Sepsis and septic shock are associated with microcirculatory dysfunction, significantly impacting patient outcomes. This study aimed to evaluate the effects of a 20 % albumin bolus on microcirculation compared to crystalloid resuscitation in fluid-responsive patients (ClinicalTrials.govID:NCT05357339).

We conducted a single-centre randomised controlled trial, enrolling 103 patients (Albumin n = 52, Control n = 51). Fluid responsiveness was assessed, and fluid was administered in boluses of 100 ml to clinical effect. Microcirculation was measured using the Side stream Dark Field camera and AVA 4.3 software. Baseline characteristics, macrohaemodynamics, and microcirculation parameters were recorded. Three patients were excluded from analysis.

The final cohort comprised 100 patients, 35 (35 %) females with a mean age of 58 years (range: 18-86). The mean APACHE score was 28 (range: 7-45), and the mean SOFA score was 9.4 (range: 1-17). No significant differences in APACHE (26.24 vs. 29.4, p = 0.069) or SOFA (9.08 vs. 9.78, p = 0.32) scores were found for albumin and control group respectively. The albumin group had worse microcirculation at baseline but demonstrated significant improvements in microvascular density and activity at 15 min and 60 min (p < 0.005), while the control group exhibited no significant changes. Additionally, both groups were fluid responsive, with a mean pulse pressure variability of 17 % at admission. There were no significant differences in overall fluid balances, vasopressor days, length of ICU stay, or mortality between groups.

This study demonstrates that a 20 % albumin bolus significantly enhances microcirculation in fluid-responsive patients with septic shock. These findings underscore the potential benefits of targeted microcirculation therapy in critically ill patients.

Acute-on-chronic liver failure (ACLF) is a complex syndrome with limited treatment options. This study aims to investigate the impact of artificial liver support system (ALSS) on the one-year prognosis of patients with Hepatitis B virus (HBV)-associated ACLF.

A retrospective study was conducted on 239 patients with HBV-ACLF in Nanfang Hospital from January 2016 to June 2021. Patients were divided into the ALSS group (n = 103) and the Standard Medical Therapy (SMT group, n = 136). Demographic, clinical, and laboratory data were collected before the first ALSS treatment for patients in ALSS group, while baseline data were collected in SMT group. According to receiving different ALSS modes, patients in ALSS group were divided into plasma exchange (PE) group and non-PE group.

The 12-week and 1-year liver transplant (LT) free survival rates in the ALSS group were significantly higher than that in the SMT group (65.05% vs 52.21%, p = 0.0011; 63.11% vs. 48.53%, p = 0.0006). ALSS therapy was the independent predictive factors associated with 12-week and 1-year mortality (hazard ratio, HR: 0.59, p = 0.04, and HR: 0.54, p = 0.01). Comparatively more ALSS-related complications were observed in PE group. After Propensity Score Matching, the 12-week and 1-year LT-free survival rates between PE and non-PE group were similar (88% vs. 80%, p = 0.227, 88% vs. 80%, p = 0.227).

ALSS therapy is a safe and effective treatment for HBV-ACLF. ALSS improves 1-year prognosis of patients with HBV-ACLF.

Acute-on-chronic liver failure (ACLF) is a syndrome that develops in approximately 30% of patients hospitalised with cirrhosis and is characterised by an acute decompensation of liver function associated with extra-hepatic organ failures and a high short-term mortality. At present, no specific therapies are available for ACLF, and current management is limited to treatment of the precipitating event and organ support. Given the high prevalence and high mortality of this severe liver disease, there is an urgent need for targeted treatments. There is increasing evidence of the important role played by systemic inflammation and immune dysfunction in the pathophysiology of ACLF and a better understanding of these immune processes is resulting in new therapeutic targets. The aim of this review is to present an overview of ongoing studies of potentially promising therapies and how they could be utilised in the management of ACLF.

In the traditional view, the occurrence of cirrhosis-related complications, such as hepatic encephalopathy, formation of ascites or variceal haemorrhage, marks the transition to the decompensated stage of cirrhosis. Although the dichotomous stratification into a compensated and decompensated state reflects a prognostic water-shed moment and remains to hold its prognostic validity, it represents an oversimplification of clinical realities. A broadening understanding of pathophysiological mechanisms underpinning decompensation have led to the identification of distinct prognostic subgroups, associated with different clinical courses following decompensation. Data provided by the PREDICT study uncovered three distinct sub-phenotypes of acute decompensation (AD). Moreover, acute-on-chronic liver failure (ACLF) has been established as a distinct clinical entity for many years, which is associated with a high short-term mortality. Recently, non-acute decompensation (NAD) has been proposed as a distinct pathway of decompensation, complementing current concepts of the spectrum of decompensation. In contrast to AD, NAD is characterized by a slow and progressive development of complications, which are often presented at first decompensation and/or in patients in an earlier stage of chronic liver disease. Successful treatment of AD or NAD may lead to a clinical stabilization or even the concept of recompensation. This review aims to provide an overview on current concepts of decompensation and to delineate recent advances in our clinical and pathophysiological understanding.

The identification of systemic inflammation (SI) as a central player in the orchestration of acute-on-chronic liver failure (ACLF) has opened new avenues for the understanding of the pathophysiological mechanisms underlying this disease condition. ACLF, which develops in patients with acute decompensation of cirrhosis, is characterized by single or multiple organ failure and high risk of short-term (28-day) mortality. Its poor outcome is closely associated with the severity of the systemic inflammatory response. In this review, we describe the key features of SI in patients with acutely decompensated cirrhosis and ACLF, including the presence of a high blood white cell count and increased levels of inflammatory mediators in systemic circulation. We also discuss the main triggers (i.e. pathogen- and damage-associated molecular patterns), the cell effectors (i.e. neutrophils, monocytes and lymphocytes), the humoral mediators (acute phase proteins, cytokines, chemokines, growth factors and bioactive lipid mediators) and the factors that influence the systemic inflammatory response that drive organ failure and mortality in ACLF. The role of immunological exhaustion and/or immunoparalysis in the context of exacerbated inflammatory responses that predispose ACLF patients to secondary infections and re-escalation of end-organ dysfunction and mortality are also reviewed. Finally, several new potential immunogenic therapeutic targets are debated.

Acute-on-chronic liver failure (ACLF) is a severe syndrome that manifests as acute liver function deterioration and organ failure. Coinfection with invasive pulmonary aspergillosis (IPA) in ACLF patients is characterized by high mortality and increasing morbidity. The aim of this study was to explore the early warning factors and prognosis of ACLF patients with IPA coinfection.

In this retrospective study, we collected clinical, biochemical, and microbiological data from patients with ACLF and IPA from May 2019 to May 2023. Univariable and multivariate analyses were used to identify independent risk factors for IPA in ACLF patients. Moreover, the area under the curve (AUC) and decision curve analysis (DCA) were used to evaluate the model performance.

A total of 438 patients with ACLF were enrolled, 408 (93.2%) non-IPA patients and 30 IPA (6.8%) including 29 probable cases and one proven case. The 28-day case fatality rate (56.7% vs 29.4%) was higher in ACLF patients with IPA than in ACLF patients without IPA, but without statistical difference. Multivariate analysis revealed that early warning factors for IPA coinfection in ACLF patients included nausea (p = 0.010), expectoration (p < 0.001), bacterial and fungal infections (p < 0.001), corticosteroid use (p = 0.037), surgery (p = 0.081), haemoptysis (p = 0.015) and increased leukocyte counts (p = 0.010). The AUC was 0.934 (p < 0.001), and DCA verified the validity and clinical effectiveness of our model.

These findings provide valuable insights for clinicians in the early diagnosis of IPA in ACLF patients and may facilitate timely intervention and treatment.

Acute-on-chronic liver failure (ACLF) is a complication of cirrhosis characterized by multiple organ failure and high short-term mortality. The pathophysiology of ACLF involves elevated systemic inflammation leading to organ failure, along with immune dysfunction that heightens susceptibility to bacterial infections. However, it is unclear how these aspects are associated with recovery and nonrecovery in ACLF.

Here, we mapped the single-cell transcriptome of circulating immune cells from patients with ACLF and acute decompensated (AD) cirrhosis and healthy individuals. We further interrogate how these findings, as well as immunometabolic and functional profiles, associate with ACLF-recovery (ACLF-R) or nonrecovery (ACLF-NR). Our analysis unveiled 2 distinct states of classical monocytes (cMons). Hereto, ACLF-R cMons were characterized by transcripts associated with immune and stress tolerance, including anti-inflammatory genes such as RETN and LGALS1 . Additional metabolomic and functional validation experiments implicated an elevated oxidative phosphorylation metabolic program as well as an impaired ACLF-R cMon functionality. Interestingly, we observed a common stress-induced tolerant state, oxidative phosphorylation program, and blunted activation among lymphoid populations in patients with ACLF-R. Conversely, ACLF-NR cMon featured elevated expression of inflammatory and stress response genes such as VIM , LGALS2 , and TREM1 , along with blunted metabolic activity and increased functionality.

This study identifies distinct immunometabolic cellular states that contribute to disease outcomes in patients with ACLF. Our findings provide valuable insights into the pathogenesis of ACLF, shedding light on factors driving either recovery or nonrecovery phenotypes, which may be harnessed as potential therapeutic targets in the future.

Albumin is the most abundant protein in the human body and is synthetized exclusively by the liver. Therefore, serum albumin levels are reduced in acute and/or chronic liver disease. In cirrhosis, low levels of albumin predict the outcome. In advanced cirrhosis, the quality of albumin is decreased due to high oxidative stress and a proinflammatory state. Therefore, the administration of i.v. albumin would seem to be of pathophysiological relevance and benefit. Yet, the questions that remain are who, when, how much, and how often. While albumin infusion is recommended after large-volume paracentesis, at diagnosis of spontaneous bacterial peritonitis, in acute kidney injury, and in hepatorenal syndrome, the amount and schedule of albumin to be administered require refinement, particularly given complications related to volume overload that have become increasingly apparent. Other indications for albumin such as infections other than spontaneous bacterial peritonitis, hyponatremia, HE, prevention of poor outcomes in hospitalized, and in outpatients with cirrhosis are still debated. The results of studies in these settings are either negative, controversial, or inconclusive. This sheds some doubts regarding the use of albumin as a "one size fits all" strategy. The indication and patient selection are crucial and not always intuitive. The amount and frequency also seem to play a role in the success or failure of albumin. This review will critically discuss the evidence and underline areas where there are indications for albumin use and others where evidence is still insufficient and will have to await the development/results of randomized controlled trials.

Albumin is the most prevalent plasma protein and serves numerous physiological roles, both in body fluid management and in various other capacities. In many diseases, a deficiency of albumin has been observed, and in certain conditions, albumin substitution has been demonstrated to improve outcome in comparison to plasma expansion using crystalloid or other colloid solutions. The favourable effects of using albumin in patients with liver cirrhosis are likely associated with the non-oncotic functions of albumin. Albumin for clinical use is obtained through fractionation of pooled donor plasma. The production procedures are optimized to ensure pure, chemically uncompromised and native protein.

We have extensively analysed commercial preparations of human albumin for clinical use from six different providers. Parameters that must correspond to the requirements of international pharmacopoeias were assessed (aluminium, ethanol, sodium, the presence of dimers and oligomers) and found to conform in all cases. In addition, we used for the first time nuclear magnetic resonance (NMR) as an additional analytical approach for investigating in greater depth the quality of a biological remedy gained from human plasma. We applied both 1H NMR and 13C-HSQC for confirming the identity of the albumin preparations, which also conformed in all cases. Moreover, we utilized T2-filtered 1H NMR and 13C-HSQC measurements to identify the presence of small molecules in the preparations. This demonstrated similar patterns of additional substances present, but also unveiled certain differences in purity in the products of the different providers.

Our analyses confirmed that albumin preparations in clinical use conform to the requirements. We furthermore demonstrate that NMR measurements can provide further depth in identity and purity measurements of biologicals. Despite largely standardized protocols in pharmaceutical albumin production, our in-depth analyses revealed differences in purity. Some samples exhibited lower levels of components other than albumin. We discuss possible causes of these observations and their potential implications for clinical therapy.

Patients with acutely decompensated (AD) cirrhosis are immunocompromised and particularly susceptible to infections. This study investigated the immunomodulatory actions of albumin by which this protein may lower the incidence of infections.

Blood immunophenotyping was performed in 11 patients with AD cirrhosis and 10 healthy volunteers (HV). Bulk and single-cell RNA sequencing (scRNA-seq) and flow cytometry were performed in peripheral blood mononuclear cells (PBMCs) from 20 patients with AD cirrhosis and 34 HV exposed to albumin. Albumin's effects on degranulation, phagocytosis, chemotaxis, and swarming of neutrophils from six patients with AD cirrhosis and nine HV were assessed by measuring myeloperoxidase enzymatic activity, the engulfment of fluorescent-labeled Escherichia coli and zymosan, and interactions of neutrophils with Candida albicans at single-cell resolution in microfluidic chambers, respectively. Whole blood RNA sequencing (RNA-seq) analyses were performed in 49 patients admitted for severe AD cirrhosis, of whom 30 received albumin during hospitalization.

Compared with HV, patients with AD cirrhosis showed severe lymphopenia and defective neutrophil antimicrobial function. Bulk and scRNA-seq analyses revealed significantly (false discovery rate [FDR] <0.05) increased signatures related to B cells, myeloid cells, and CD4+ T cells in PBMCs incubated with albumin. Changes in the B cell population were confirmed by flow cytometry. Neutrophils exposed to albumin also exhibited augmented chemotactic and degranulation responses, enhanced phagocytosis, and increased pathogen-restrictive swarming. RNA-seq data analysis in patients who had received albumin revealed specific upregulation of signatures related to B cells and neutrophils together with transcriptional changes in CD4+ T cells (FDR <0.05).

The finding that albumin promotes the transcriptional reprogramming and expansion of the B cell compartment and improves neutrophil antimicrobial functions indicates mechanisms that may lower the incidence of infections in patients with severe AD cirrhosis receiving albumin therapy.

Patients with acutely decompensated cirrhosis receiving albumin as treatment have a lower incidence of infections. The reason for this protection is currently unknown, but the present study provides data that support the ability of albumin to boost the antimicrobial functions of immune cells in these patients. Moreover, these findings encourage the design of controlled clinical studies specifically aimed at investigating the effects of albumin administration on the immune system.

The mechanisms underlying the state of systemic immune suppression that develops following major trauma are poorly understood. A post-injury increase in circulating levels of prostaglandin E2 (PGE2) has been proposed as a contributory factor, yet few studies have addressed how trauma influences PGE2 biology.

Blood samples from 95 traumatically-injured patients (injury severity score ≥8) were collected across the pre-hospital (≤2 hours), acute (4-12 hours) and subacute (48-72 hours) post-injury settings. Alongside ex vivo assessments of lipopolysaccharide (LPS)-induced cytokine production by monocytes, neutrophil reactive oxygen species production and phagocytosis, serum concentrations of PGE2 and its scavenger albumin were measured, and the expression of enzymes and receptors involved in PGE2 synthesis and signalling analysed. Leukocytes from trauma patients were treated with cyclooxygenase (COX) inhibitors (indomethacin or NS-398), or the protein kinase A inhibitor H89, to determine whether injury-induced immune suppression could be reversed by targeting the PGE2 pathway. The effect that trauma relevant concentrations of PGE2 had on the anti-microbial functions of neutrophils, monocytes and monocyte-derived macrophages (MDMs) from healthy controls (HC) was examined, as was the effect of PGE2 on efferocytosis. To identify factors that may trigger PGE2 production post-trauma, leukocytes from HC were treated with mitochondrial-derived damage associated molecular patterns (mtDAMPs) and COX-2 expression and PGE2 generation measured.

PGE2 concentrations peaked in blood samples acquired ≤2 hours post-injury and coincided with significantly reduced levels of albumin and impaired LPS-induced cytokine production by monocytes. Significantly higher COX-2 and phospholipase A2 expression was detected in neutrophils and/or peripheral blood mononuclear cells isolated from trauma patients. Treatment of patient leukocytes with indomethacin, NS-398 or H89 enhanced LPS-induced cytokine production and neutrophil extracellular trap generation. Exposure to physiological concentrations of PGE2 suppressed the anti-microbial activity of monocytes, neutrophils and MDMs of HC, but did not influence efferocytosis. In a formyl-peptide receptor-1 dependent manner, mtDAMP treatment significantly increased COX-2 protein expression in neutrophils and monocytes, which resulted in increased PGE2 production.

Physiological concentrations of PGE2 suppress the anti-microbial activities of neutrophils, monocytes and MDMs. Targeting the PGE2 pathway could be a therapeutic approach by which to enhance innate immune function post-injury.

Background: Early risk stratification is crucial due to septic patients' heterogeneity. Serum albumin level may reflect the severity of sepsis and host status. This study aimed to evaluate the prognostic ability of the initial sequential organ failure assessment (SOFA) score alone and combined with serum albumin levels for predicting 28-day mortality in patients with septic shock. Methods: We conducted an observational study using a prospective, multicenter registry of septic shock patients between October 2015 and May 2022 from 12 emergency departments in the Korean Shock Society and the results were validated by examining those from the septic shock cohort in Asan Medical Center. The primary outcome was 28-day mortality. The area under the receiver operating characteristic (ROC) curve was used to compare the predictive values of SOFA score alone and SOFA score combined with serum albumin level. Results: Among 5805 septic shock patients, 1529 (26.3%) died within 28 days. Mortality increased stepwise with decreasing serum albumin levels (13.6% in albumin ≥3.5, 20.7% in 3.5-3.0, 29.7% in 3.0-2.5, 44.0% in 2.5-2.0, 56.4% in <2.0). The albumin SOFA score was calculated by adding the initial SOFA score to the 4 points assigned for albumin levels. ROC analysis for predicting 28-day mortality showed that the area under the curve for the albumin SOFA score was 0.71 (95% CI 0.70-0.73), which was significantly higher than that of the initial SOFA score alone (0.68, 95% CI: 0.67-0.69). Conclusions: The combination of the initial SOFA score with albumin can improve prognostic accuracy for patients with septic shock, suggesting the albumin SOFA score may be used as an early mortality stratification tool.

Use of albumin is suggested for some patients with shock, but preferences for its use may vary among intensive care unit (ICU) physicians.

We conducted an international online survey of ICU physicians with 20 questions about their use of albumin and their opinion towards a randomised trial among adults with shock comparing the use versus no use of albumin.

A total of 1248 respondents participated, with a mean response rate of 37%, ranging from 18% to 75% across 21 countries. Respondents mainly worked in mixed ICUs and 92% were specialists in intensive care medicine. The reported use of albumin in general shock varied as 18% reported 'almost never', 22% 'rarely', 34% 'occasionally', 22% 'frequently' and 4% 'almost always' using albumin. In septic shock, 19% reported 'almost never', 22% 'rarely', 29% 'occasionally', 22% 'frequently' and 7% 'almost always' using albumin. Physicians' preferences were more consistent for haemorrhagic- and cardiogenic shock, with more than 45% reporting 'almost never' using albumin. While the reported use of albumin for other purposes than resuscitation was infrequent (40%-85% reported 'almost never' for five other indications), the most frequent other indications were low serum albumin levels and improvement of the efficacy of diuretics. Most respondents (93%) would randomise adult ICU patients with shock to a trial of albumin versus no albumin.

In this international survey, the reported preferences for the use of albumin in adult ICU patients with shock varied considerably among surveyed ICU physicians. The support for a future randomised trial was high.

Bacterial infections in patients with cirrhosis lead to a 4-fold increase in mortality. Immune dysfunction in cirrhosis further increases the risk of bacterial infections, in addition to alterations in the gut microbiome, which increase the risk of pathogenic bacteria. High rates of empiric antibiotic use contribute to increased incidence of multidrug-resistant organisms and further increases in mortality. Despite continous advances in the field, major unknowns regarding interactions between the immune system and the gut microbiome and strategies to reduce infection risk and improve mortality deserve further investigation. Here, we highlight the unknowns in these major research areas and make a proposal for a research agenda to move toward improving disease progression and outcomes in patients with cirrhosis and infections.

Systemic inflammation and immunodeficiency are important components of cirrhosis-associated immune dysfunction (CAID), the severity of which is dynamic, progressive, and associated with the greater deterioration of liver function. Two inflammation phenotypes have been described: low-grade and high-grade systemic inflammation. Both of these phenotypes are related to liver cirrhosis function; thus, high-grade inflammation is correlated with the severity of hepatic insufficiency, bacterial translocation, and organic insufficiency, with which the risk of infections increases and the prognosis worsens. Bacterial translocation (BT) plays a relevant role in persistent systemic inflammation in patients with cirrhosis, and the prophylactic employment of antibiotics is useful for reducing events of infection and mortality.

Liver failure profoundly affects the immune system, leading to dysregulation of innate and adaptive immune response. This review explores the intricate relationship between liver function and immune homeostasis. The role of the liver as a central hub in immune response initiation is elucidated, emphasizing its involvement in hepatic inflammation induction and subsequent systemic inflammation. Cytokines, chemokines, growth factors, and lipid mediators orchestrate these immune processes, serving as both prognostic biomarkers and potential therapeutic targets in liver failure-associated immune dysregulation, which might result from acute-on-chronic liver failure (ACLF) and cirrhosis. Furthermore, the review delves into the mechanisms underlying immunosuppression in liver failure, encompassing alterations in innate immune cell functions such as neutrophils, macrophages, and natural killer cells (NK cells), as well as perturbations in adaptive immune responses mediated by B and T cells. Conclusion: Understanding the immunological consequences of liver failure is crucial for developing targeted therapeutic interventions and improving patient outcomes in liver disease management.

The utilization of traditional therapies (TTS), such as chemotherapy, reactive oxygen species-based therapy, and thermotherapy, to induce immunogenic cell death (ICD) in tumor cells has emerged as a promising strategy for the activation of the antitumor immune response. However, the limited effectiveness of most TTS in inducing the ICD effect of tumors hinders their applications in combination with immunotherapy. To address this challenge, various intelligent strategies have been proposed to strengthen the immune activation effect of these TTS, and then achieve synergistic antitumor efficacy with immunotherapy. These strategies primarily focus on augmenting the tumor ICD effect or facilitating the antigen (released by the ICD tumor cells) presentation process during TTS, and they are systematically summarized in this review. Finally, the existing bottlenecks and prospects of TTS in the application of tumor immune regulation are also discussed.

Prostaglandins (PGs) play a crucial and multifaceted role in various physiological processes such as intercellular signaling, inflammation regulation, neurotransmission, vasodilation, vasoconstriction, and reproductive functions. The diversity and biological significance of these effects are contingent upon the specific types or subtypes of PGs, with each PG playing a crucial role in distinct physiological and pathological processes. Particularly within the immune system, PGs are essential in modulating the function of immune cells and the magnitude and orientation of immune responses. Hence, a comprehensive comprehension of the functions PG signaling pathways in immunosuppressive regulation holds substantial clinical relevance for disease prevention and treatment strategies. The manuscript provides a review of recent developments in PG signaling in immunosuppressive regulation. Furthermore, the potential clinical applications of PGs in immunosuppression are also discussed. While research into the immunosuppressive effects of PGs required further exploration, targeted therapies against their immunosuppressive pathways might open new avenues for disease prevention and treatment.

Cirrhosis is an immune dysfunction state, and as such, patients with cirrhosis are susceptible to bacterial, fungal, and viral infections. Because of infection, these patients have a propensity to develop multiorgan failure, which is associated with high mortality. Bacterial infections are the most prevalent type of infection in patients with cirrhosis, with the prevalence of bacterial infections in patients admitted for an acute decompensating event ranging from 24% to 29%. Together with invasive fungal infections, bacterial infections are the most severe. Multidrug-resistant organisms have been evolving at a rapid and alarming rate around the world, which presents enormous challenges. The development of effective measures for the prevention, early detection, and treatment of infections in patients with cirrhosis is challenging, given the rising incidence of infections in this patient population.

Ferroptosis, an iron-dependent form of cell death characterized by uncontrolled lipid peroxidation, is governed by molecular networks involving diverse molecules and organelles. Since its recognition as a non-apoptotic cell death pathway in 2012, ferroptosis has emerged as a crucial mechanism in numerous physiological and pathological contexts, leading to significant therapeutic advancements across a wide range of diseases. This review summarizes the fundamental molecular mechanisms and regulatory pathways underlying ferroptosis, including both GPX4-dependent and -independent antioxidant mechanisms. Additionally, we examine the involvement of ferroptosis in various pathological conditions, including cancer, neurodegenerative diseases, sepsis, ischemia-reperfusion injury, autoimmune disorders, and metabolic disorders. Specifically, we explore the role of ferroptosis in response to chemotherapy, radiotherapy, immunotherapy, nanotherapy, and targeted therapy. Furthermore, we discuss pharmacological strategies for modulating ferroptosis and potential biomarkers for monitoring this process. Lastly, we elucidate the interplay between ferroptosis and other forms of regulated cell death. Such insights hold promise for advancing our understanding of ferroptosis in the context of human health and disease.

Complications of acute-on-chronic liver failure (ACLF) include increased short-term mortality. Extrahepatic organ failures result from chronic liver disease and acute hepatic injury. This combination characterizes end-stage liver disease. Its rapid progression makes it challenging for hepatologists and intensivists to treat. The varied definitions of this condition lead to varied clinical presentations. Hepatic or extrahepatic failures are more prevalent in chronic hepatitis B or cirrhosis patients who receive an additional injury. Numerous intensity parameters and prognosis ratings, including those for hepatitis B virus (HBV), have been developed and verified for various patients and causes of the disease. Liver regeneration, liver transplantation (LT), or antiviral therapy for HBV-related ACLF are the main treatment aims for various organ failures. LT is the best treatment for HBV-ACLF. In some HBV-related ACLF patients, nucleos(t)ide analogs and artificial liver assistance may enhance survival. Combining epidemiological and clinical studies, this review updates our understanding of HBV-ACLF's definition, diagnosis, epidemiology, etiology, therapy, and prognosis.

Acute-on-chronic liver failure is a well-established description of a high-mortality syndrome of chronic liver disease (usually cirrhosis) with organ failure. While the exact definition is under refinement, the accepted understanding of this entity is in patients with chronic liver disease and various organs in failure and where systemic inflammation is a major component of the pathobiology. There are limited therapies for a disease with such a poor prognosis, and while improvements in the critical care management and for very few patients, liver transplantation, mean 50% can survive to hospital discharge, rapid application of new therapies is required. Here we explain the current understanding of the immunologic abnormalities seen in acute-on-chronic liver failure across the innate and adaptive immune systems, the role of the hepatic cell death and the gut-liver axis, and recommendations for future research and treatment paradigms.

The administration of an appropriate empirical antibiotic treatment is essential in cirrhosis and severe bacterial infections. We aimed to investigate the predictors of clinical response of empirical antibiotic treatment in a prospective cohort of patients with cirrhosis and bacterial and fungal infections included in the International Club of Ascites "Global Study."

Patients hospitalized with cirrhosis and bacterial/fungal infection were prospectively enrolled at 46 centers. Clinical response to antibiotic treatment was defined according to changes in markers of infection/inflammation, vital signs, improvement of organ failure, and results of cultures.

From October 2015 to September 2016, 1302 patients were included at 46 centers. A clinical response was achieved in only 61% of cases. Independent predictors of lack of clinical response to empirical treatment were C-reactive protein (OR = 1.16; 95% CI = 1.02-1.31), blood leukocyte count (OR = 1.39;95% CI = 1.09-1.77), serum albumin (OR = 0.70; 95% CI = 0.55-0.88), nosocomial infections (OR = 1.96; 95% CI = 1.20-2.38), pneumonia (OR = 1.75; 95% CI = 1.22-2.53), and ineffective treatment according to antibiotic susceptibility test (OR = 5.32; 95% CI = 3.47-8.57). Patients with a lack of clinical response to first-line antibiotic treatment had a significantly lower resolution rate of infections (55% vs. 96%; p < 0.001), a higher incidence of second infections (29% vs. 15%; p < 0.001), shock (35% vs. 7%; p < 0.001) and new organ failures (52% vs. 19 %; p < 0.001) than responders. Clinical response to empirical treatment was an independent predictor of 28-day survival ( subdistribution = 0.20; 95% CI = 0.14-0.27).

Four out of 10 patients with cirrhosis do not respond to the first-line antibiotic therapy, leading to lower resolution of infections and higher mortality. Broader-spectrum antibiotics and strategies targeting systemic inflammation may improve prognosis in patients with a high degree of inflammation, low serum albumin levels, and severe liver impairment.

Autoimmune diseases can damage specific or multiple organs and tissues, influence the quality of life, and even cause disability and death. A 'disease in a dish' can be developed based on patients-derived induced pluripotent stem cells (iPSCs) and iPSCs-derived disease-relevant cell types to provide a platform for pathogenesis research, phenotypical assays, cell therapy, and drug discovery. With rapid progress in molecular biology research methods including genome-sequencing technology, epigenetic analysis, '-omics' analysis and organoid technology, large amount of data represents an opportunity to help in gaining an in-depth understanding of pathological mechanisms and developing novel therapeutic strategies for these diseases. This paper aimed to review the iPSCs-based research on phenotype confirmation, mechanism exploration, drug discovery, and cell therapy for autoimmune diseases, especially multiple sclerosis, inflammatory bowel disease, and type 1 diabetes using iPSCs and iPSCs-derived cells.

Decompensated liver cirrhosis has a poor prognosis, with a median overall survival of two to four years, which is worse than for many oncological disorders. These patients are highly susceptible to infections due to increased systemic inflammation leading to kidney failure and death. The aim was to study the efficacy of albumin in reducing episodes of decompensation, preventing bacterial infection, kidney dysfunction and mortality.

Study involved patients with Child B or C cirrhosis with an albumin level below 3.0 g/dL, who were administered 20% human albumin weekly with standard medical treatment (SMT) for three months or till serum albumin levels were 4.0 g/dL (whichever is earlier) and compared with age and sex-matched controls who received only SMT. The primary end-point was six-month mortality and the secondary end-points were reduction in infections, kidney dysfunction, ascites recurrence, hepatic encephalopathy (HE), gastrointestinal (GI) bleed and complications of cirrhosis.

From September 2021 to January 2023, 88 cases and 86 controls were taken and followed up for six months. Overall, six-month survival was not statistically significant between groups (95.1% vs. 91.9%; p = 0·330). The incidence of recurrence of ascites (34.09% vs. 59.3%, p < 0.001), kidney dysfunction (6.8% vs. 24.4%, p < 0.001), HE (15.9% vs, 37.2%, p = 0.015), spontaneous bacterial peritonitis (SBP) (3.4% vs 17.4%, p = 0.002) and non-SBP infections (7.9% vs. 18.6%, p = 0.038) were significantly less in cases as compared with controls; however, GI bleed (14.8% vs. 17.4%, p = 0.632) was not statistically significant.

Long-term human albumin acts as a disease-modifying treatment in patients with decompensated cirrhosis.

Administration of chimeric-antigen receptor T-cell (CAR-T) therapy is complex and associated with unique toxicities. Identifying patients at risk for inferior outcomes is important for individualized management. The Glasgow-prognostic score (GPS) is a simple score shown to be highly prognostic of outcomes in the setting of traditional chemotherapy or checkpoint inhibitor administration. We sought to evaluate the value of the GPS to predict outcomes of patients with relapse refractory multiple myeloma (RRMM) receiving anti-BCMA CAR-T therapy. We included all patients treated with commercial CAR-T therapy for RRMM between 5/1/2021 and 2/1/2023 at the Moffitt Cancer Center. The GPS (CRP >1 mg/dL, 1 point; albumin <3.5, 1 point) was calculated for all patients at lymphodepletion (day -6) and patients were grouped as high-risk GPS (score = 2) or low-risk GPS (0 or 1). The primary endpoint was overall survival (OS) at day 100. A total of 139 pts were included, with a median follow-up of 6.7 months (95% CI, 6.2 to 8.9 months). Pts were treated with either idecabtagene vicleucel (83%) or ciltacabtagene autoleucel (17%). In total, 14% were classified with high-risk GPS, with significantly increased risk for grade 3 cytokine release syndrome (P = .003) and ICANS of any grade (P < .001). Patients in the high-risk GPS group had significantly lower day-100 OS (68.4% versus 97.3%, P < .001), OS at 6 months (56% versus 91.8% P = .0019) and PFS at 6 months (38.3% versus 72.3%, P = .03). The association of GPS with day-100 OS remained significant in a multivariable model. In conclusion, the GPS identifies a group of high-risk patients with RRMM receiving CAR-T therapy who experience increased rates of immune-mediated toxicity and are at higher risk for early mortality.

Human serum albumins (HSAs) are synthesized in the liver and are the most abundant proteins in plasma of healthy human. They play an important role in the pathophysiological processes of the liver and even the whole organism. Previous studies have mainly focused on the regulation of HSAs' expression. However, with the progress of research in recent years, it has been found that the content of circulating albumin cannot fully reflect the biological function of albumin itself. Given the aforementioned fact, the concept of serum 'effective albumin concentration' has been proposed. It refers to the content of albumin that is structurally and functionally intact. Alterations in the molecular structure and function of albumin have been reported in a variety of diseases, including liver disease. Moreover, these changes have been verified to affect the progression of oxidative stress‑related diseases. However, the link between albumin structure and function has not been fully elaborated, and the mechanisms by which different forms of albumin affect disease also need to be further investigated. In this context, the present review mainly expounded the biological characteristics and functions of albumin, summarized the different types of post‑translational modification of albumin, and discussed their functional changes and possible mechanisms in non‑alcoholic fatty liver disease, alcoholic hepatitis, viral hepatitis and different stages of cirrhosis. This will help to improve understanding of the role of albumin in disease development and provide a more comprehensive physiological basis for it in disease treatment.

The Glasgow Prognostic Score (GPS) has proven to be a good biomarker for lung cancer prognosis. However, its usefulness in lung cancer patients receiving checkpoint inhibitor immunotherapy remains controversial. Therefore, we performed a meta-analysis to explore the prognostic value of the GPS in non-small cell lung cancer patients receiving immunotherapy.

PubMed, Web of Science, Scopus, and Embase were systematically searched for relevant studies up to May 31, 2023, and hazard ratios (HRs) with 95% confidence intervals (95% CIs) were merged to investigate the prognostic value of the GPS for overall survival (OS) and progression-free survival (PFS).

Seven studies comprising 833 patients were included in the primary analysis, and the pooled results indicated that a higher baseline GPS was associated with poorer OS and PFS in non-small cell lung cancer patients treated with immune checkpoint inhibitors (ICIs) (OS: HR = 1.95, 95% CI: 1.47-2.58, p < 0.01; PFS: HR = 1.63, 95% CI: 1.26-2.11, p < 0.01). These findings were robust after subgroup and sensitivity analyses.

The GPS can serve as a biomarker in non-small cell lung cancer patients receiving immunotherapy with significant prognostic value; however, these findings require more prospective evidence for validation.

Antibiotics and albumin infusion constitute the standard of treatment in patients with decompensated cirrhosis who have spontaneous bacterial peritonitis (SBP). Recent studies have also shown that the use of albumin in patients with advanced liver disease who have infections other than SBP leads to the resolution of acute and chronic liver failure and prevents the development of nosocomial infections. The recommended dose of albumin for these patients is out of reach for many in resource-limited settings like India. The evidence for this recommendation is also scarce. This study aimed to assess the efficacy of a lower dose of albumin infusion in addition to antibiotics on short-term mortality and morbidity in patients with cirrhosis and infections.

A prospective, open-label, randomized control study was performed. Consecutive patients with cirrhosis and infections were randomized in a 2:1 ratio into two groups: group A (116) and group B (58) patients. In addition to antibiotics and standard medical therapy, group A was given albumin in a dose of 20 g/day for five days, and group B was given the recommended dose (1.5 g/kg/body weight and 1 g/kg body weight on days one and three, respectively). The primary outcome was in-hospital mortality. Secondary outcomes were improvements in clinical and laboratory parameters.

Except for etiology, all the baseline clinical and laboratory variables in both groups were comparable. The in-hospital mortality in groups A and B was (11 [10.67%] vs. 6 [10.09%], (P = 0.965). The duration of hospitalization, 30-day mortality, improvement in shock and sensorium, and absolute improvements in serum creatinine, international normalized ratio (INR), and serum bilirubin were also comparable in both groups.

Low-dose albumin infusion in patients with cirrhosis and infections can have the same results as standard-dose albumin and can be used in resource-limited situations.

CTRI/2020/03/023794.

Acute-on-chronic liver failure (ACLF), a clinical syndrome that can develop at any stage in the progression of cirrhotic liver disease, is characterized by an acute decompensation in liver function with associated multiorgan failure and high short-term mortality. Current evidence points to ACLF being reversible, particularly in those at the lower end of the severity spectrum. However, there are no specific treatments for ACLF, and overall outcomes remain poor. Expedited liver transplantation as a treatment option is limited by organ shortage and a lack of priority allocation for this indication. Other options are therefore urgently needed, and our improved understanding of the condition has led to significant efforts to develop novel therapies. In conclusion, this review aims to summarize the current understanding of the pathophysiological processes involved in the onset, progression, and recovery of ACLF and discuss novel therapies under development.

Albumin is the most abundant circulating protein and provides about 70% of the plasma oncotic power. The molecule also carries many other biological functions (binding, transport and detoxification of endogenous and exogenous compounds, antioxidation, and modulation of inflammatory and immune responses). Hypoalbuminemia is a frequent finding in many diseases, representing usually only a biomarker of poor prognosis rather than a primary pathophysiological event. Despite that, albumin is prescribed in many conditions based on the assumption that correction of hypoalbuminemia would lead to clinical benefits for the patients. Unfortunately, many of these indications are not supported by scientific evidence (or have been even disproved), so that a large part of albumin use is nowadays still inappropriate. Decompensated cirrhosis is the clinical area where albumin administration has been extensively studied and solid recommendations can be made. Besides prevention and treatment of acute complications, long-term albumin administration in patients with ascites has emerged in the last decade has a potential new disease-modifying treatment. In non-hepatological settings, albumin is widely used for fluid resuscitation in sepsis and critical illnesses, with no clear superiority over crystalloids. In many other conditions, scientific evidence supporting albumin prescription is weak or even absent. Thus, given its high cost and limited availability, action is needed to avoid the use of albumin for inappropriate and futile indications to ensure its availability in those conditions for which albumin has been demonstrated to have a real effectiveness and an advantage for the patient.

Acute-on-chronic liver failure (ACLF) is a clinically and pathophysiologically distinct condition from acutely decompensated cirrhosis and is characterised by systemic inflammation, extrahepatic organ failure, and high short-term mortality.

To provide a narrative review of the diagnostic criteria, prognosis, epidemiology, and general management principles of ACLF. Four specific interventions that are explored in detail are intravenous albumin, extracorporeal liver assist devices, granulocyte-colony stimulating factor, and liver transplantation.

We searched PubMed and Cochrane databases for articles published up to July 2023.

Approximately 35% of hospital inpatients with decompensated cirrhosis have ACLF. There is significant heterogeneity in the criteria used to diagnose ACLF; different definitions identify different phenotypes with varying mortality. Criteria established by the European Association for the Study of the Liver were developed in prospective patient cohorts and are, to-date, the most well validated internationally. Systemic haemodynamic instability, renal dysfunction, coagulopathy, neurological dysfunction, and respiratory failure are key considerations when managing ACLF in the intensive care unit. Apart from liver transplantation, there are no accepted evidence-based treatments for ACLF, but several different approaches are under investigation.

The recognition of ACLF as a distinct entity from acutely decompensated cirrhosis has allowed for better patient stratification in clinical settings, facilitating earlier engagement with the intensive care unit and liver transplantation teams. Research priorities over the next decade should focus on exploring novel treatment strategies with a particular focus on which, when, and how patients with ACLF should be treated.

Acute-on-chronic liver failure (ACLF) is the most severe form of acutely decompensated cirrhosis and is characterised by the presence of one or more organ failures, intense systemic inflammation, peripheral blood lymphopenia, and a high risk of death without liver transplantation within 28 days. Herein, we propose the hypothesis that intense systemic inflammation may lead to organ failures through five different non-mutually exclusive mechanisms. First, pathogen-associated molecular patterns and inflammatory mediators (i.e. cytokines and lipid mediators) stimulate the production of the vasorelaxant nitric oxide in the walls of splanchnic arterioles, leading to enhanced splanchnic and systemic vasodilation which, in turn, induces enhanced activity of endogenous vasoconstrictor systems causing renal vasoconstriction and acute kidney injury. Second, neutrophils that reach the systemic circulation are prone to adhere to the vascular endothelium. Cytokines and lipid mediators act on the endothelium in microvessels of vital organs, an effect that favours the migration of neutrophils (and probably other leukocytes) to surrounding tissues where neutrophils can cause tissue damage and thereby contribute to organ failure. Third, cytokines and lipid mediators promote the formation of microthrombi that impair microcirculation and tissue oxygenation. Fourth, acute inflammation stimulates intense peripheral catabolism of amino acids whose products may be metabotoxins that contribute to hepatic encephalopathy. Fifth, acute inflammatory responses, which include the production of a broad variety of biomolecules (proteins and lipids), and an increase in biomass (i.e., granulopoiesis requiring de novo nucleotide synthesis), among others, are energetically expensive processes that require large amounts of nutrients. Therefore, immunity competes with other maintenance programmes for energy. The brain stem integrates the energy demand of each organ system, with immunity considered a top priority. The brain stem may "decide" to make a trade-off which involves the induction of a dormancy programme that permits the shutdown of mitochondrial respiration and oxidative phosphorylation in peripheral organs. In the context of acutely decompensated cirrhosis, the consequence of a shutdown of mitochondrial respiration and ATP production would be a dramatic decrease in organ function.

Decompensated liver cirrhosis (DLC), a terminal-stage complication of liver disease, is a major cause of morbidity and mortality in patients with hepatopathies. Human umbilical cord mesenchymal stem cell (hUCMSC) therapy has emerged as a novel treatment alternative for the treatment of DLC. However, optimized therapy protocols and the associated mechanisms are not entirely understood.

We constructed a DLC rat model consistent with the typical clinical characteristics combined use of PB and CCL₄. Performing dynamic detection of liver morphology and function in rats for 11 weeks, various disease characteristics of DLC and the therapeutic effect of hUCMSCs on DLC in experimental rats were thoroughly investigated, according to ascites examination, histopathological, and related blood biochemical analyses. Flow cytometry analysis of rat liver, immunofluorescence, and RT-qPCR was performed to examine the changes in the liver immune microenvironment after hucMSCs treatment. We performed RNA-seq analysis of liver and primary macrophages and hUCMSCs co-culture system in vitro to explore possible signaling pathways. PPARγ antagonist, GW9662, and clodronate liposomes were used to inhibit PPAR activation and pre-exhaustion of macrophages in DLC rats' livers, respectively.

We found that changing the two key issues, the frequency and initial phase of hUCMSCs infusion, can affect the efficacy of hUCMSCs, and the optimal hUCMSCs treatment schedule is once every week for three weeks at the early stage of DLC progression, providing the best therapeutic effect in reducing mortality and ascites, and improving liver function in DLC rats. hUCMSCs treatment skewed the macrophage phenotype from M1-type to M2-type by activating the PPARγ signaling pathway in the liver, which was approved by primary macrophages and hUCMSCs co-culture system in vitro. Both inhibition of PPARγ activation with GW9662 and pre-exhaustion of macrophages in DLC rats' liver abolished the regulation of hUCMSCs on macrophage polarization, thus attenuating the beneficial effect of hUCMSCs treatment in DLC rats.

These data demonstrated that the optimal hUCMSCs treatment effectively inhibits the ascites formation, prolongs survival and significantly improves liver structure and function in DLC rats through the activation of the PPARγ signaling pathway within liver macrophages. Our study compared the efficacy of different hUCMSCs infusion regimens for DLC, providing new insights on cell-based therapies for regenerative medicine.

Acute-on-chronic liver failure (ACLF) has been recognized as a severe clinical syndrome based on the acute deterioration of chronic liver disease and is characterized by organ failure and high short-term mortality. Heterogeneous definitions and diagnostic criteria for the clinical condition have been proposed in different geographic regions due to the differences in aetiologies and precipitating events. Several predictive and prognostic scores have been developed and validated to guide clinical management. The specific pathophysiology of ACLF remains uncertain and is mainly associated with an intense systemic inflammatory response and immune-metabolism disorder based on current evidence. For ACLF patients, standardization of the treatment paradigm is required for different disease stages that may provide targeted treatment strategies for individual needs.

Cirrhosis transcends various progressive stages from compensation to decompensation driven by the severity of portal hypertension. The downstream effect of increasing portal hypertension severity leads to various pathophysiological pathways, which result in the cardinal complications of cirrhosis, including ascites, variceal hemorrhage, and hepatic encephalopathy. Additionally, the severity of portal hypertension is the central driver for further advanced complications of hyperdynamic circulation, hepatorenal syndrome, and cirrhotic cardiomyopathy. The management of these individual complications has specific nuances which have undergone significant developments. In contrast to the classical natural history of cirrhosis and its complications which follows an insidious trajectory, acute-on-chronic failure (ACLF) leads to a rapidly downhill course with high short-term mortality unless intervened at the early stages. The management of ACLF involves specific interventions, which have quickly evolved in recent years. In this review, we focus on complications of portal hypertension and delve into an approach toward ACLF.