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The aim of this study was to evaluate the potential role of intestinal ultrasound scan (IUS) in predicting short-term treatment outcomes in pediatric acute severe ulcerative colitis (ASUC). This prospective longitudinal study was conducted across 10 European centers. Biologic-naïve children with ASUC were included. Each patient underwent 2 IUS, the first within 48 hours of initiating intravenous corticosteroids, and the second between day 5 and 7 of treatment. Key metrics assessed included colonic wall thickness (CWT), colonic wall stratification (CWS), and colonic wall blood flow via power Doppler. The Milan ultrasound score was also calculated for each colonic quadrant. The study prospectively enrolled 60 patients (61.7% girls; median age at enrollment, 13.5 years). Escalation to infliximab was required in 39 patients (65%) who were corticosteroid nonresponders. Nonresponders had significantly higher CWT assessed in the left-lower quadrant (LLQ) (6 vs 4.2 mm, P < .001) and left upper quadrant (5 vs 4 mm, P = .003) and had more frequent hypervascularity (Limberg's score ≥3) assessed in the same sections. Receiver operator characteristic curve analysis identified LLQ CWT >5 mm (area under the curve [AUC] = 0.819) and Milan Ultrasound Criteria >7.8 (AUC = 0.834) as optimal cutoffs for predicting steroid resistance. Ten patients (16.7%) who did not respond to medical therapy underwent colectomy within the 8-week period of the study. At the second IUS, CWT >4.8 mm and Milan Ultrasound Criteria >8.7 in LLQ were associated with medical therapy failure (AUC = 0.844 and 0.878, respectively). Patients in steroid-free clinical remission at week 8 had lower CWT (3.5 vs 5 mm, P = .037) and Milan Ultrasound Criteria (5.3 vs 8.7, P < .001) at the second IUS. IUS is an effective noninvasive tool to predict first-line therapy failure and the need for colectomy in patients with ASUC.

Following injury, prostaglandin E2 (PGE2) drives intestinal epithelial repair by inducing revival stem cells (RSCs), which compensate for the loss of homeostatic Lgr5+ stem cells. Using intestinal organoid models, we demonstrate that melatonin potentiates the PGE2- or damage-induced RSC emergence by rewiring cellular plasticity toward a fetal-like state and sustaining pro-regenerative YAP activity, thereby enhancing overall repair capacity. To translate this finding into a therapeutic application, we developed a biohybrid heterospheroid (Mel-HS) by combining melatonin-loaded poly(lactic-co-glycolic acid) microspheres with 3D-cultured mesenchymal stem cells (MSCs), which serve as a PGE2 source. We confirmed that this biohybrid construct preserves the paracrine capacity of MSCs to secrete PGE2. Notably, Mel-HS demonstrates superior in vivo retention compared with naive 3D-MSCs, underscoring the cytoprotective effect of encapsulated melatonin in enhancing MSC viability. Furthermore, Mel-HS promoted robust RSC induction while simultaneously providing protection against inflammatory- and oxidative insults in vitro. In a colitis model, Mel-HS accelerated mucosal healing through the dual mechanisms-immunomodulation and enhanced RSC-driven repair-resulting in marked clinical improvement. Collectively, our findings highlight the therapeutic potential of enhancing endogenous regeneration with melatonin and MSCs, establishing a promising framework for next-generation biohybrid cell therapeutics in inflammatory bowel disease management.

The pathogenesis of inflammatory bowel disease (IBD) involves a self-perpetuating cycle driven by oxidative stress, microbial dysbiosis, and immune dysregulation. Restoring intestinal microbiota homeostasis and immune balance is therefore critical for intestinal health and long-term disease remission. In this study, an M2 macrophage-based biohybrid system (GaInMg@PDA@M2) was constructed to achieve synergistic intervention against these multiple pathological pathways. This biohybrid system utilized M2 macrophages with inherent inflammatory tropism as delivery vehicles, loaded with multifunctional nanoparticles (GaInMg@PDA) composed of liquid metal (GaIn), magnesium ions (Mg²⁺) and polydopamine (PDA). The nanoparticles effectively scavenged reactive oxygen species and exhibited synergistic antibacterial effects with the GaIn component, while the released Mg²⁺ further promoted macrophage polarization towards the anti-inflammatory M2 phenotype. In a DSS-induced murine colitis model, GaInMg@PDA@M2 demonstrated inflammatory targeting for the diseased colonic tissue and significantly ameliorating clinical symptoms including disease activity index, colon shortening and histopathological damage. The therapeutic mechanisms involved downregulation of pro-inflammatory cytokines, upregulation of anti-inflammatory cytokines, enhancement of antioxidant enzyme activity, restoration of intestinal tight-junction protein expression, and rebalancing of gut microbiota homeostasis. This "cell-homing and multi-effect synergy" strategy represented a precise therapeutic approach capable of disrupting the key pathological cycle in IBD. STATEMENT OF SIGNIFICANCE: Inflammatory bowel disease (IBD) is driven by a self-perpetuating cycle of oxidative stress, microbial dysbiosis, and immune dysregulation, making restoration of intestinal ecosystem balance a major therapeutic challenge. Conventional therapies often lack specificity or fail to address these interconnected pathologies simultaneously, owing to systemic side effects, non-specific immunosuppression, and diminished efficacy over time. In response, a paradigm shift toward a multi-targeted strategy that concurrently tackles oxidative stress, corrects dysbiosis, and resolves inflammation is imperative to break this cycle. To this end, an M2 macrophage-based biohybrid system was developed to achieve synergistic intervention across these key pathological pathways, overcoming the limitations of conventional drugs and enabling simultaneous modulation of multiple core disease mechanisms.

Appropriate T-cell functional polarization is critical for maintaining immune stability and immune tolerance. The role of Fam234a in the functional polarization of T cells is unknown. In a DSS-induced inflammatory bowel disease model in Rag2-/- mice with either naive WT or Fam234a-deficient CD4+ T cells, mice with Fam234a-deficient CD4+ T cells presented milder symptoms of colitis, accompanied by a decreased ratio of Th17/Treg cells. Consistent with the in vivo observations, Th17 differentiation was significantly decreased and Treg induction was increased in the in vitro naive Fam234a-deficient CD4+ T-cell polarizing induction system. Similarly, knocking down FAM234A in human T cells using siRNA also revealed that FAM234A deficiency significantly decreased the Th17/Treg cell ratio in human T cells. Coimmunoprecipitation-mass spectrometry (Co-IP-MS), protein interaction, and biochemical studies revealed that FAM234A may directly interact with the deubiquitinase USP4 to affect its deubiquitination function. The reduction in Th17 cells and increase in Treg cells among Fam234a-deficient T cells were significantly reversed by restoring USP4 overexpression. RNA sequencing and molecular studies indicated that Fam234a knockout reduced USP4-mediated Rheb and RORγt deubiquitination, mTOR activation, and Hif1α expression and ultimately affected Th17 and Treg differentiation. Therefore, Fam234a intrinsically balances the Th17 and Treg differentiation of naive CD4+ T cells by directly preventing USP4-mediated deubiquitination of Rheb to regulate mTOR-HIF1α-related oxidative phosphorylation and glycolytic gluconeogenesis metabolism pathways as well as USP4-mediated deubiquitination of RORγt pathways. This research revealed the critical role of FAM234A in the orchestration of Th17/Treg cell fate decisions and may offer potential therapies for their related diseases.

Inflammatory bowel disease (IBD) is a chronic, relapsing disorder of the gastrointestinal (GI) tract driven by complex interactions among mucosal immune dysregulation, epithelial barrier degradation, and microbial dysbiosis. Current therapies achieve only partial disease control and are limited by systemic toxicity, suboptimal response rates, and an inability to simultaneously restore epithelial integrity and microbial homeostasis. Colon-targeted oral delivery offers direct mucosal access with reduced systemic exposure; however, conventional oral formulations remain constrained by GI barriers, including proteolytic degradation, bile salt emulsification, and mucus entrapment, highlighting the need for more biocompatible delivery platforms. Edible extracellular vesicles (EEVs), encompassing plant- and milk-derived vesicles, have emerged as biogenic vehicles with the potential to partially withstand these delivery barriers. Their relative structural stability and cross-kingdom regulatory cargoes may allow EEVs to better traverse the oral-gut axis. Mechanistic studies reveal that these vesicles reprogram the intestinal inflammatory milieu by modulating immune networks, fortifying the epithelial barrier, and restoring microbiota homeostasis. Furthermore, their biodistribution enables therapeutic targeting beyond the colon, mitigating extraintestinal manifestations. In this review, we summarize the biophysical properties and immunomodulatory mechanisms of natural EEVs. We also discuss the translational limitations of native EEVs, including batch variability and payload leakage, and highlight the bioengineering strategies developed to address these challenges. Finally, we explore how integrating stimuli-responsive architectures from synthetic nanomedicine with EEVs' GI resilience may inform the design of next-generation oral platforms for IBD management.

Ulcerative colitis (UC) is a chronic inflammatory bowel disease for which effective and durable therapeutic strategies remain limited. In this study, an acetylated glucomannan polysaccharide, Aloe barbadensis polysaccharide 7 (ABPA7), was isolated and purified from the gel of Aloe barbadensis with a purity of 97.65%. Structural characterization revealed that ABPA7 is a highly homogeneous β-(1 → 4)-linked mannan, low branching, site-specific O-acetylation at the O-2/O-2,3 positions, and a high molecular weight of approximately 647 kDa. Functionally, ABPA7 markedly alleviated disease severity in a dextran sulfate sodium (DSS)-induced mouse colitis model. Mechanistic investigations demonstrated that ABPA7 reinforced intestinal barrier integrity by restoring tight junction protein expression and suppressing pro-inflammatory cytokine production. In parallel, ABPA7 was associated with alterations in gut microbiota composition and microbial metabolic networks. Transcriptomic analyses further indicated that ABPA7 upregulates the extracellular matrix (ECM) related gene expression of the intestinal. Collectively, these findings support the involvement of a coordinated "microbiota-metabolism-host" regulatory framework underlying the anti-colitis effects of ABPA7, encompassing inflammation attenuation, barrier reinforcement, and controlled ECM remodeling. This study underscores the therapeutic potential of structurally defined aloe polysaccharides and provides a mechanistic reference for the rational development of polysaccharide-based interventions for ulcerative colitis.

Understanding how molecular architecture dictates the bioactivity of functional oligosaccharides remains a major challenge. Here, mannan oligosaccharides (MOS) were prepared from yeast cell wall mannan, and Gleditsia sinensis Lam. endosperm galactomannan, to investigate structure-function relationships in preventing inflammatory bowel disease. The protective effects of yeast-derived MOS (Y-MOS) and Gleditsia-derived MOS (G-MOS) were comparatively evaluated using a dextran sodium sulfate (DSS)-induced colitis mice model. Structural analysis revealed that Y-MOS primarily consisted of α-1,6 linked mannose with α-1,2/α-1,3 linked side chains, whereas G-MOS featured a β-1,4 linked mannose backbone with α-1,6 linked galactose branches. Furthermore, both MOSs mitigated colitis symptoms, preserved colonic epithelial barrier integrity, and suppressed inflammatory cytokines, primarily through suppressing JAK2-STAT3 and NF-κB signaling pathways, regulating gut microbiota, and promoting short-chain fatty acid production. Notably, G-MOS was more effective than Y-MOS, particularly in immune regulation and modulation of gut microbiota. Molecular docking further revealed that the rigid β-linked conformation of G-MOS exhibited stronger binding affinity toward inflammatory receptors, leading to more effective pathway inhibition, as validated in LPS-treated RAW264.7 cells. These findings elucidate a glycosidic topology-dependent molecular mechanism underlying MOS bioactivity, and identify β-linked G-MOS as a promising, sustainable candidate for inflammation management.

Ulcerative colitis (UC) is a chronic and recurrent inflammatory intestinal disorder characterized by gut dysbiosis, but effective strategies are currently limited. Here, we demonstrated that Agrimoniae Herba Polysaccharides (AHP), the key active components of a herb widely used for intestinal inflammation in East Asia countries, significantly reversed colitis-related phenotypes in a gut microbiota dependent, as antibiotic treatment abolished its therapeutic effect, while gut microbes from AHP-treated mice reproduced the anti-inflammatory effect. Bacterial 16S rRNA sequencing analysis showed AHP greatly reshaped the overall structure of microbiota, especially boosting colonization of Faecalibaculum rodentium (F. rodentium), which led to a significant alleviation of intestinal inflammation, accompanied by the promotion of CD4+ T cell differentiation toward Treg. Additionally, we identified quinic acid as a key metabolite of F. rodentium enriched by AHP treatment, and found that it induced the differentiation of naïve CD4+T cells sorted from UC patients into Treg cells in vitro, which correlated with the enhancement of TAZ/Foxp3 acetylation axis. Collectively, our results show that AHP exerts the beneficial effects in the treatment of UC by acting as a prebiotic to enrich the commensal bacterium F. rodentium, and offer a novel microbiota-dependent strategy for inflammatory bowel disease.

Inflammatory bowel disease (IBD) is a debilitating condition driven by the dual pathologies of chronic inflammation and impaired intestinal barrier function. A significant clinical need exists for therapies that can effectively target both issues simultaneously. In this study, we investigated the therapeutic potential and mechanism of 5-hydroxy-N,N,N-trimethyltryptamine (5-OH-TMT), a quaternary ammonium salt derivative of bufotenine. We demonstrate that oral administration of 5-OH-TMT significantly ameliorates disease in two distinct murine models of experimental colitis (dextran sulfate sodium-induced and 2,4,6-trinitrobenzene sulfonic acid-induced colitis). The 5-OH-TMT treatment markedly improved clinical symptoms, potently suppressed pro-inflammatory cytokine production, and promoted a vital restoration of intestinal barrier integrity. Further exploration of the molecular basis of action of 5-OH-TMT using an unbiased proteomic screen revealed that 5-OH-TMT directly binds to and inhibits the mitochondrial serine protease high-temperature requirement A2 (HTRA2) protein. Additional mechanistic studies demonstrated that this inhibition of HTRA2 activates the Dectin-1/CARD9 signaling pathway, a key axis in mucosal defense. Subsequent work confirmed that siRNA-mediated silencing of HTRA2 could phenocopy the drug's effects, including the suppression of pro-inflammatory NF-κB phosphorylation. In conclusion, our findings establish that 5-OH-TMT mitigates colitis through a newly identified mechanism involving direct HTRA2 inhibition. This inhibition unleashes a protective Dectin-1-dependent program that both suppresses inflammation and restores barrier function. This work identifies the HTRA2-Dectin-1 axis as a promising new therapeutic target for IBD. 5-OH-TMT mitigates colitis through HTRA2 binding-mediated activation of the Dectin-1 signaling pathway. This figure is created with biorender.com.

Oral therapy for inflammatory bowel disease (IBD) requires drug formulations that can withstand gastrointestinal stress and achieve localized action at the inflamed mucosa, yet existing extracellular vesicles (EVs)-based or small-molecule approaches often fail due to poor stability and limited colonic delivery. This study aimed to develop a dual-coated oral delivery platform that enhances gastrointestinal stability and targeted drug release. We engineered macrophage-derived EVs sequentially coated with a cationic lipid and sodium alginate (SA) to encapsulate 5-aminosalicylic acid (5-ASA). This stepwise surface charge-switching strategy preserved EV identity, conferred resistance to acids and enzymes, and enabled delayed uncoating at colonic pH. In a gastrointestinal-mimicking Caco-2-THP-1 co-culture model, dual-coated EVs (DCEVs) exhibited enhanced epithelial uptake, transepithelial transport, and macrophage delivery compared to unmodified EVs. In a dextran sodium sulfate (DSS)-induced colitis model, 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP) facilitated endosomal escape and SA enabled timed release, resulting in increased colonic exposure, significant recovery of colon length, restoration of intestinal tight junctions, suppression of pro-inflammatory cytokines, and increased IL-10 expression. Collectively, these results demonstrate that a sequential coating strategy can effectively integrate EV-mediated immunomodulation with pharmacologic therapy, providing a pH-stable oral EV platform for localized treatment of IBD.

Inflammatory bowel disease (IBD) is a chronic and relapsing gastrointestinal disorder marked by persistent inflammation and disruption of the intestinal barrier. Current treatments often focus solely on inflammation control and lack effective mucosal repair capabilities, leading to suboptimal outcomes and adverse effects. To address this, we developed tea polyphenol and serotonin nanoparticles (TPSNs) through oxidative copolymerization of epigallocatechin gallate (EGCG) and serotonin (5-HT), combining the anti-inflammatory, antioxidant, and mucosal repair functions of both components. The therapeutic efficacy was systematically evaluated in dextran sulfate sodium (DSS)-induced acute colitis models in both zebrafish and mice, as well as in IL-10 knockout mice models of chronic colitis. Mechanistic studies revealed that TPSNs effectively scavenged reactive oxygen and nitrogen species (RONS), promoted M1-to-M2 macrophage repolarization, inhibited pyroptosis and NF-κB signaling, and activated MAPK and PI3K-AKT pathways to enhance epithelial cell proliferation and migration. TPSNs were further incorporated into a thermosensitive in situ forming gel for rectal delivery to enhance localized and sustained drug release. In vivo administration demonstrated significant amelioration of disease symptoms and histopathological features, while biosafety assessments confirmed no considerable toxicity to major organs or disruption of liver and kidney function. These findings highlight TPSNs as a safe and effective nanotherapeutic candidate for integrated IBD treatment by addressing inflammatory and mucosal repair pathways.

Resmetirom, a thyroid hormone beta (THR-β) agonist, has been shown to improve metabolic dysfunction-associated steatohepatitis (MASH) and fibrosis in patients with non-cirrhotic MASH in a phase III serial liver biopsy study. In the phase III MAESTRO-NASH trial, the impact of resmetirom compared with placebo on histologic fibrosis features was evaluated using artificial intelligence (AI)-based digital pathology (qFibrosis). qFibrosis was a secondary analysis of liver biopsies from 966 patients with biopsy-confirmed MASH and fibrosis stages F1B, F2, or F3 enrolled in the multicenter, double-blind, placebo-controlled, phase III MAESTRO-NASH trial. Biopsies from baseline and week 52 were assessed using second harmonic generation (SHG) and two-photon excitation fluorescence microscopy. Pre-specified assessments by treatment group included qFibrosis continuous values (qFC), categorical stages (qFS), and qSteatosis. Post hoc analyses evaluated regional qFibrosis features and 30 clinical outcome-associated qFibrosis features, including correlations of these features with pathologist-assessed fibrosis improvement and non-invasive tests. Resmetirom 80 mg and 100 mg resulted in qFS improvement (≥1-stage decrease) in 24.4% and 22.3% more patients than placebo, respectively, and reduced qFS worsening (≥1-stage increase) relative to placebo (nominal p ≤0.001 for both doses). Mean placebo-corrected reductions in qFC were -0.95 (95% CI -1.22 to -0.69) and -1.08 (95% CI -1.34 to -0.81) for the 80 mg and 100 mg doses, respectively. Six of the 30 clinical outcome-associated qFibrosis features, primarily from the portal tract and Zone 2 regions, showed the strongest positive correlations with pathologist-assessed fibrosis stage and biomarkers, including liver stiffness measures. Individual fibrosis features in the portal region and chicken wire fibrosis showed the greatest reductions with resmetirom treatment. Resmetirom treatment led to significant improvements in qFC, qFS, and individual collagen features associated with fibrosis progression. These digital pathology findings support the antifibrotic efficacy of resmetirom and demonstrate the potential of AI-based quantification to help define the fibrogenic response in MASH. This study provides the first evidence from a pivotal phase III trial that AI-based digital pathology, including qFibrosis and region-specific collagen features, can sensitively detect the antifibrotic effects of resmetirom in MASH beyond conventional ordinal staging. These continuous metrics offer deeper insight into the pathophysiological mechanisms underlying fibrosis progression and reversal in MASLD, including early matrix remodeling, while enabling more granular, reproducible, and biologically plausible analyses. The ability to quantify spatially distinct patterns of collagen remodeling - particularly in the portal tract and Zone 2 regions - may refine understanding of treatment-related antifibrotic effects in MASH and help clarify how such changes may reduce progression to cirrhosis and improve clinical outcomes. NCT03900429.

Steatotic liver disease (SLD) comprises a heterogeneous group of liver diseases defined by pathological hepatic lipid accumulation with varying degrees of steatohepatitis and progressive fibrosis, which may culminate in cirrhosis and/or hepatocellular carcinoma. SLD encompasses metabolic dysfunction-associated steatotic liver disease (MASLD), formerly called non-alcoholic fatty liver disease (NAFLD); MetALD, describing patients with MASLD consuming moderately high amounts of alcohol; and alcohol-associated/related liver disease (ALD). In addition, SLD encompasses less common aetiologies, including drug-induced and monogenic causes, as well as cryptogenic disease, which lacks metabolic risk factors or an identifiable cause. As the leading cause of chronic liver disease worldwide, MASLD, including metabolic dysfunction-associated steatohepatitis (MASH), is a complex multisystem disorder associated with extrahepatic organ dysfunction. Consequently, MASLD has become a major focus of multidisciplinary research, driving innovation across hepatology, immunology, cardiometabolism, addiction medicine, nutrition, prevention, and beyond. Over the past two decades, a broad array of in vivo, in vitro, and ex vivo experimental models have been developed to recapitulate diverse aspects of SLD pathophysiology, genetics, inflammation, treatment response, and multi-organ crosstalk, substantially advancing mechanistic understanding and therapeutic development. However, the rapid expansion and heterogeneity of available models have also highlighted the need for improved categorisation, standardisation, and harmonisation in line with evolving disease definitions and clinical concepts. In this EASL position paper, we critically review and classify currently available experimental SLD models and propose key criteria required for their appropriate use across distinct SLD subtypes. These criteria encompass systemic and hepatic metabolism, cardiometabolic comorbidities, histopathology, immunopathology, and molecular features relevant to disease stage and aetiology. This position paper aims to guide informed model selection, promote consistent nomenclature, and enhance rigour and translational relevance in preclinical and experimental SLD research.

Di(2-ethylhexyl) phthalate (DEHP) is a widely used industrial plasticizer, raising global concerns due to its potential endocrine-disrupting effects and environmental persistence. Human exposure to DEHP primarily occurs through the ingestion of contaminated food and water, inhalation of airborne particles, and dermal contact with products containing DEHP. Understanding the toxicological mechanisms of DEHP is essential for evaluating its health risks and developing effective strategies to mitigate its adverse effects. In this study, we conducted long-term exposure experiments to DEHP using both an animal model and in vitro system to investigate the complex interplay among DNA methylation, hyperactivation of macroautophagy/autophagy, mitochondrial dysfunction, and lipid accumulation induced by DEHP. The results revealed that DEHP exposure induced the degradation of DNMT1 (DNA methyltransferase 1) by enhancing its interaction with the autophagy-related protein SQSTM1 (sequestosome 1). DNMT1 degradation resulted in decreased methylation of the promoter regions of genes associated with autophagosome formation, subsequently increasing their expression. The resulting demethylation excessively activated autophagy, contributing to mitochondrial dysfunction and lipid accumulation in the liver. This study uncovered a previously unrecognized interplay among hyperactivation of autophagy, mitochondrial dysfunction, and lipid accumulation in the context of DEHP exposure. These findings enhanced our understanding of DEHP's toxicity and underscored concerns about the long-term health effects of environmental pollutants, particularly regarding metabolic diseases.Abbreviation: ATG5:autophagy related 5; ATG16L1: autophagy related 16 like 1; BECN1:beclin 1; COX4/COXIV: cytochrome c oxidase subunit 4; BS-seq:bisulfite sequencing; DCFH-DA: 2',7'-dichlorodihydrofluoresceindiacetate; DEHP: di(2-ethylhexyl) phthalate; DNMT1: DNAmethyltransferase 1; DNMT3A: DNA methyltransferase 3A; FABP4: fattyacid binding protein 4; FASN: fatty acid synthase; LPL: lipoproteinlipase; MAP1LC3/LC3: microtubule associated protein1 light chain 3; NAFLD: nonalcoholic fatty liver disease; NR1H3:nuclear receptor subfamily 1 group H member 3; PPARG: peroxisomeproliferator activated receptor gamma; RB1CC1: RB1 induciblecoiled-coil 1; SQSTM1: sequestosome 1; SREBF2: sterol regulatoryelement binding transcription factor 2; VDAC1: voltage dependentanion channel 1.

Lactoferrin (LF), a multifunctional glycoprotein, has been implicated in the regulation of glucose and lipid metabolism. This study employed in vivo and in vitro models to investigate the direct effects of LF on non-alcoholic steatohepatitis (NASH) and to elucidate its underlying mechanisms. LF intervention alleviated hepatic lipid metabolic disorders and liver injury in high-fat, high-cholesterol cholate-containing diet (HFCCD)-fed mice by mitigating oxidative stress, suppressing the inflammatory cGAS/STING pathway, and reducing M1 proinflammatory macrophage polarization. These effects were validated in free fatty acid (FFA)-treated HepG2 cells and AML12 cells. Furthermore, LF ameliorated HFCCD-induced gut microbiota dysbiosis and increased short-chain fatty acid levels. The critical role of gut microbiota in mediating the hepatoprotective effects of LF was confirmed through antibiotic-induced microbiome depletion and fecal microbiota transplantation. Mechanistically, LF modulated gut-liver serotonin signaling and promoted fatty acid β-oxidation through the HTR2A-PPARα-CPT-1A pathway, an effect abolished by the HTR2A agonist DOI. In a co-culture system, LF treatment of the Caco-2/HT29 monolayer alleviated lipid accumulation and regulated the HTR2A-PPARα-CPT-1A pathway in FFA-treated HepG2 cells. These findings indicate that LF attenuates NASH by remodeling gut microbiota to modulate microbiota-derived serotonin signaling and enhance fatty acid oxidation.

Pyoderma gangrenosum (PG) is a rare neutrophilic dermatosis characterized by sterile ulcerative skin lesions. Multiple comorbidities and clinical features have been associated with PG, but no standardized guidelines exist for classifying PG phenotypes. To develop an expert-established classification framework for PG phenotypes to inform treatment guidelines and future research endeavors. In this modified Delphi consensus study that included 23 board-certified dermatologists and Medical Dermatology Society members with expertise in PG, panelists completed 5 rounds of anonymous, iterative online surveys that were administered from December 2023 through July 2025. Before the beginning of the consensus exercise, a literature review was performed by nonvoting researchers to summarize existing data on PG clinical associations and comorbidities. A PubMed search from inception to September 2023 identified observational studies, narrative reviews, systematic reviews, and meta-analyses describing PG clinical associations and comorbidities that were published in English. Experts indicated their agreement with proposed PG phenotypes and disease modifiers with a consensus threshold of 70% or greater. Anonymous comments and aggregated results were presented in each subsequent round. In the final round, a framework of PG phenotypes and disease modifiers was proposed for agreement. Twenty-three board-certified dermatologists and Medical Dermatology Society members with expertise in PG completed 5 rounds of iterative surveys. Consensus was reached on the final set of PG phenotypes and disease modifiers, with 83% of experts in agreement. PG phenotypes were overall classified into 2 major groups: PG with autoinflammatory syndromes and nonsyndromic PG. Nonsyndromic PG included 4 phenotypes: inflammatory bowel disease-associated PG, PG in association with hematologic cancers and blood dyscrasias, drug-induced PG, and other (including idiopathic) PG. Disease modifiers of PG phenotype presentations included involvement of special sites (head/neck, genitals, or peristomal skin) and extracutaneous manifestations. This expert-established, descriptive framework provides a standardized classification system for distinct PG phenotypes and its modifiers. This nomenclature may inform upcoming clinical guidelines and allow for consistency in reporting epidemiological research and outcomes among patients with PG.

Autoimmune responses are often attributed to failed tolerance to self-proteins, yet protein expression alone cannot explain why certain antigens dominate disease, why autoreactivity emerges under stress, or why specific HLA alleles shape risk. This review presents a framework in which autoimmunity arises from posttranslational remodeling of antigen identity. Rather than limiting PTMs to side chain chemistry, we consider how covalent modifications, altered processing, aberrant translation, peptide recombination, and supramolecular assembly expand the repertoire of molecular forms available for immune recognition. Classical PTMs such as citrullination, deamidation, oxidation, glycosylation, phosphorylation, sulfation, and ubiquitin-like remnants can modify proteolysis, HLA binding, and antibody recognition. Noncanonical pathways, including signal peptide processing, ERAP-dependent trimming, defective ribosomal products, cryptic ORFs, proteasome-catalyzed splicing, and hybrid insulin peptides, further demonstrate that the presented antigenome extends beyond annotated proteins. We also propose that aggregation functions as a supramolecular antigenic modification by altering uptake, persistence, protease accessibility, and local reaction chemistry. Examples from rheumatoid arthritis, celiac disease, type 1 diabetes, multiple sclerosis, systemic lupus erythematosus, inflammatory bowel disease, and autoimmune thyroid disease illustrate how these mechanisms converge. Finally, we discuss mass spectrometry and immunopeptidomics strategies for identifying, validating, and functionally interpreting remodeled antigens in autoimmune disease.

Immune cells play a central role in the pathogenesis and progression of autoimmune diseases. Recent evidence indicates that metabolites produced by the gut microbiota are essential for maintaining immune cell homeostasis. Indole-3-carboxaldehyde (IAld), a key gut microbial metabolite, has garnered considerable attention due to its immunomodulatory properties in autoimmune diseases. In multiple sclerosis (MS), IAld alleviates inflammation through modulation of mast cells and astrocytes; in rheumatoid arthritis (RA), IAld suppresses macrophage-mediated inflammation while concurrently promoting angiogenesis and osteoclastogenesis; in inflammatory bowel disease (IBD), IAld confers protection through reducing inflammatory responses, promoting intestinal barrier repair, and modulating the gut microbiota composition. IAld mediates its immunomodulatory effects by directly or indirectly modulating immune cell function, including secretion and regulatory activity (including neutrophils, macrophages, innate lymphoid cells, T cells, and others) via the aryl hydrocarbon receptor (AhR) signaling pathway. In this review, we summarize the mechanisms by which IAld acts on immune cells and discuss its implications for autoimmune disease pathogenesis. Finally, we outline current challenges in this field and provide a perspective on future research priorities.

Predicting outcomes of primary sclerosing cholangitis (PSC) by reliable and simple tools is an unmet need. Retrospective studies have suggested that liver stiffness measurement (LSM) by vibration-controlled transient elastography (Fibroscan®) can predict outcomes. We aimed to validate the prognostic value of LSM statics and determine the relevance of LSM dynamics in a large, prospective, cohort study. Clinical, biological and LSM data of adult patients with uncomplicated PSC were prospectively recorded annually for 5 years. LSM was assessed either continuously or according to 3 Baveno-VII classes (<10kPa, >10-<15kPa, >15kPa). The primary endpoint was transplant-free survival. Adjusted hazard ratios (aHRs) and 95% confidence intervals (95%CIs) were determined using time-dependent multivariable Cox regression analyses. Effect of LSM change was evaluated using joint modeling. Progression was defined by a significantly positive individual LSM slope. 538 patients with at least one reliable LSM and follow-up available (median: 60.7 months, Q1-Q3(48.6-66.0)) were analyzed. Median baseline LSM was 7.6(5.8-11.7)kPa. Nineteen patients died and 72 were transplanted. Baseline LSM was strongly and independently linked to the risk of death or transplantation (RDT). For the groups 2.5--<10kPa, 10--<15kPa, >15kPa, 5 years transplant-free survival was 93.9%(90.3-%-96.2%), 78.1%(66.2%-86.3%) and 46.0%(34.6%-56.7%) respectively. Progressors experienced a worst transplant-free survival vs non-progressors: aHR 3.12(1.55-6.24), P=0.001. Each one kPa/year increment was associated with 18% increase in RDT. This observational study validates the strong prognostic value of both static and dynamic LSM in PSC, as assessed by Fibroscan®. These results support the use of LSM as a risk stratification tool and potential surrogate endpoint in clinical trials.

Primary sclerosing cholangitis (PSC) has a variable disease course, complicating patient counseling and the timing of liver transplantation. Vitamin B6 deficiency predicts reduced liver transplantation-free survival in Scandinavian PSC cohorts. Here, we aimed to validate this observation in US and German PSC cohorts and to expand our analyses to include hepatic decompensation as a clinical outcome. Serum active vitamin B6 (pyridoxal 5'-phosphate [PLP]) was analyzed using liquid chromatography-tandem mass spectrometry in retrospective cohorts of people with PSC from Norway (n = 315), the USA (n = 756), and Germany (n = 149). Cox proportional hazards and Fine and Gray competing risk models were fitted to estimate the ability of PLP to predict liver transplantation-free survival and the cumulative incidence of hepatic decompensation, respectively. The prevalence of vitamin B6 deficiency (PLP <20 nmol/L) in pre-transplant PSC was 50% in the Norway cohort and 25% in the USA cohort. The prevalence was higher among those with previous hepatic decompensation. The cumulative incidence of hepatic decompensation was higher in the USA cohort, while individuals in the Norway cohort were more commonly transplanted for indications other than hepatic decompensation. Despite differences in clinical practice, low PLP was consistently associated with shorter liver transplantation-free survival, and PLP added predictive value for liver transplantation or death from PSC over and above contemporary prediction models. Low PLP was also associated with a higher incidence of hepatic decompensation, which was mainly evident in the USA cohort, where decompensation was more common. The risk of both outcomes increased sharply within the deficient and marginal ranges and plateaued at sufficient PLP levels. Vitamin B6 deficiency is common in PSC outside Scandinavia and is consistently associated with poor outcomes across geographically distinct PSC populations. We previously showed that vitamin B6 deficiency is prevalent and associated with reduced liver transplantation-free survival in Scandinavian PSC cohorts. The current work shows that these observations generalize to a US population and that low vitamin B6 is also associated with the development of hepatic decompensation. Our results indicate that vitamin B6 provides incremental value for predicting outcomes in PSC across geographically distinct populations and that efforts to restore B6 sufficiency should be focused on the many individuals who present with vitamin B6 levels within the marginal-to-definitive deficiency range.

The distinction between benign and neoplastic bile duct strictures remains challenging. Pathologic assessment of endoscopic retrograde cholangiopancreatography (ERCP)-obtained specimens has limited sensitivity, particularly among patients with primary sclerosing cholangitis (PSC). Next-generation sequencing of bile duct specimens provides a promising diagnostic approach, but a prospective, multi-institutional, and comprehensive DNA/RNA analysis is lacking. A 6-year, prospective, multi-institutional study was conducted using BiliSeq version 2 (28 cancer-associated genes and 167 fusion genes) and BiliSeq version 3 (161 cancer-associated genes and 763 fusion genes) for 2908 ERCP-obtained brushings, biopsies, and bile from 2116 patients at 28 medical institutions. Molecular results were compared with clinical, imaging, and pathologic parameters including diagnostic pathology and/or at least 1-year follow-up. BiliSeqV2/V3 testing was performed for 2865 (99%) specimens from 2080 (98%) patients. Based on follow-up from 1979 (95%) patients, BiliSeq version 2/version 3 demonstrated 82% sensitivity and 98% specificity for a neoplastic stricture. In comparison, pathologic assessment had a sensitivity of 44% and a specificity of 99%. Combining BiliSeq version 2/version 3 testing with pathologic assessment improved the sensitivity to 88% and maintained a high specificity of 97%. High-risk populations, such as Hispanic, germline carrier, and PSC patients, also showed improvement in sensitivity with BiliSeq version 2/version 3 (74% to 86%) compared with pathologic assessment (26% to 50%). Further, actionable molecular alterations were identified in 20% of BiliSeq version 3-positive neoplasms and modified patient management in 30% of these cases. Applying BiliSeq version 2/version V3 testing to ERCP-obtained specimens improved the diagnostic evaluation of bile duct strictures, achieving higher sensitivity, especially for PSC, and maintained high specificity compared with traditional methods. This study highlights the importance of next-generation sequencing for precise diagnosis and therapeutic intervention.

Hypoxemia is a common and serious complication during sedated gastrointestinal endoscopy for out- and in-patients. Though diagnostic and severity scoring systems of obstructive sleep apnea (OSA) and difficult airway assessment (DAA) are widely used to assess hypoxemia risk, there is no exclusively designed prediction model and convenient tool in real-world practice. We aimed to develop and validate a robust and accurate hypoxemia risk prediction model for pre-operative use in this context. Using data from out-patients undergoing gastrointestinal endoscopy between May 2020 and November 2023 across seven hospitals in China with diverse regional and ethnic backgrounds, we developed and independently validated a hypoxemia risk prediction model for sedated gastrointestinal endoscopy (HAPPY-12K). The model was developed to pre-operatively predict occurrence of hypoxemia during sedated gastrointestinal endoscopy, defined as SpO2 falling below 95% for a duration exceeding 10 s. HAPPY-12K was a logistic regression model incorporating eight predictors: body mass index, Mallampati grade, limited jaw protrusion, short thyromental distance, large tongue, history of snoring, short neck with large circumference and pre-operative mean arterial pressure. The model was constructed by a well-established 3-D modeling strategy composed of Double types of effects, Double steps of screening, and Double steps of modeling. The discriminative ability was evaluated using the area under the receiver operating characteristic curve (AUC). The model calibration was examined through calibration slope, expected-to-observed (E:O) ratio and Brier score. For clinical utility, decision curve analysis was performed to assess net benefit (NB) and net reduction (NR). Furthermore, we systematically compared HAPPY-12K with other newly developed models using scores or raw variables from questionaries of OSA and DAA using DeLong's test. This study is registered in the Chinese Clinical Trial Registry (ChiCTR2300074128). We included 11,957 patients, divided into a Training Set (n = 2,518, hypoxemia rate 10.37%), and five validation sets (n = 9,439, hypoxemia rate raining from 8.40% to 28.45%). HAPPY-12K was developed in a Han Chinese population and exhibited satisfactory discrimination ability with AUCs ranging from 0.818 to 0.895 in external populations of the same ethnicity, and an acceptable AUC of 0.771 in a Uygur Chinese population. Although its Brier scores were satisfactory across all ethnic populations, HAPPY-12K displayed acceptable calibration (calibration slope < 1.2) in external Han Chinese populations, and good calibration (E:O ratio = 0.962) in independent homogenous populations comparable to the training set. The average NB and NR were 45.2‰ and 59.5%, respectively. It was estimated that HAPPY-12K would identify over half a million patients with truly developing hypoxemia during sedated gastrointestinal endoscopy and could help avoid over six million unnecessary interventions annually in China. Meanwhile, a head-to-head comparison revealed that HAPPY-12K outperformed other models. HAPPY-12K has been implemented as an interactive online tool available at http://bigdata.njmu.edu.cn/HAPPY-12K/. HAPPY-12K could enable efficient and precise hypoxemia risk assessment before sedated gastrointestinal endoscopy, providing timely alerts for high-risk outpatients. National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Science and Technology Project of Jiangsu Disease Control and Prevention Administration; Science and Technology Development Project of Nanjing Medical University; Priority Academic Program Development of Jiangsu Higher Education Institutions; and Outstanding Young Level Academic Leadership Training Program of Nanjing Medical University.

Generative indigo carmine chromoendoscopy (generative chromoendoscopy), produced using deep learning-based synthetic image transformation, is a novel image-enhanced endoscopic approach, whose clinical feasibility has not been validated. This proof-of-concept study evaluated whether generative chromoendoscopy improves the visibility of gastric neoplasms compared with conventional white-light imaging (WLI) and real chromoendoscopy. This prospective multicenter study was conducted at three Japanese institutions between January and August 2025. A deep neural network-based program converted WLI into generative chromoendoscopy images. Patients with early gastric cancer or adenoma sequentially underwent endoscopy using WLI, generative chromoendoscopy, and real chromoendoscopy. During live endoscopy, two endoscopists independently assessed lesion visibility using a 7-point Likert-type scale (-3 to +3). The primary end point was visibility of gastric neoplasms with generative chromoendoscopy relative to WLI, with comparison to real chromoendoscopy. Secondary end points included clinicopathologic factors associated with improved visibility. 60 patients were included. Mean (SD) visibility scores were 0.67 (0.93) for generative chromoendoscopy and 0.51 (1.00) for real chromoendoscopy. The mean difference was 0.16 (95%CI 0.01 to 0.30). Differentiated-type histology (odds ratio [OR] 2.19, 95%CI 1.03 to 4.62), current Helicobacter pylori infection (OR 2.14, 95%CI 1.02 to 4.46), and expert endoscopist status (OR 2.14, 95%CI 1.22 to 3.76) were significantly associated with higher visibility scores using generative chromoendoscopy. Generative chromoendoscopy was feasible during live endoscopic procedures. It improved visibility of pre-identified gastric neoplasms compared with WLI and achieved visibility comparable to real chromoendoscopy.

Women remain underrepresented in advanced endoscopy. Factors such as ergonomics, concerns over radiation exposure, and traditional family roles have been identified as barriers in prior studies. To date, no published study has surveyed potential reasons for this at an international level. We aimed to assess factors that may contribute to poor uptake of advanced endoscopy training among women on a global scale. A cross-sectional survey was designed by the mentees of the inaugural Women in Endoscopy Mentorship Program, including questions on demographics, endoscopy, family, wellbeing, mentorship, and leadership. This was shared via social media and professional networks. There were 553 responses to the survey (282 from men), with 24% of respondents reporting that fewer than 10% of endoscopists at their center were female. Women were significantly less likely to have a partner; if they had a partner, they were more likely to be in full-time employment than male respondents' partners (67% vs. 43%; P < 0.001). Women were more likely to feel they had delayed having a family in favor of career progression, and that they had sacrificed career progression to have a family. They were also more likely to feel their gender held them back (61.3% vs. 19.9%; P < 0.001). More male respondents felt that they got the same opportunities as colleagues of the opposite gender at the same time (75.2% vs. 50.9%; P < 0.001). Family responsibilities and perception of gender bias remain significant barriers to a career in advanced endoscopy for women worldwide.

Luminal proteases have been implicated in epithelial barrier dysfunction and visceral hypersensitivity in irritable bowel syndrome (IBS), yet their impact on the enteric nervous system (ENS), the principal regulator of gastrointestinal function, remains unknown. To investigate whether faecal mediators differentially activate enteric neurons across IBS subtypes and whether proteolytic and proteomic profiles explain neuronal phenotypes. The effects of faecal supernatants (FSN) from 21 IBS-D (diarrhoea-predominant), 9 IBS-C (constipation-predominant) and 18 healthy control (HC) patients recruited across centres in three countries on guinea pig distal colon submucous plexus neurons were assessed using a neuroimaging technique. Faecal proteolytic activities and proteomic profiles were analysed. IBS-D and IBS-C supernatants evoked significantly stronger neuronal activation than HC, demonstrating that FSN directly modulate ENS. In IBS-D, but not IBS-C, effects were mediated by serine and cysteine proteases and PAR-1. Proteome analysis revealed a significant difference in 47 proteins between IBS-D and HC, including several immunoglobulin components, underlying the role of microinflammation in IBS-D. A combination of amylases, trypsin-2 and an immunoglobulin protein demonstrated high diagnostic performance to distinguish IBS-D from HC. These findings uncover a previously unrecognised luminal-ENS axis in IBS and reveal fundamentally different pathological mechanisms between IBS-D and IBS-C. IBS-D is characterised by proteases and PAR-1-dependent neuronal activation and a distinct immune-enriched faecal proteome, whereas mediators in IBS-C act independently of these factors. These findings establish a functional link between faecal protease activity, ENS signalling and molecular biomarkers, highlighting new therapeutic and diagnostic avenues for subtype-specific management of IBS.

Gut microbiota modulate emotion, yet mechanistic insight and therapeutic targets remain limited. Here, we identify reduced gut microbiota-derived indole causally modulating emotion through hippocampal aryl hydrocarbon receptor (AhR). We found that decreased abundance of Alistipes shahii reduced intestinal indole levels via loss of tryptophanase, the rate-limiting step for indole production in microbial tryptophan metabolism, in irritable bowel syndrome (IBS) patients and model mice. In the brain, indole acts via AhR, which is enriched in the ventral dentate gyrus (vDG), a hub in regulating emotion. Reduced indole diminished nuclear AhR expression and vDG granule cell activity, leading to affective symptoms. Tryptophanase-producing microbiota transplantation, indole/tryptophanase supplementation, chemogenetic activation of vDG neurons, or diosmin, a clinically approved AhR agonist, rescued emotional symptoms in IBS mice. Together, these findings define an Alistipes shahii-tryptophanase-indole-AhR-vDG pathway as a mechanistic and translationally tractable gut-brain axis underlying affective disturbances.

Decompensated cirrhosis is associated with cirrhosis-associated immune dysfunction (CAID), predisposing patients to bacterial infections and poor outcomes. The mechanisms driving CAID remain incompletely understood. To examine whether portal hypertension (PH) is a key upstream driver of CAID and whether its reduction by transjugular intrahepatic portosystemic shunt (TIPS) reverses immune dysfunction. In a prospective cohort study, patients undergoing TIPS (n=75) and controls with compensated cirrhosis (n=15) were included. Plasma markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation were measured in controls and longitudinally before and after TIPS. The effects of patient sera from different stages of cirrhosis on healthy donor-derived monocytes were assessed in vitro. Bulk RNA sequencing was performed on patient monocytes. Immunological findings were correlated with clinical outcomes, which were also validated in an external prospective cohort and a retrospective multicentre cohort of 1180 patients. Patients with decompensated cirrhosis showed elevated markers of gut barrier dysfunction, bacterial translocation, systemic inflammation and monocyte activation compared with compensated controls. These markers significantly decreased after TIPS. Sera from decompensated patients, but not from post-TIPS patients, induced anti-inflammatory markers (MER Tyrosine Kinase (MERTK), CD163) and suppressed interleukin 6 secretion in monocytes in vitro. Transcriptomic analysis identified an anti-inflammatory monocyte signature in decompensated cirrhosis that resolved after TIPS. CAID improvement occurred only in patients with ascites resolution and was associated with fewer bacterial infections. PH is a central driver of CAID in decompensated cirrhosis. Its reduction by TIPS restores gut barrier integrity, reduces inflammation and re-establishes immune homeostasis.

Non-cirrhotic portal hypertension has historically been described using heterogeneous and region-specific terminology, such as idiopathic portal hypertension (IPH), non-cirrhotic portal fibrosis (NCPF), obliterative portal venopathy, and nodular regenerative hyperplasia, leading to substantial variability in diagnosis, reporting, and international research collaboration. Differences in guideline definitions from major societies (AASLD, EASL, and APASL), together with the presence of characteristic histologic lesions in patients without clinically overt portal hypertension, have further complicated disease classification. To address these challenges, a large, multisociety, international initiative was convened to harmonize nomenclature and diagnostic criteria. Representatives from liver, pathology, and pediatric hepatology societies across the Americas, Europe, and Asia participated in a structured consensus process that included specialized working groups and external Delphi validation. The initiative produced a globally harmonized and implementable diagnostic framework. Consensus was reached that the terms porto-sinusoidal vascular disorder (PSVD) and NCPF may be used interchangeably when identical diagnostic criteria are applied, and that they should be written as PSVD or NCPF. The diagnosis was defined as fundamentally clinicopathological, requiring integrated assessment. Core principles include the need for a high-quality liver biopsy (≥10 mm), mandatory exclusion of cirrhosis, and systematic exclusion of specific alternative conditions. Importantly, the consensus recognizes that PSVD or NCPF may be diagnosed even without clinical portal hypertension and may coexist with other liver diseases, provided cirrhosis is excluded. Standardized major and minor histologic criteria were developed collaboratively by expert pathologists and externally validated. Features of portal hypertension were harmonized into specific and nonspecific categories applicable to routine clinical practice. An integrated diagnostic scoring system incorporating histology, clinical features, associated conditions, and concommitant etiologies was developed and validated using the Delphi method. This consensus provides the first internationally endorsed, unified framework for the diagnosis of PSVD or NCPF. Its global implementation is expected to reduce diagnostic variability, improve comparability across regions, and facilitate the development of robust, internationally harmonized clinical and translational research cohorts.

The optimal tracking control problem for multiplayer differential game systems (MDGS) with unknown dynamics is investigated in this article. A two-stage asynchronous learning scheme is proposed to achieve Nash equilibrium solutions without requiring initial admissible control policies. In the first stage, stabilizing control policies are constructed through a homotopic-based iterative process. In the second stage, an asynchronous policy iteration (PI) method is employed, in which players sequentially update their policies using partial real-time information, contributing to improved convergence efficiency compared to synchronous approaches. The proposed scheme is further extended to a data-driven framework, relaxing the requirement of explicit system dynamic information. Convergence under stabilizability and detectability conditions is theoretically proven. Finally, two simulation examples are conducted to demonstrate the effectiveness of the proposed method in tracking a sinusoidal reference. Additionally, comparison experiments are provided to highlight the superiority of the proposed algorithm.

Allicin, a bioactive compound derived from garlic, exhibits therapeutic potential against metabolic disorders but is hindered by instability and a pungent odor, limiting its clinical application. This study develops an allicin oleogel (OG) formulation, leveraging molecular interactions with unsaturated fatty acids and gelators to stabilize allicin and mitigate its odor for transcutaneous delivery. The skin analysis confirmed superior transdermal delivery and accumulation in subcutaneous fat with OG, highlighting its advantages for topical application. In a high-fat diet (HFD)-induced mouse model of obesity, OG demonstrated superior efficacy in suppressing weight gain, reducing food intake, and improving metabolic parameters, including fasting blood glucose, oral glucose tolerance, and insulin sensitivity, compared to orally administered allicin oleogel (OGO) and metformin (MET). OG also ameliorated non-alcoholic fatty liver disease (NAFLD), as evidenced by reduced hepatic lipid accumulation and normalized adipose tissue metabolism. Notably, OG treatment shifted macrophage polarization toward an anti-inflammatory M2 phenotype and increased mitochondrial activity, facilitating adipose tissue remodeling and enhancing energy expenditure and thermogenesis. Safety evaluations revealed no systemic toxicity, supporting its potential for long-term use. This study underscores transcutaneously delivered OG as a promising therapeutic strategy for obesity and related metabolic disorders.

Acute pancreatitis (AP) represents a significant global health challenge. Despite recent advances in medical treatment, the development of novel therapeutic strategies remains crucial. Rhein, a natural compound of the Chinese herb Rheum, shows promise in the treatment of AP. However, the exact mechanism underlying its therapeutic effect is still not fully understood. To investigate the association between the rhein-related gut microbiota and AP, we conducted antibiotic-mediated microbiota depletion experiments, fecal microbiota transplantation (FMT), and in vitro bacterial culture experiments. Concurrently, we performed 16S rRNA gene sequencing, metagenomic sequencing, and liquid chromatography‒mass spectrometry (LC‒MS) analyses on mouse fecal samples to characterize alterations in the microbiota and metabolome. Transcriptomic studies were also performed to elucidate the mechanisms underlying acinar cell inflammation. Rhein alleviated AP by modulating the gut microbiota, as demonstrated by changes in the gut microbiota composition and improvements in AP after FMT in rhein-treated mice compared with those in cerulein-induced AP mice. Specifically, rhein is concentrated mainly in the stomach and intestines, where it exerts anti-inflammatory effects on acinar cells by antagonizing the TLR4/NF-κB/NLRP3 signaling pathway activated by trimethylamine-N-oxide (TMAO). This mechanism is associated with lipid peroxidation and necrosis mediated by oxidative stress. Clinically, disease severity in patients with AP is positively correlated with serum TMAO concentration. Rhein alleviates AP by modulating the intestinal microbiota to reduce TMAO production, thereby suppressing TMAO-induced activation of the TLR4/NF-κB/NLRP3 signaling pathway and inhibiting acinar cell inflammation.

Transcription factor EB (TFEB) deficiency contributes to insufficient autophagic degradation, resulting in zymogen granule (ZG) accumulation and subsequent premature activation, which underlies the pathogenesis of alcoholic pancreatitis (AP). Despite this mechanistic insight, pharmacological activation of TFEB via plant-derived agents remains an underdeveloped therapeutic avenue. This study aims to investigate Wogonin's role as a key Scutellaria baicalensis (Huangqin, HQ) component in protecting against AP, with specific focus on TFEB-mediated autophagy activation. Using TFEB-AcGFP and mRFP-GFP-LC3 reporter systems, we assessed Wogonin-enriched HQ extracts on TFEB nuclear translocation and autophagic flux. Pharmacological and genetic approaches were combined to established HQ/Wogonin's effects on alcohol-induced pancreatic injury through TFEB-mediated autophagic restoration. Structure-based virtual screening and molecular docking techniques were employed to predict the binding activity of Wogonin with upstream kinases regulating TFEB. Prioritized interactions underwent biophysical validation via surface plasmon resonance (SPR), isothermal titration calorimetry (ITC) and cellular thermal shift assay (CETSA) assays. HQ/Wogonin enhanced TFEB nuclear translocation and transcriptional activity, thereby restoring autophagic degradation to exert protection against alcohol-induced ZG accumulation and pancreatic injuries. Acinar TFEB knockout abolished HQ's protective effects against AP. Mechanistic studies revealed Wogonin directly bound with AMPK (AMP-activated protein kinase) to promote its protein stability, leading to improved TFEB activation. This study establishes Wogonin as the pivotal bioactive driver behind HQ's therapeutic efficacy, orchestrating AMPK-TFEB-autophagy coordination to mitigate AP. Atomic-level resolution of Wogonin's adenine-mimetic binding to AMPK provides novel therapeutic strategies for developing kinase-stabilizing botanicals targeting TFEB activation to treat pancreatitis.

Antiretroviral therapy (ART) regimens without tenofovir have risks related to hepatitis B virus (HBV). As these regimens are being used more frequently, clinicians and policy makers would benefit from an accurate estimate of the risk of HBV outcomes following tenofovir cessation. We conducted a systematic review of HBV reactivation and infection in people with HIV who discontinue tenofovir. We searched Medline, Embase, Google Scholar, and the Cochrane database (1 January 2006-15 February 2026) for studies related to tenofovir cessation in people with HIV and (1) active HBV: positive HBV surface antigen (HBsAg); (2) resolved HBV: positive HBV core antibody (HBcAb) without HBsAg; and (3) susceptibility to HBV: negative HBsAg, HBcAb, and HBV surface antibody. We used a random effects model to calculate the pooled incidence rate of HBV reactivation (in resolved HBV) and new HBV infection (in those susceptible to HBV) after tenofovir cessation. We used multivariable meta-regression to compare pooled outcomes across subgroups. We used I2 to assess inter-study heterogeneity, and we tested for publication bias using Egger's test. This review is registered with Prospero (#2025-CRD420251080460). Of 144 abstracts and articles, 53 underwent full-text review, and 22 unique observational studies were included. In eight studies of active HBV infection, only descriptive data could be retrieved without a meta-analysis: HBV DNA increase or hepatitis flares commonly occurred in most studies after tenofovir cessation or interruption. In six observational studies of resolved HBV infection with active surveillance of HBV serological markers after tenofovir cessation, pooled incidence of HBV reactivation was 3.79/100 person-years (95% CI 1.98-7.23; I2 = 57.6%; moderate certainty). This was higher than the pooled incidence in studies without active monitoring for HBV reactivation (0.35/100 person-years, 95% CI 0.12-1.03; p < 0.001). Six observational studies reported new HBV infections in susceptible people following transition to tenofovir-sparing ART (pooled incidence = 1.63/100 person-years, 95%CI = 0.27-9.92; I2 = 78.6%; very low certainty). Egger's test showed no statistically significant evidence of publication bias (p = 0.216). In people with HIV, tenofovir-sparing ART is associated with risks related to HBV reactivation and infection. Higher quality prospective studies are needed in people with HIV who stop tenofovir. National Institutes of Health and Harvard University Center for AIDS Research.

Post-endoscopy upper gastrointestinal cancer (PEUGIC) is defined as cancer diagnosed 6-36 months after a prior index endoscopy during which cancer was not diagnosed. Few studies have examined PEUGIC survival. We describe survival in PEUGIC patients compared with upper gastrointestinal cancer (UGIC) patients who did not undergo endoscopy without a cancer diagnosis prior to their diagnosis. This was a population-based retrospective survival analysis of UGIC patients diagnosed between January 2009 and December 2018 in England. Patients were categorized into "detected UGIC" (without prior endoscopy) and "PEUGIC" diagnosed 6-12, 12-18, 18-24, or 24-36 months after index endoscopy. PEUGIC survival was analyzed according to pre-existing Barrett's esophagus (BE), esophageal cancer histological, and gastric cancer. Kaplan-Meier all-cause survival curves investigated survival from both diagnosis and index endoscopy date. 98710 UGIC patients (9068 PEUGIC [9.2%]) were studied. Pre-existing BE was recorded for 9975 UGIC patients (10.1%), including 2583 PEUGIC (25.9%). PEUGIC survival was better than detected UGIC survival but the difference decreased as time between index endoscopy and diagnosis increased. Patients with pre-existing BE and PEUGIC had much better survival, with more stage 1 cancer (39.5% versus 8.4% for PEUGIC without BE; P < 0.001). Survival in PEUGIC and detected UGIC patients was similar when BE patients were excluded. Survival in PEUGIC patients with squamous cell carcinoma and gastric cancer was the same as for detected UGIC. Better survival in patients with PEUGIC compared with detected UGIC appeared to be related to BE surveillance. Epidemiological biases, including selection, lead time, and immortal time, should be considered when reporting PEUGIC survival outcomes.

This guideline is an update of the 2021 ESGE Guideline on Endoscopic diagnosis and management of nonvariceal upper gastrointestinal hemorrhage. The following are the new and/or revised recommendations. 1: ESGE does not recommend the routine use of video capsule endoscopy or telemetric blood-sensing capsules in the management of patients with suspected upper gastrointestinal hemorrhage (UGIH). 2: ESGE suggests, if intravenous erythromycin is unavailable, pre-endoscopy administration of intravenous metoclopramide in selected patients with clinically severe or ongoing active UGIH. 3: ESGE suggests that pre-endoscopy high dose intravenous proton pump inhibitor (PPI) therapy be considered in patients presenting with acute UGIH; however, this should not delay early endoscopy. 4: ESGE does not recommend emergent (≤6 hours) or urgent (≤12 hours) upper GI endoscopy unless the patient remains hemodynamically unstable despite adequate resuscitation. 5: ESGE suggests that patients with peptic ulcers presenting with an adherent clot (Forrest IIb) should undergo endoscopic therapy, with clot removal and subsequent endoscopic hemostasis if indicated, provided that the endoscopist has the technical competence to safely remove the clot and manage potential conversion to a higher risk bleeding lesion. 6: ESGE could not reach a consensus for or against the routine use of a Doppler endoscopic probe in treatment decisions of high risk endoscopic stigmata of peptic ulcer bleeding. 7: ESGE suggests the use of over-the-scope (OTS) clips as monotherapy as an alternative to combination therapy as first-line therapy for peptic ulcer bleeding with high risk stigmata (FIa, FIb) owing to a lower risk of further bleeding compared with standard endoscopic hemostatic therapy. 8: ESGE recommends, for patients with an ulcer with a nonbleeding visible vessel (FIIa), contact or noncontact thermal therapy, mechanical therapy (e.g. through-the-scope or OTS clips), or injection of a sclerosing agent, each as monotherapy or in combination with epinephrine injection. 9: ESGE suggests, for patients with an ulcer with a nonbleeding visible vessel (FIIa), OTS clips may be used as alternative monotherapy. 10: ESGE suggests hemostatic forceps with soft coagulation may be used as monotherapy in the treatment of peptic ulcer bleeding with high risk stigmata (FIa, FIb, and FIIa). 11: ESGE suggests that hemostatic agents should not be used as monotherapy in the first-line treatment of patients with high risk stigmata of peptic ulcer bleeding. 12: ESGE suggests that, in patients with persistent bleeding refractory to standard hemostasis modalities, the use of a topical hemostatic agent or OTS clips should be considered. 13: ESGE recommends that, in patients with persistent bleeding refractory to all modalities of endoscopic hemostasis, including topical hemostatic agents and OTS clips, transcatheter angiographic embolization (TAE) should be considered. Surgery is indicated when TAE is not locally available or after unsuccessful TAE. 14: ESGE suggests that prophylactic TAE be considered in selected high risk cases of peptic ulcer bleeding (e.g. patients with hemodynamic instability at presentation, posterior duodenal wall ulcer location, large ulcer size [>2 cm], or when durable endoscopic hemostasis is considered uncertain). 15: ESGE could not reach a consensus for or against the routine use of potassium-competitive acid blockers for patients who have undergone endoscopic hemostasis. 16: ESGE recommends that, for patients with clinical evidence of recurrent peptic ulcer bleeding, use of an OTS clip should be considered. Should this second attempt at endoscopic hemostasis also be unsuccessful, TAE should be considered. Surgery is indicated when TAE is either locally unavailable or after unsuccessful TAE. 17: ESGE recommends that, in patients with peptic ulcer hemorrhage who require ongoing anticoagulation therapy, anticoagulation should be resumed as soon as clinically indicated based on thromboembolic risk. 18: ESGE suggests that iron therapy be initiated prior to hospital discharge in patients with peptic ulcer bleeding and iron deficiency and/or anemia. 19: ESGE suggests that early oral nutrition, within 24 hours following endoscopic hemostasis, be initiated in patients with peptic ulcer bleeding in whom durable hemostasis has been achieved.

Natural products are biologically active compounds used for therapeutic interventions for various diseases, particularly infections. Autophagy is an intracellular catabolic pathway involving lysosomal degradation and is closely associated with immunological pathways, effectively combating bacterial, viral, fungal, and parasitic infections. Accumulating evidence suggests that autophagy activation or inhibition by natural products promotes antimicrobial responses against various pathogens. Numerous natural products can modulate autophagy through diverse signaling pathways, suggesting their potential as a host-directed therapeutic strategy that may complement conventional drug regimens or help mitigate drug resistance in various infectious diseases. However, it remains largely unclear whether these effects are mediated by direct modulation of autophagy or indirectly through associated mechanisms, including enhanced immune defense, attenuation of pathological inflammation, or crosstalk with other organelle functions. Additionally, multiple pathogens can evade host responses; thus, autophagy activation may inadvertently create favorable conditions for certain pathogens. This review discusses the current knowledge of natural products in terms of their antimicrobial actions through autophagy regulation, particularly the roles of distinct natural product classes, such as polyphenols, alkaloids, terpenoids, quinones, peptides, and macrolides in modulating autophagy for potentially contributing to control various infectious diseases. Exploring the intricate molecular interplay between natural products and autophagy in limiting infections may provide valuable insights that could inform the development of innovative host-directed antimicrobial treatments based on autophagy regulation.Abbreviations: 3-MA: 3-methyladenine; AM: alveolar macrophages; AMP: antimicrobial peptides; AMPK: 5' adenosine monophosphate-activated protein kinase; ARDS: acute respiratory distress syndrome; ART: artemisinin; ASFV: African swine fever virus; ATG: autophagy related; AZM: azithromycin; BafA1: bafilomycin A1; BECN1: beclin 1; BMDM: bone marrow-derived macrophage; BNIP3: BCL2 interacting protein 3; BNIP3L: BCL2 interacting protein 3 like; CALCOCO2/NDP52: calcium binding and coiled-coil domain 2; CAMKK2: calcium/calmodulin-dependent protein kinase kinase 2; CBD: cannabidiol; CF: cystic fibrosis; CGA: chlorogenic acid; CGAS: cyclic GMP-AMP synthase; CHUK/IKKα: component of inhibitor of nuclear factor kappa B kinase complex; CLP: cecal ligation and puncture; CLR: clarithromycin; CMA: chaperone-mediated autophagy; CoV: coronavirus; DHT: dihydrotanshinone I; EGCG: epigallocatechin-3-gallate; EIF2A: eukaryotic translation initiation factor 2A; EIF2AK2: eukaryotic translation initiation factor 2 alpha kinase 2; ESKAPE: Enterococcus faecium, Staphylococcus aureus, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, and Enterobacter spp.; ESRRA: estrogen related receptor alpha; FOXO1: forkhead box O1; FUNDC1: FUN14 domain containing 1; HBV: hepatitis B virus; HCV: hepatitis C virus; HDT: host-directed therapy; HIV: human immunodeficiency virus; HMGB1: high mobility group box 1; HSV: herpes simplex virus; IAV: influenza A virus; ICT: isocryptotanshinone; IFN: interferon; IKBKB/IKKβ: inhibitor of nuclear factor kappa B kinase subunit beta; IL: interleukin; INH: isoniazid; IRF3: IFN regulatory factor 3; KEAP1: kelch like ECH associated protein 1; LAMP: lysosomal associated membrane protein; LAP: LC3-associated phagocytosis; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MAPK: mitogen-activated protein kinase; MDM: monocyte-derived macrophage; MDR: multidrug-resistant; MON: monotropein; Mtb: Mycobacterium tuberculosis; MTOR: mechanistic target of rapamycin kinase; mtROS: mitochondrial ROS; NET: neutrophil extracellular trap; NFE2L2/Nrf2: NFE2 like bZIP transcription factor 2; NFKB/NF-κB: nuclear factor kappa B; NLRP3: NLR family pyrin domain containing 3; NLRX1: NLR family member X1; NOTCH1: notch receptor 1; NTM: nontuberculous mycobacteria; OMS: ohmyungsamycin; PAK1: p21 (RAC1) activated kinase 1; PINK1: PTEN induced kinase 1; PKM/PKM2: pyruvate kinase M1/2; PLD: phospholipase D; PM: peritoneal macrophage; PPM1A: protein phosphatase, Mg2+/Mn2+ dependent 1A; PRKN/parkin: parkin RBR E3 ubiquitin protein ligase; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; PTEN: phosphatase and tensin homolog; RB1CC1/FIP200: RB1 inducible coiled-coil 1; RELA/p65: RELA proto-oncogene, NF-kB subunit; RIF: rifampicin; ROS: reactive oxygen species; RSV: resveratrol; RUBCN/rubicon: rubicon autophagy regulator; SAR: selective autophagy receptor; SIRT: sirtuin; STING1: stimulator of interferon response cGAMP interactor 1; STX17: syntaxin 17; Tat: trans-activator of transcription; TB: tuberculosis; TBK1: TANK binding kinase 1; TFEB: transcription factor EB; TLR: toll like receptor; TNA: tanshinone IIA; TNF: tumor necrosis factor; UA: ursolic acid; ULK1/Atg1: unc-51 like autophagy activating kinase 1; UPR: unfolded protein response; UVRAG: UV radiation resistance associated; VAMP8: vesicle associated membrane protein 8; VDR: vitamin D receptor; WIPI2: WD repeat domain, phosphoinositide interacting 2; ZFYVE1/DFCP1: zinc finger FYVE-type containing 1; ZIKV: Zika virus.

In December 2025, the Advisory Committee on Immunization Practices (ACIP) voted to replace the universal hepatitis B birth-dose recommendation with shared clinical decision-making for infants born to mothers who screen negative for hepatitis B surface antigen. Although the proposal would not alter recommendations for infants of unscreened mothers, historical data suggest that removing a universal birth-dose vaccine recommendation may reduce vaccination coverage in this group. To estimate the impact of replacing universal hepatitis B virus (HBV) birth-dose vaccination with a targeted recommendation on neonatal and subsequent chronic HBV infections in the US. A compartmental model and simulated a US birth cohort (n = 3 659 289) under the 2 vaccine recommendations: universal birth-dose vaccination and targeted birth-dose vaccination vaccine recommendations, where the birth dose was recommended to infants of screened-positive or unscreened mothers and shared-decision making is recommended for infants of screened-negative mothers. Parameter values were literature derived and uncertainty was incorporated across 5000 iterations. These data were analyzed from September through November 2025. Birth-dose vaccine recommendations and birth-dose vaccination coverage among infants of unscreened mothers. Numbers of neonatal and subsequent chronic HBV infections. With the current maternal HBV screening rate of 86%, the universal birth-dose vaccine recommendation resulted in a median of 1292 neonatal infections (95% percentile interval [PI], 670-2228). In comparison, the targeted birth-dose vaccine recommendation was associated with 628 additional neonatal infections (95% PI, 340-1034) when birth-dose vaccination coverage among infants of unscreened mothers was 10% (mirroring historic coverage declines under a targeted recommendation) and 69 additional infections (95% PI, -32 to 190) when coverage was 80% (mirroring levels under a universal recommendation.) To offset the excess infections under the targeted birth-dose vaccine recommendation, more than 100 000 additional pregnant individuals would need to be screened if the birth-dose vaccination coverage among infants of unscreened mothers was 80%, and more than 400 000 if coverage was 10%. Findings from this study indicate that the targeted birth-dose vaccine recommendation will likely increase neonatal infections unless maternal screening rises substantially or vaccination coverage among infants of unscreened mothers exceeds current levels. As historic data show such improvements are unlikely, these findings underscore the continued importance of universal screening and vaccination as complementary safeguards.

Biliary tract cancers (BTCs) are a group of rare but highly lethal malignancies that include intrahepatic cholangiocarcinoma (iCCA), extrahepatic cholangiocarcinoma (eCCA), and gallbladder carcinoma (GBC). A major challenge in modeling and treating these cancers is their highly heterogeneous mutational landscapes, both within and across subtypes, as well as across geographic and etiological contexts. This heterogeneity necessitates large cohorts to enable robust statistical analyses. Here, we collate and analyze data from more than 30 next-generation sequencing studies to provide a comprehensive overview of BTC mutational patterns and their potential clinical implications. Mutation data from 5,123 BTC samples from 13 countries were standardized, focusing on a set of 29 bona fide oncogenes and tumor suppressor genes. We performed statistical analyses to evaluate hypotheses related to mutation prevalence, etiology, co-mutation patterns, and recurrent mutations. This analysis provides robust estimates of mutation prevalence across geographic regions, BTC subtypes, and hepatitis status, highlighting genes whose alteration frequencies vary by anatomical location and etiology. or example, iCCA in Eastern vs. Western hemispheres showed large differences in alteration prevalence for FGFR2, IDH1, KRAS, TP53, CDKN2A, and BAP1, whereas eCCA and GBC exhibited only modest hemispheric differences. We further show that these differences, as well as those observed between iCCA and eCCA, are partly explained by variation in the mutation profiles and prevalences of small- vs. large-duct subtypes. The large sample size also enabled systematic characterization of gene-gene co-occurrence and mutual exclusivity across BTC subtypes, along with a clinically oriented catalogue of recurrent mutations in oncogenes and tumor suppressor genes. This integrative cross-study analysis provides a global view of BTC genomics, clarifying how geography, etiology, and anatomical subtype collectively shape driver mutation landscapes. Our results provide statistical depth, uncover new mutational relationships, and suggest high-priority avenues for basic and translational research in biliary tract cancer. By integrating data across diverse geographic and etiological contexts, this study highlights how mutation prevalence and co-mutation patterns vary systematically with anatomical subtype, hepatitis status, and region. These findings offer a more nuanced framework for interpreting BTC genomics and underscore the importance of stratified approaches to research and treatment. Collectively, this work establishes a robust foundation for future biological studies, biomarker development, and the design of clinical trials that are tailored to geographic origin, underlying etiology, and specific mutational and co-mutation landscapes, ultimately supporting more precise and effective therapeutic strategies in BTC.

Artificial intelligence (AI) has emerged as a promising tool to detect early dysplasia in Barrett's esophagus (BE). However, the cost-effectiveness of AI-assisted BE surveillance has not been evaluated. A Markov model simulated 1000 Australian individuals with nondysplastic Barrett's esophagus (NDBE) undergoing surveillance from age 50 to 80 years, with follow-up until age 100. We compared AI-assisted surveillance with targeted biopsies against standard endoscopy with four-quadrant biopsies under 3-yearly and 5-yearly surveillance. The primary outcome was the incremental cost-effectiveness ratio (ICER). Secondary outcomes included cumulative incidence of high grade dysplasia (HGD)/T1 lesions and advanced esophageal adenocarcinoma (EAC), as well as their relative differences. A health care system perspective was employed, with costs and utilities discounted at an annual rate of 3%. AI-assisted surveillance was cost effective across both intervals, with ICERs of AUD 14 039/quality-adjusted life year (QALY) (3-yearly) and 3609/QALY (5-yearly). Compared with standard surveillance, AI reduced the cumulative incidence of advanced EAC by 5 and 3 cases per 1000 people (relative reductions of 3.5% and 1.6%) for 3- and 5-yearly surveillance, respectively. Conversely, AI increased HGD/T1 detection by 27 and 38 cases per 1000 people (relative increases of 21.8% and 27.7%) for 3- and 5-yearly surveillance, respectively. Additionally, AI reduced missed HGD/T1 incidence by 37 and 45 cases per 1000 people (relative reductions of 72.9% and 72.2%) for 3- and 5-yearly surveillance, respectively. AI-assisted endoscopic surveillance in BE was a cost-effective strategy in the Australian health care setting, reducing the cumulative incidence of advanced EAC and missed HGD/T1 lesions.

Enteropathogenic viruses are a major cause of childhood diarrheal illness and deaths, particularly posing a disproportionate burden on developing countries. This study systematically analysed multi-pathogen surveillance studies for gastroenteric viruses in raw and treated effluent to investigate their prevalence pattern, treatment reduction, relative viability, and viral diversity using meta-analysis and sensitivity analysis. Based on PCR findings, human norovirus with pooled prevalence of 87% (95% CI; 71-94) and aichivirus with 87% (95% CI; 59-97) predominated in raw wastewater worldwide, followed by enterovirus 86% (95% CI; 66-95), adenovirus 81% (95% CI; 63-91), sapovirus 71 (95% CI; 35-92), astrovirus 64% (95% CI; 32-87), rotavirus 62% (95% CI; 46-76), and hepatitis A virus (HAV) 37% (95% CI; 19-60). In treated effluent, human adenovirus with estimated pooled prevalence of 51% (95% CI; 11-90), was most prevalent, followed by norovirus 50% (95% CI; 18-81), enterovirus 34% (95% CI; 14-63), rotavirus 29% (95% CI; 16-46), HAV 21% (95% CI; 10-37), aichivirus 17% (95% CI; 1-81), and sapovirus 2% (95% CI; 0-9). Viable rotavirus was higher in effluent samples (29.4% vs 16.4%), followed by adenovirus (68.9% vs 11.1%), while enterovirus (60.5% vs 2.1%) had the least detected infectious viral particles post treatment. Human norovirus GII (56.5%; 2402/4179) predominated over the GI norovirus (42.5%, 1777/4179), with GII.4 and GI.2 being the most prevalent species within GII and GI, respectively. Rotavirus genotype G3 (24%) and G2 (22%) dominated the VP7 strains, while genotype P[8] (63%) and P[4] (30%) predominated other circulating VP4 strains. This study confirms high circulation of human norovirus, adenovirus, enterovirus, and aichivirus in wastewater treatment systems. Their persistence during treatment emphasizes the importance of considering these viruses as crucial biological targets in water quality monitoring, improving wastewater treatment strategies, and leveraging wastewater surveillance for public health protection.

Heart failure and chronic liver disease account for substantial morbidity and mortality worldwide. Both conditions share common risk factors and a bidirectional pathophysiology, and the coexistence of both conditions is expected to increase over time. Management of coexisting heart failure and liver disease is challenged by the under-representation of participants with liver disease in landmark heart failure clinical trials, impaired hemodynamics at advanced stages of liver disease, altered drug metabolism, and higher risk of adverse events than portended by either condition alone. Moreover, diagnostic pitfalls might be encountered in relation to assessing the primary etiologies driving the disease process, estimating the degree of liver fibrosis, and differentiating primary liver disease from heart failure-related liver congestion particularly, given the complex interplay between sinusoidal pressure, congestion, and structural fibrosis. Cardiovascular-hepatic cross-thematic research, clinical education, and health care services could optimize management and patient outcomes. The purpose of the current review is to (i) highlight the growing epidemiology of concurrent heart failure-liver disease; (ii) provide diagnostic clues for liver disease and an approach for interpreting liver marker abnormalities amongst heart failure patients; (iii) describe the main therapeutic strategies in real-world clinical settings; and (iv) discuss current gaps in knowledge and future directions. This update on the framework of the heart failure-liver disease overlap phenomenon can inform clinical care policies and facilitate novel research in the field.