 8.0 vs. 9.0 days and p < 0.001), and higher hospital cost (median: $10,607 vs. $6260 and p < 0.001). No significant differences in 90-day morbidity or readmission rates. Risk factors for 90-day morbidity included the ASA score ≥ 2, diabetes, IMM grade 3, and portal hypertension.

HALR for repeat hepatectomy is feasible and safe, with perioperative outcomes comparable to OR. HALR may be a viable alternative for selected patients.

Triggering receptor expressed on myeloid cells 2 (TREM2)-expressing macrophages and systemic levels of soluble TREM2 (sTREM2) appear critical in the development of chronic liver disease (CLD) and seem relevant in its detection. The aim of this study was to examine sTREM2 as a marker for early CLD and its potential to predict posthepatectomy liver failure (PHLF) in patients undergoing partial hepatectomy.

sTREM2 was assessed in the plasma of 108 patients undergoing liver resection. Blood was drawn prior to surgery (preop) and on the first and fifth postoperative day.

Preop sTREM2 levels were similar across different indications for resection (p = 0.091). Higher preop sTREM2 levels were associated with advanced hepatic fibrosis (p = 0.030) and PHLF (p = 0.007). Fibrosis-4 index (FIB-4) (p = 0.619) and model for end-stage liver disease (MELD) (p = 0.590) did not show a difference between patients grouped by their CLD. Comparing the AUC from receiver-operating characteristic analysis, sTREM2 (AUC = 0.708) outperformed FIB-4 (AUC = 0.529), MELD (AUC = 0.587), Child-Pugh grading (AUC = 0.570) and LiMAx (liver maximum capacity test) (AUC = 0.516) in predicting PHLF. Similarly, in uni- and multivariate analysis, only sTREM2 proved predictive for PHLF (p = 0.023). High-risk (p = 0.003) and low-risk (p = 0.011) cut-offs for systemic sTREM2 levels could identify patients at risk for adverse outcomes after surgery. Finally, high sTREM2 was associated with decreased overall survival after liver surgery (p <0.001).

Circulating sTREM2 shows sensitivity for early-stage, asymptomatic liver disease, irrespective of the underlying indication for liver surgery. Assessment of CLD via sTREM2 monitoring could improve early detection of CLD and improve outcomes after liver surgery.

Soluble TREM2 (sTREM2) has previously been shown to correlate with the degree of chronic liver disease. We found that even in patients undergoing liver resection, who generally do not suffer from end-stage liver disease, sTREM2 reflects liver fibrosis status and predicts postoperative development of liver dysfunction. This is especially relevant for liver surgeons and patients, as postoperative liver dysfunction is the main reason for postoperative mortality. Our findings are also important for hepatologists, as early detection of liver fibrosis and cirrhosis is paramount for overall patient survival and we can show that even in a cohort with a median model for end-stage liver disease score of 6, sTREM2 is able to distinguish patients based on their liver fibrosis status.

Transjugular intrahepatic portosystemic shunt (TIPS) placement leads to a reduction in portal pressure and an improvement in survival in patients with recurrent and refractory ascites and variceal haemorrhage. Prediction of post-TIPS survival is primarily determined by factors identified before the TIPS procedure, as data collected during or after TIPS implantation are limited. The aim of the study was to evaluate the influence of early hemodynamic changes after TIPS placement on survival, in order to refine post TIPS management.

In this prospective bicentric study, consecutive patients (n = 105) undergoing TIPS placement for ascites or variceal haemorrhage underwent measurement of portal pressure gradient (PPG) immediately at TIPS insertion (PPG0) and 24 h later (PPG24h) and the ΔPPG was calculated from PPG24h and PPG0 (ΔPPG = PPG24h-PPG0). Kaplan-Meier survival analysis and uni- and multivariable regression analyses were conducted to identify survival predictors.

Patients with lack of increased ΔPPG exhibited poorer 90-day and 1-year survival compared to patients with increased ΔPPG. This worse survival was independent of The Model for End-Stage Liver Disease (MELD) score, Child-Pugh score, bilirubin levels, creatinine and the Freiburg index of post-TIPS survival (FIPS) > 0.92. Among these patients with poorer outcome, elevated bilirubin (> 25 μmol/L) further distinguished survivors from non-survivors.

Lack of increased ΔPPG post-TIPS insertion identifies a high-risk patient group with worse survival. We propose incorporating this second PPG measurement and determining ΔPPG into clinical practice to identify these patients early and tailor post-TIPS patient care.

Acute-on-chronic liver failure (ACLF) is a complicated syndrome associated with high short-term mortality and reversibility. Whether the prior decompensation should be included in the definition of ACLF is controversial.

A total of 532 patients with decompensation (prior or first) of chronic liver disease were retrospectively enrolled and analyzed from January 2018 to June 2023. Clinical data were used to identify the characteristics and determine prognosis.

Of the 532 patients, 99 patients did not meet APASL-ACLF criteria due to the existence of prior decompensation and 433 patients met the Asian Pacific Association for the Study of the Liver (APASL)-ACLF criteria. The two groups had similar characteristics including prognosis scores (Chinese Group on the Study of Severe Hepatitis B (COSSH)-ACLF II score: 7.59 vs. 7.67, p = 0.934; Chronic Liver Failure (CLIF) Consortium ACLF score: 42.90 vs. 44.81, p = 0.273), the distribution of patients with APASL ACLF research consortium score (AARC score) (5-7: 19.2%/12.0%; 8-10: 56.6%/55.0%; 11-15: 24.2%/33.0%, p > 0.05) and the 28-/90-day mortality rates (30.5%/43.2% vs. 36.3%/43.1%, p = 0.267/0.978). In all integrated ACLF patients, Receiver Operating Characteristic (ROC) curve analysis and decision curve analysis (DCA) showed that COSSH-ACLF IIs had higher prognostic efficiency and clinical net benefit than AARC score and CLIF-C ACLFs for 28-/90-day mortality.

Prior decompensated patients exhibited clinical characteristics and high short-term mortality similar to those of first decompensated patients. The COSSH-ACLF IIs demonstrated the highest prognostic efficiency for all integrated ACLF patients. Including prior decompensation in the ACLF definition can help to simplify and improve clinical management.

Background: Chronic liver disease (CLD) and cirrhosis contribute to approximately 2 million deaths annually, with primary causes including alcohol-related liver disease (ALD), metabolic dysfunction-associated steatotic liver disease (MASLD), and chronic hepatitis B and C infections. Among these, MASLD has emerged as a significant global health concern, closely linked to metabolic disorders and a leading cause of liver failure and transplantation. Objective: This review aims to highlight the interplay between cirrhosis and cardiac dysfunction, emphasizing the pathophysiology, diagnostic criteria, and management of cirrhotic cardiomyopathy (CCM). Methods: A comprehensive literature review was conducted to evaluate the hemodynamic and structural cardiac alterations in cirrhosis. Results: Cirrhosis leads to portal hypertension and systemic inflammation, contributing to CCM, which manifests as subclinical cardiac dysfunction, impaired contractility, and electrophysiological abnormalities. Structural changes, such as increased left ventricular mass, myocardial fibrosis, and ion channel dysfunction, further impair cardiac function. Vasodilation in the splanchnic circulation reduces peripheral resistance, triggering compensatory tachycardia, while the activation of the renin-angiotensin-aldosterone system (RAAS) promotes fluid retention and increases cardiac preload. Chronic inflammation and endotoxemia exacerbate myocardial dysfunction. The 2005 World Congress of Gastroenterology (WCG) and the 2019 Cirrhotic Cardiomyopathy Consortium (CCC) criteria provide updated diagnostic frameworks that incorporate global longitudinal strain (GLS) and tissue Doppler imaging (TDI). Prolonged QT intervals and arrhythmias are frequently observed. Managing heart failure in cirrhotic patients remains complex due to intolerance to afterload-reducing agents, and beta-blockers require careful use due to potential systemic hypotension. The interaction between CCM and major interventions, such as transjugular intrahepatic portosystemic shunt (TIPS) and orthotopic liver transplantation (OLT), highlights the critical need for thorough preoperative cardiac evaluation and vigilant postoperative monitoring. Conclusions: CCM is a frequently underdiagnosed yet significant complication of cirrhosis, impacting prognosis, particularly post-liver transplantation. Early identification using echocardiography and thorough evaluations of arrhythmia risk in cirrhotic patients are critical for optimizing management strategies. Future research should focus on targeted therapeutic approaches to mitigate the cardiac burden in cirrhotic patients and improve clinical outcomes.

Biliary tract cancers (BTC) comprise a heterogeneous group of malignancies, including gallbladder cancer, intrahepatic cholangiocarcinoma, and extrahepatic cholangiocarcinoma. The main determinants of prognosis in BTC are the stage of the disease and the eligibility for curative treatment. Additionally, liver functional capacity is also one of the factors influencing survival in biliary tract cancers. The age-bilirubin-INR-creatinine (ABIC) score has been previously shown to predict prognosis in hepatic diseases. The aim of our study is to demonstrate the relationship between the ABIC score and prognosis in BTC.

In this study, a retrospective analysis was performed on 41 patients with non-metastatic BTC and 73 patients with metastatic BTC who were followed up in our clinic between 2003 and 2025. All patients were ≥18 years old at the time of diagnosis, and BTC was pathologically confirmed. The ABIC score was calculated separately for each group. A threshold value for the ABIC score was determined using Receiver Operating Characteristic (ROC) analysis, and based on this threshold, patients were divided into low and high ABIC score groups. Both the relationship between the ABIC score and prognosis and the other factors affecting prognosis were investigated.

In the non-metastatic BTC group, the cutoff value for the ABIC score was 6.89. The median survival time of patients with a high ABIC score was significantly shorter. In the metastatic BTC group, the cutoff value for the ABIC score was 7.41. Similarly, in this group, patients with a high ABIC score had a significantly shorter median survival time. Additionally, in the non-metastatic BTC group, tumor localization and stage were prognostic factors affecting survival, while in the metastatic BTC group, CEA and first-line chemotherapy were the prognostic factors influencing overall survival. Conclusions: We demonstrate that the ABIC score is a prognostic factor determining median survival in both non-metastatic and metastatic BTC patients.

Liver cirrhosis represents the final stage of liver diseases. The transition from the compensated to the decompensated form is a critical phase, as it is associated with a negative impact on patient prognosis. Therefore, having a tool to identify patients at higher risk of complications and mortality is an ideal goal. Currently, the validated scores for this purpose are the model for end-stage liver disease score and the Child-Pugh score. However, these scores have limitations, as they do not account for other factors associated with liver cirrhosis that are equally relevant from a prognostic perspective. Among these, alterations in body composition, particularly sarcopenia, increase the risk of mortality and should therefore be considered in the comprehensive assessment of patients with liver cirrhosis.

Patients with liver cirrhosis are at an increased risk of mortality from coronavirus disease 2019 (COVID-19). Remdesivir, an adenosine analog, exhibits activity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and is thus recommended for inpatients with COVID-19. This study evaluated the effectiveness and safety of remdesivir in patients with COVID-19 and liver cirrhosis.

This retrospective study was conducted using data from Taiwan's largest healthcare system. The study cohort comprised adult patients with COVID-19 and liver cirrhosis who visited our emergency department between April 2021 and September 2022. Remdesivir's adverse effects, including bradycardia, anemia, unstable glucose levels, and abnormal liver function test results, were recorded. Treatment outcomes were assessed in terms of hospitalization duration, mortality, intubation, and intensive care unit admission.

This study included 1368 patients with COVID-19 and liver cirrhosis, of whom 46 received remdesivir. Remdesivir recipients were older (66.5 vs. 62 years; p = 0.042) and had a higher rate of oxygen therapy use (56.52% vs. 32.22%; p = 0.001) than nonrecipients. Common adverse effects of remdesivir included lower heart rates (83 vs. 96 bpm; p < 0.001) and decreased hemoglobin levels (9.5 vs. 10.2 g/dL; p = 0.003) without fatal consequences. No statistically significant difference between remdesivir recipients and nonrecipients in hospitalization duration, intubation rates, or mortality rates was found.

Remdesivir is safe for treating COVID-19 in patients with liver cirrhosis. Although remdesivir recipients exhibited trends toward improved outcomes in our study, large-scale studies are required to confirm its efficacy in this population.

Over the past six decades, liver transplantation (LT) has evolved from an experimental procedure into a standardized and life-saving intervention, reshaping the landscape of organ transplantation. Driven by pioneering breakthroughs, technological advancements, and a deepened understanding of immunology, LT has seen remarkable progress. Some of the most notable breakthroughs in the field include advances in immunosuppression, a revised model for end-stage liver disease, and artificial intelligence (AI)-integrated imaging modalities serving diagnostic and therapeutic roles in LT, paired with ever-evolving technological advances. Additionally, the refinement of transplantation procedures, resulting in the introduction of alternative transplantation methods, such as living donor LT, split LT, and the use of marginal grafts, has addressed the challenge of organ shortage. Moreover, precision medicine, guiding personalized immunosuppressive strategies, has significantly improved patient and graft survival rates while addressing emergent issues, such as short-term complications and early allograft dysfunction, leading to a more refined strategy and enhanced post-operative recovery. Looking ahead, ongoing research explores regenerative medicine, diagnostic tools, and AI to optimize organ allocation and post-transplantation car. In summary, the past six decades have marked a transformative journey in LT with a commitment to advancing science, medicine, and patient-centered care, offering hope and extending life to individuals worldwide.

The associations between gray matter (GM) change and neurotransmitter systems in hepatitis B virus-related cirrhosis (HBV-RC) are still poorly understood.

We recruited 60 HBV-RC patients and 60 healthy controls (HCs). Difference of GM volume between HBV-RC and HC groups was evaluated at global and voxel levels. The potential relationship between GM morphology and prognostic models of liver function was evaluated at voxel level in HBV-RC patients. The spatial correspondence between regional GM alteration and the distribution of multiple neurotransmitter systems in HBV-RC compared to healthy controls was assessed by the JuSpace toolbox covering various neurotransmitter maps.

Total GM volume in HBV-RC group was smaller than in HC group (p < 0.05), and the pattern of GM volume alterations showed significantly increased volume in bilateral thalamus and ventral diencephalon and decreased volume in bilateral basal ganglia and cerebellum (p < 0.05, FWE corrected). In HBV-RC group, the volume of left superior frontal gyrus medial segment and right middle frontal gyrus was positively correlated with serum albumin level and negatively correlated with ALBI score, and serum bilirubin level was negatively correlated with right hippocampus and caudate (p < 0.05, FWE corrected). GM alterations in HBV-RC patients relative to HCs were significantly associated with the intrinsic distribution of various neurotransmitter pathways, including GABAergic, cholinergic, serotonergic, and dopaminergic (p < 0.05).

The pattern of GM alteration correlated with liver function and specific neurotransmitter deficits in HBV-RC patients. These findings provide new insight into the complex neuropathogenesis of HBV-RC and the possible therapeutic targets based on neurotransmitter modulation.