Medicine and Pharmacology

Abstract: Background/Objectives: The development of GLP-1 receptor agonists (GLP-1RAs) and dual GLP-1/GIP receptor agonists has expanded the possibilities for multimodal obesity treatment. However, evidence regarding the integration, combination, or sequencing of these therapies with bariatric/metabolic endoscopy and bariatric/metabolic surgery has not been comprehensively synthesized. Methods: A scoping review was conducted following the methodological framework of Arksey and Levac, the recommendations of the Joanna Briggs Institute, and the PRISMA-ScR guidelines. A systematic search was performed in PubMed, Scopus, and Embase from database inception through May 16, 2026. Studies involving adults that evaluated GLP-1/GIP agonists in relation to endoscopic and/or surgical bariatric/metabolic procedures were included. Data extraction was independently performed by two reviewers, and the evidence was synthesized using descriptive and narrative analyses. Results: A total of 61 studies were included, of which 14 directly evaluated multimodal integration strategies involving pharmacotherapy, bariatric/metabolic endoscopy, and/or bariatric/metabolic surgery, encompassing approximately 6,401 participants. Retrospective cohort studies predominated (71.4%). Semaglutide and liraglutide were the most frequently investigated medications. The intragastric balloon was the most evaluated endoscopic intervention, followed by transoral outlet reduction (TORe), endoscopic sleeve gastroplasty (ESG), revisional ESG (R-ESG), and revisional procedures. Pharmacologic-endoscopic combinations were the most common strategy (42.9%), and most studies were conducted in the postoperative setting (71.4%). Overall, combined and sequential strategies achieved greater weight loss than isolated interventions, whereas revisional surgery demonstrated superior outcomes compared with pharmacotherapy in comparative studies. Conclusions: Evidence regarding multimodal strategies for obesity treatment remains limited and is predominantly observational. The integration of pharmacotherapy with endoscopic and surgical interventions shows promising results; however, high-quality prospective studies and randomized clinical trials are needed to define the optimal treatment sequence and identify the patients most likely to benefit from these multimodal approaches.

Abstract: Nonalcoholic fatty liver disease (NAFLD) is a globally prevalent metabolic disorder for which no pharmacotherapy has been approved. We applied an integrated computational framework to a ten-herb traditional Chinese medicine (TCM) transdermal formula administered via umbilical (Shenque) acupoint therapy, combining network pharmacology, multi-dataset machine learning, immune-infiltration analysis, molecular docking, and molecular dynamics (MD). Network pharmacology of 5276 drug-likeness-filtered compounds yielded 380 shared herb–disease targets. Across three training cohorts (n=346, ComBat-corrected) and an independent validation cohort (GSE167523, n=98), LASSO and random forest identified four hub genes—FOS, HSP90AB1, HIF1A, and MAPK8 (validation AUC 0.760, 0.701, 0.802, and 0.744)—all dysregulated in NAFLD. GSEA highlighted upregulated ECM–receptor interaction and suppressed ribosome, IL-17, and NF-κB signalling, whereas ssGSEA revealed elevated follicular helper and exhausted CD4+ T cells. Three-dimensional screening (transdermal ADMET, ligand similarity, AutoDock Vina) prioritised danshenspiroketallactone as the strongest HSP90AB1 binder (ΔG=−11.7 kcal/mol). Across six complexes, 3×100 ns MD with MM-PBSA confirmed favourable binding (ΔGbind −14.2 to −18.0 kcal/mol). These findings propose a multitarget inflammation–proteostasis–fibrosis mechanism and a “thermal activation–chemical fine-tuning” model for Shenque therapy, generating hypotheses that warrant experimental validation.

Abstract: Objectives: Exenatide is a glucagon-like peptide-1 receptor agonist (GLP-1 RA) that slows gastrointestinal (GI) motility. Whether exenatide produces clinically detectable GI motility slowing in real-world practice — and how this compares to other GLP-1 RAs — has not been systematically evaluated. We addressed this question using federated, electronic health record (EHR) data. Further, we present clinical data on vurolenatide, a long-acting variant of exenatide, in patients with short bowel syndrome (SBS), a condition defined by nutritional insufficiency where reducing GI motility could be beneficial to patient outcomes. Methods: We queried de-identified EHR data on the nSights platform to identify treatment episodes for exenatide, semaglutide, and tirzepatide among patients with documented GI hypermotility. Anti-constipation medication prescriptions, body weight, and HbA1c trajectories were compared between pre- and post-treatment periods. Given exenatide’s GI potency, we enrolled 9 SBS patients in a Ph 1b/2a study looking at vurolenatide, dosed subcutaneously every 2 weeks. Safety, tolerability, total urine output, and total stool output were the primary endpoints with the latter serving as a metric for GI motility. Results: We identified patients on exenatide (n=387), semaglutide (10,315), and tirzepatide (5,095) and found the prevalence of anti-constipation prescriptions increased significantly in the exenatide cohort over 12 months (11.09% to 18.62%; p=6.75×10⁻⁴). No significant change was detected with semaglutide (17.54% to 17.70%, p=0.734), and tirzepatide was associated with a decrease in use (18.72% to 14.84%, p<0.001). Exenatide did not impact body weight (-0.5%, p=0.299), compared to semaglutide (-3.95%, p<0.001) and tirzepatide (-8.44%, p<0.001), nor impact HbA1c (-0.02 %-points, p=0.926), compared to semaglutide (-0.26 %-points, p<0.001) and tirzepatide (-0.56 %-points, p<0.001). Consistent with exenatide’s potency at slowing GI motility, biweekly dosing of vurolenatide in human SBS patients showed immediate reduction in total stool output and in the number of bowel movements patients experienced. Conclusions: Exenatide is associated with potent slowing of GI motility in retrospective analysis of EHR data as well as in prospective treatment of SBS patients. This real-world signal proxies the mechanism underlying vurolenatide in SBS and provides a first-in-kind pharmacoepidemiological basis for GLP-1 RA–mediated modulation of GI motility.

Abstract: Liver fibrosis is a serious complication of non-alcoholic fatty liver disease (NAFLD) and the metabolic syndrome (MetS), conditions closely linked to obesity. We investigated the levels and dynamics of liver fibrosis biomarkers and liver fat content during personalized weight loss intervention in individuals with obesity, NAFLD, and MetS (n=30), with assessments at baseline, 1, and 5 months. Liver fat content decreased significantly (p < 0.0001), corresponding with complete resolution of steatosis in 36.7% of the participants, after 1 month of weight loss. Similarily, the fibrosis markers: T1 (p < 0.001), CK18 (p < 0.01), PIIINP (p < 0.05), TIMP1 (p < 0.001), and MACK3 (p < 0.001) dropped after 1 month. CK18 (p < 0.01), PIIINP (p < 0.0001), and MACK3 (p < 0.001) further changed from 1 to 5 months, while FNI decreased after 5 months (p < 0.01). Except for CK18, the dynamics of these changes were more pronounced from baseline to 1 month compared with 1 to 5 months. Finally, MACK3 showed promise for explaining T1. Our study underlines the importance of weight loss in swiftly mitigating liver steatosis and supports the integration of non-invasive biomarkers to monitor fibrosis risk in individuals with obesity, NAFLD, and MetS.

Abstract: Introduction: Hepatitis C virus (HCV) infection often coexists with comorbidities, increasing vulnerability, complications, and adverse events. Direct-acting antivirals (DAAs) have dramatically improved HCV management, but they differ in drug–drug interaction (DDI) profiles. Sofosbuvir/velpatasvir (SOF/VEL) is associated with minimal clinically relevant interactions. Areas covered: A narrative review of the literature was conducted by searching PubMed and major international guidelines, focusing on studies published in the DAA era addressing HCV patients with major comorbidities, focusing on diabetes, metabolic syndrome, and cardiovascular disease; neuropsychiatric disorders; cancer; transplants; use of substances or treatment with opioid agonists; patients requiring hormone therapy including transgenders. Expert opinion: Based on literature and real-world data, managing polypharmacy in HCV patients with comorbidities is effective and well tolerated, provided thorough drug review, potential DDI analysis, proactive monitoring, and coordinated multidisciplinary care are ensured. DAAs have dramatically improved the management of HCV patients, however they have different DDI profiles that should be carefully checked. SOF/VEL has been shown to be associated with minimal clinically relevant interactions and offers a simple dosing regimen. DAA treatment is strongly advised in HCV comorbid patients not only to cure HCV but also to improve the course of comorbidities, provided that DDIs are no longer considered mere minor details.

Abstract: Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MASLD) is a metabolic disorder with an increasing incidence, for which pharmacotherapy is still very limited. One of the pharmacotherapeutic approaches for MASLD is to prevent oxidative stress processes, in which polyphenolic flavonoids, including quercetin, may play an extremely important role. Quercetin has been reported in several publications to have a potential hepatoprotective effect, but despite numerous research results, it has not lived up to the expectations placed on it so far. This study provides a comprehensive overview of the effects of quercetin on MASLD, including its role in autophagy during disease progression. Methods: This review describes the etiopathogenesis of MASLD and provides a comprehensive overview of the main physiological and pharmacological effects of quercetin, as well as its potential clinical applications. Conclusions: The effects of quercetin and commonly used biopharmaceuticals in folk medicine for the treatment of MASLD still do not show clear results. The extremely positive effects obtained in in vitro studies cannot be replicated or can only be replicated in a very limited form in pre- and clinical studies. Further research is needed to resolve this dilemma.

Abstract: Background/Objectives: We conducted a scoping review to explore the available literature on the association between lead exposure and NAFLD/MAFLD. The primary objective of this review was to discern the extent to which lead exposure has been posited as a deter-minant or risk factor for NAFLD/MAFLD. Methods: The scoping literature review, conducted following the framework proposed by Arksey and O'Malley, aimed to summarize evidence on the relationship between lead ex-posure and NAFLD/MAFLD. Inclusion criteria were observational studies analyzing hu-man populations, excluding review articles, case reports, and animal studies. The types of participants, exposure of interest (lead), and outcomes (NAFLD/MAFLD onset and out-comes) were reviewed and descriptively summarized to chart the available literature. Results: The review identified 62 documents, with ten articles meeting the inclusion crite-ria. These studies predominantly utilized population health surveys and observational approaches. Positive risk-adjusted associations between blood lead levels (BLL) and NAFLD were reported in six studies, with one study indicating correlations between BLL and fatty liver indexes and another suggesting a link between lead exposure duration and liver fibrosis. Notably, the fourth quartile of BLL consistently exhibited higher odds of NAFLD/MAFLD across studies. Conclusion: Our scoping review reveals a consistent pattern linking higher lead exposure, particularly in the fourth blood lead level quartile, to increased odds of Non-Alcoholic Fatty Liver Disease/Metabolic-Associated Fatty Liver Disease (NAFLD/MAFLD).

Abstract: Background/Objectives: Gastric endoscopic submucosal dissection (ESD) is an established organ-preserving treatment for gastric neoplasia, but the short-term safety of ESD in patients aged 80 years or older remains clinically important. We evaluated the efficacy and short-term safety of gastric ESD in patients aged ≥80 years treated under a uniform peri-procedural surveillance protocol. Methods: This retrospective cohort study included consecutive patients who underwent gastric ESD for gastric adenoma or gastric cancer at a single institution between April 2013 and March 2026. Patients were classified as <80 years or ≥80 years. Under the institutional protocol, standard admission was 3 nights/4 days, with extended monitoring for patients receiving antithrombotic agents. Efficacy and safety outcomes were compared between age groups, and multivariable models adjusted for sex, Charlson Comorbidity Index (CCI), and antithrombotic-agent use. Results: Among 2,021 gastric ESD cases, 285 were performed in patients aged ≥80 years and 1,736 in patients aged <80 years. En bloc resection rates were similarly high in the ≥80-year and <80-year groups (98.6% vs. 99.0%; P=0.524). Post-ESD pneumonia was rare, and no 30-day mortality occurred in either group. Post-ESD bleeding/perforation was not increased in patients aged ≥80 years (2.8% vs. 3.1%; P=0.783), and delirium occurred in only one patient in the ≥80-year group. In multivariable analysis, age ≥80 years was not independently associated with post-ESD bleeding/perforation, whereas Charlson Comorbidity Index and antithrombotic-agent use were significant predictors. Conclusions: Under a uniform peri-procedural surveillance protocol, gastric ESD showed comparable technical success and low short-term complication rates in carefully selected patients aged ≥80 years and younger patients. Chronological age alone should not preclude gastric ESD when standardized monitoring and individualized risk assessment are applied.

Abstract: Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD), a leading cause of chronic liver disease, encompasses a continuum from steatosis to metabolic dysfunction-associated steatohepatitis (MASH), fibrosis, cirrhosis, and hepatocellular carcinoma. This review aimed to synthesize current evidence on how metabolomic, lipidomic, and spatial multi-omic approaches illuminate MASLD pathogenesis and support precision hepatology. Methods: A structured narrative review was conducted through searches of PubMed, Scopus, and Web of Science, complemented by manual screening of key references. Studies were prioritized when they addressed MASLD biology, metabolic rewiring, lipid remodeling, mitochondrial dysfunction, inflammatory and fibrogenic pathways, gut–liver–adipose crosstalk, biomarker development, or therapeutic monitoring. Results: The reviewed evidence identifies MASLD as a systemic metabolic disorder shaped by excess lipid flux, enhanced de novo lipogenesis, impaired mitochondrial adaptation, oxidative and endoplasmic reticulum stress, sterile inflammation, and hepatic stellate-cell activation. Recurrent metabolomic signatures include altered amino acid, fatty acids, bile acid, and microbial co-metabolite pathways. Lipidomic studies consistently implicate depletion of protective polyunsaturated fatty acids, lysophosphatidylcholines, and phosphatidylcholines, in association with accumulation of diacylglycerols and ceramides, in the transition from steatosis to MASH and fibrosis. Emerging spatial and multi-omic analyses further resolve cell-specific metabolic niches involving hepatocytes, macrophages, endothelial cells, and stellate cells. Conclusions: Metabolomics provides a mechanistic and translational bridge between molecular injury, histological progression, and non-invasive risk stratification in MASLD. Future progress requires standardized analytical workflows, longitudinal validation, causal pathway interrogation, and integration with imaging, genetics, microbiome profiling, and treatment-response phenotyping.

Abstract: Liver fibrosis develops from chronic stress and death of hepatocytes, sustained by persistent injury, immune responses, metabolic stress, and vascular changes. Multiple cells and signaling pathways are involved, with inflammation amplifying fibrogenesis and hepatic stellate cell activation driving the process. Progressive fibrotic changes, potentially culminating in cirrhosis, contribute substantially to global morbidity and mortality, and their most advanced stages re-main often irreversible in clinical practice. Here, we present current insights into liver fibrosis, including epidemiological trends, clinical associations, and future research directions. Modulated by age, sex, lifestyle habits, comorbidities and drug use, liver fibrosis and cirrhosis occur in approximately 3.3% and 1.3% of the general population, respectively. We also discuss techniques for assessing liver fibrosis in clinical practice and research. Moreover, sex differences in liver fibrosis are analyzed together with the role of liver fibrosis in the development of liver-related and extrahepatic outcomes. Finally, we examine the principles of medical treatment of liver fibrosis in the context of its systemic nature and clinical implications.

Abstract: Background/Objectives: Alpha-gal syndrome (AGS) is a tick-induced, IgE-mediated hypersensitivity to the oligosaccharide galactose-α-1,3-galactose (α-gal), which is expressed on glycoproteins and glycolipids of non-primate mammals but absent in humans. Gastrointestinal (GI) symptoms dominate the clinical presentation in a substantial proportion of patients yet remain systematically under-recognized, frequently being attributed to irritable bowel syndrome (IBS), non-celiac gluten sensitivity (NCGS), or lactose intolerance. This narrative review synthesizes the current evidence on the epidemiology, GI and systemic phenotype, immunological mechanisms, diagnostic strategies, management approaches, quality-of-life burden, and multi-level public health interventions for AGS, and it identifies critical knowledge gaps as of 2026. Methods: We searched PubMed/MEDLINE, Embase, and Web of Science from database inception through 31 March 2026, and synthesized the evidence narratively in accordance with the Scale for the Assessment of Narrative Review Articles (SANRA). Results: GI symptoms occur in 47–69% of patients with AGS, with abdominal pain (58%), diarrhea (42%), nausea (39%), and vomiting (31%) as the cardinal manifestations. A characteristic 2–6 h delay between the ingestion of mammalian-derived food and symptom onset—explained by the glycolipid–chylomicron delivery mechanism—drives diagnostic confusion with functional GI disorders. Among 295,400 tested individuals in the United States, 30.5% were α-gal IgE positive, and an estimated 96,000–450,000 Americans were affected between 2010 and 2022. Despite this burden, 42% of U.S. healthcare providers had never heard of AGS. Strict avoidance of mammalian meat improves symptoms in 53–86% of adherent patients, although the condition carries a meaningful risk of anaphylaxis even among GI-predominant presenters. Conclusions: AGS is a prevalent, frequently misdiagnosed, and clinically morbid condition whose GI phenotype lies squarely within the gastroenterologist’s domain. A coordinated response that integrates clinician education, institutional diagnostic algorithms, and national surveillance infrastructure is urgently needed.

Abstract: Acute-on-chronic liver failure (ACLF) is a rapidly progressing and highly lethal clinical syndrome characterized by multiorgan failure, driven primarily by a severe systemic inflammatory response. The pathophysiological cascade, triggered by an initial “cytokine storm,” subsequently evolves into profound immune paralysis. This phenomenon is driven by the dysfunction of monocytes, neutrophils, and other immune cells, compounded by their impaired cellular energetics resulting from a metabolic shift toward less efficient energy-yielding mechanisms, such as aerobic glycolysis and the pentose phosphate pathway. This process is further exacerbated by disruptions within the gut-liver axis, wherein severe dysbiosis and impaired intestinal barrier integrity promote pathogen translocation. Coupled with generalized endothelial dysfunction, this ultimately leads to failure of peripheral organs. To date, no specific targeted therapies are available, and liver transplantation remains the sole intervention capable of substantially improving patient prognosis. Experimental immunomodulatory approaches including granulocyte colony-stimulating factor (G-CSF), intravenous albumin supplementation, therapeutic plasma exchange, mesenchymal stem cell therapy, and anti-cytokine agents represent promising therapeutic avenues. Nevertheless, appropriately tailoring these interventions to the evolving pathophysiological phases of the disease remains a significant clinical challenge, underscoring the critical need for developing precision therapies targeted at specific molecular pathways.

Abstract: Background/Objectives: Microsatellite-stable colorectal cancer (MSS CRC) accounts for the vast majority of CRC cases and remains largely resistant to immune checkpoint inhibitors. Emerging evidence suggests that the gut microbiome is an important regulator of antitumor immunity and may contribute to immunotherapy resistance through multiple mechanisms involving the tumor microenvironment. This review aims to summarize current knowledge of the microbiome–immunity–therapy axis in MSS CRC and to explore microbiome-based strategies to enhance immunotherapy responsiveness. Methods: A narrative review of the recent literature was conducted, focusing on studies published within the last five years that investigated gut microbiota composition, microbial metabolites, tumor immune regulation, immunotherapy response, and microbiome-targeted therapeutic interventions in CRC. Evidence from mechanistic studies, translational research, clinical investigations, and multi-omics analyses was integrated. Results: Current evidence indicates that gut dysbiosis contributes to immune resistance in MSS CRC through immune exclusion, myeloid-driven immuno-suppression, T-cell dysfunction, chronic inflammation, and altered microbial metabolite signaling. Specific microorganisms, including Fusobacterium nucleatum, enterotoxigenic Bacteroides fragilis, pks-positive Escherichia coli, and other CRC-associated pathobionts, have been implicated in tumor progression and modulation of antitumor immunity. Microbial metabolites such as short-chain fatty acids, tryptophan-derived compounds, bile acids, succinate, and inosine represent key functional mediators linking microbial communities to host immune responses. Emerging microbiome-targeted interventions, including fecal microbiota transplantation, next-generation probiotics, postbiotics, selective microbial depletion, and engineered bacterial therapeutics, show potential to restore antitumor immunity and improve immunotherapy efficacy. In parallel, advances in metagenomics, metabolomics, spatial transcriptomics, and artificial intelligence are facilitating the development of precision immuno-microbiome oncology approaches. Conclusions: The gut microbiome functions as a critical regulator of immune resistance in MSS CRC through coordinated effects on microbial composition, metabolite production, and tumor immune remodeling. Microbiome-targeted interventions, combined with multi-omics-based patient stratification, may provide new opportunities to overcome immunotherapy resistance and expand the clinical benefits of immune checkpoint blockade in this traditionally refractory disease.

Abstract: Background/Objectives: To evaluate the technical feasibility, safety, and therapeutic outcomes of the transradial approach for drug-eluting bead transarterial chemoembo-lization (DEB-TACE) as a patient-centric alternative to the conventional transfemoral route. Methods: Between August 2018 and August 2022, patients with unresectable hepato-cellular carcinoma (HCC) eligible for DEB-TACE were prospectively enrolled in this study (ClinicalTrials.gov identifier: NCT07160374). To prevent radial artery spasm and occlusion, a standardized intra-arterial cocktail solution containing 3,000 IU of heparin, 200 μg of nitroglycerin, and 2.5 mg of verapamil was administered immediately after sheath insertion. The primary endpoint was technical success without crossover to the femoral approach. Secondary endpoints included safety profile, tumor response, and procedural parameters. Results: A total of 37 patients were enrolled. Technical success was achieved in 100% of patients using the transradial approach, with zero crossover to the transfemoral ap-proach. A single major adverse event (liver abscess) occurred (2.7%). Radial artery pa-tency was preserved in all patients. All patients achieved immediate post-procedural ambulation. The objective response rate was 73% at first follow-up visit (median, 35 days; range, 14–60 days). The mean fluoroscopy time was 24 ± 9 minutes, and the mean dose area product was 142 ± 182 Gy·cm². Conclusions: The transradial approach demonstrated high technical success and a fa-vorable safety profile for DEB-TACE without increasing radiation exposure. These findings suggest that this method represents a feasible and effective alternative to the conventional transfemoral route.

Abstract: Functional dyspepsia and related disorders of gut–brain interaction are still managed without mechanism-based stratification, and trials of vagal neuromodulation have rarely measured the microbiome alongside autonomic and symptomatic endpoints. We argue that the obstacle is conceptual rather than technical: what is missing is a framework in which these readouts are coupled, not a new technology. Borrowing the logic of the cardiac stress test, we treat the gut–brain axis as a coupled, bidirectional reactivity system whose functional properties surface only under controlled perturbation. Perturbing the system in both directions yields an individual reactivity profile. Three composite indices capture overall system reactivity, vagal arc engagement, and acute modulation. A fourth coordinate, the Neural–Peripheral Dominance Index, weighs trait neural vulnerability against acute peripheral reactivity, while a fifth, the microbial Substrate Index, fixes the trait-level compositional context of the gut. Autonomic engagement is read out not from any single signal but from a sign-aligned composite of paced-breathing heart rate variability, electrodermal activity, and pupillometry. We position the profile as a mechanistic layer beneath Rome IV classification, meant to explain the heterogeneity that persists within symptom-defined subtypes, and we outline a two-phase strategy for testing mechanism-aligned therapeutic responses prospectively.

Abstract: Background & Aims: Hepatic encephalopathy (HE) significantly impairs quality of life (QoL) in patients with cirrhosis. While rifaximin is established in HE treatment and prevention, its specific impact on QoL remains less clearly defined. This systematic review aims to evaluate the effects of rifaximin on QoL in patients with HE. Methods: A comprehensive literature search was conducted in MEDLINE/PubMed, Embase, and CENTRAL through November 2025. Clinical studies evaluating rifaximin's impact on QoL in patients with decompensated cirrhosis and HE were included. Study selection followed PRISMA guidelines. Data extraction focused on study design, population, treatment, and QoL outcomes. Results: Out of 4,343 records screened, 10 studies met the inclusion criteria. Most studies evaluated rifaximin in comparison with placebo and focused on patients with minimal or covert HE. Rifaximin was almost consistently associated with statistically significant improvements in overall and domain-specific QoL scores compared with placebo, particularly in fatigue, activity and emotional function. These benefits were observed across different dosages and treatment durations. In comparative studies, rifaximin showed QoL outcomes comparable to those of lactulose, L-ornithine L-aspartate, and combination regimens. One study reported greater improvement in QoL with nitazoxanide, although rifaximin showed significant improvements in specific QoL domains. Conclusion: Rifaximin is associated with improvements in QoL in patients with cirrhosis and HE, with benefits observed across multiple domains and outcomes comparable to alternative therapies. Further high-quality comparative trials, particularly in patients with overt HE and in prophylactic settings, are needed to confirm these findings and to better inform patient-centered management strategies.

Abstract: Autism Spectrum Disorder (ASD) is a complex neurodevelopmental condition increasingly associated with gastrointestinal dysfunction, immune dysregulation, neuroinflammation, and alterations in gut microbial composition. Growing evidence supports the role of the gut–brain axis as an important mediator linking intestinal health and neurodevelopmental outcomes. To review current evidence regarding the relationship between the gut microbiome, neuroinflammation, and ASD, and to describe clinical observations obtained from a retrospective observational cohort of children participating in a microbiome-oriented supportive intervention program. This retrospective observational case series included 42 children aged 1–6 years diagnosed with Autism Spectrum Disorder (ASD) and/or Developmental Speech and Language Delay (DSLD). Clinical evaluation included assessment of gastrointestinal symptoms, nutritional deficiencies, developmental characteristics, laboratory findings, and available microbiome analyses, including 16S rRNA sequencing in a subset of participants. Children received microbiome-oriented supportive interventions that included postbiotic-based therapy, dietary modification, nutritional correction, and individualized supportive measures. Clinical outcomes were assessed descriptively during follow-up periods of up to 15 months. Gastrointestinal symptoms were present in 90.5% of participants, food selectivity in 85.7%, sleep disturbances in 83.3%, attention difficulties in 81.0%, hyperactivity in 78.6%, and speech delay in 95.2%. Across clinical subgroups, a characteristic temporal sequence of improvement was observed. Early changes (1–3 days) primarily involved gastrointestinal function, including normalization of bowel habits and reduction of abdominal discomfort. Intermediate improvements (3–4 weeks) were observed in sleep quality, appetite, emotional regulation, and behavioral stability. Later improvements (8–12 weeks) involved communication, social engagement, attention, and speech development. No serious adverse events were reported. The observations presented in this cohort support the growing body of evidence linking gastrointestinal health, microbial metabolism, immune regulation, and neurodevelopment. A characteristic sequence of clinical improvements was observed, with gastrointestinal changes preceding behavioral and neurodevelopmental improvements. Although causal relationships cannot be established within an observational study, the findings support further investigation of microbiome-oriented and postbiotic-based interventions in prospective controlled trials involving children with ASD and Developmental Speech and Language Delay.

Abstract: Introduction: Intraductal papillary mucinous neoplasms (IPMNs) are precursor lesions of pancreatic cancer. This study investigated the association between MRI-derived pancreatic fat fraction and IPMN.. Material Methods: This retrospective case-control study included 60 patients with IPMN and 120 controls evaluated between 2018 and 2025. All participants underwent pancreatic MRI with proton density fat fraction (PDFF) imaging. Pancreatic fat fraction was measured in the pancreatic head, body, and tail on PDFF maps, and mean pancreatic fat fraction was calculated. Group comparisons, receiver operating characteristic analysis, and logistic regression analyses were performed to evaluate the association between pancreatic fat fraction and IPMN. Results: A total of 180 participants were included in the study, comprising 60 patients with IPMN and 120 controls without IPMN. Patients with IPMN were significantly older than controls (72.5 vs. 57.0 years, p=0.001). The IPMN group demonstrated higher glucose and LDH levels and lower HDL cholesterol, hemoglobin, hematocrit, and platelet counts compared with controls (all p&lt;0.05). Pancreatic fat fraction measurements were significantly increased in patients with IPMN across all pancreatic regions. Head, body, tail, and mean pancreatic fat fractions were markedly higher in the IPMN group than in controls (all p=0.001). In multivariable logistic regression analyses, age and pancreatic fat fraction remained independently associated with IPMN presence. ROC analysis demonstrated excellent diagnostic performance, with mean pancreatic fat fraction showing the highest discriminative ability (AUC=0.968), followed by head (AUC=0.934), body (AUC=0.922), and tail fat fraction (AUC=0.876). Conclusion: Pancreatic fat fraction was significantly higher in patients with IPMN and remained independently associated with IPMN presence after multivariable adjustment. Mean pancreatic fat fraction demonstrated excellent diagnostic performance for distinguishing IPMN from non-IPMN individuals. Quantitative MRI-based assessment of pancreatic fat may represent a useful imaging biomarker for IPMN detection.

Abstract: Cholangiocarcinoma (CCA) is a highly heterogeneous malignancy with limited thera-peutic options and poor prognosis, underscoring the need for more effective precision medicine strategies. In this context, digital twins (DTs) and biological twins (BTs) have emerged as complementary approaches to model disease complexity and personalize treatment. DTs integrate multi-modal patient data, including imaging, clinical, and multi-omics information, into computational frameworks capable of predicting disease trajectories and therapeutic responses. BTs, such as patient-derived organoids and xenografts, enable functional validation of these predictions in patient-specific ex-perimental systems. This review synthesizes current advances in DT- and BT-based approaches in CCA, highlighting their respective strengths and limitations, and dis-cusses emerging hybrid frameworks that iteratively connect computational modeling with biological experimentation. Despite promising developments, significant chal-lenges remain, including data integration, model validation, regulatory alignment, and clinical adoption. Addressing these barriers will be critical to translating twin-based strategies into clinically actionable tools for personalized oncology.

Abstract: Peroxisome proliferator-activated receptors (PPARs) are ligand-activated nuclear transcription factors comprising three isoforms, PPARα, PPARγ, and PPARβ/δ, that regulate hepatic lipid metabolism, glucose homeostasis, inflammation, bile acid synthesis, and fibrogenesis. Because liver diseases involve overlapping metabolic, inflammatory, cholestatic, and fibrotic pathways, PPAR agonists have emerged as a versatile therapeutic class across a spectrum of hepatic conditions. PPARα agonists (e.g., fenofibrate) promote fatty acid β-oxidation and suppress de novo lipogenesis; PPARγ agonists (e.g., pioglitazone) improve insulin sensitivity and exert anti-inflammatory and antifibrotic effects; and PPARδ agonists (e.g., seladelpar) regulate bile acid and cholesterol metabolism. Dual agonists (elafibranor [PPARα/δ], saroglitazar [PPARα/γ]) and pan-PPAR agonists (lanifibranor [PPARα/γ/δ], bezafibrate) aim to simultaneously address multiple pathogenic mechanisms. In primary biliary cholangitis (PBC), elafibranor and seladelpar received accelerated FDA approval in 2024 based on phase 3 trials (ELATIVE and RESPONSE, respectively) demonstrating significant biochemical response rates of 51% and 62% versus 4% and 20% with placebo. Bezafibrate has shown survival benefit in large retrospective analyses and is used as second-line therapy in Europe and Japan. In metabolic dysfunction-associated steatotic liver disease (MASLD)/metabolic dysfunction-associated steatohepatitis (MASH), pioglitazone remains the most extensively studied PPAR agonist, with meta-analytic evidence supporting MASH resolution and fibrosis reduction regardless of diabetes status. Lanifibranor demonstrated histological improvement in the phase 2b NATIVE trial and is currently in phase 3 development (NATiV3). Elafibranor, however, failed to meet its primary endpoint in the phase 3 RESOLVE-IT trial for MASH, suggesting that the benefit of pan-PPAR agonism in MASH may derive primarily from the PPARγ component. In alcohol-associated liver disease (ALD), preclinical models have demonstrated that both elafibranor and PPARα agonists attenuate steatosis, inflammation, and fibrosis, though no completed human clinical trials exist. Evidence for PPAR agonists in primary sclerosing cholangitis (PSC) remains limited to open-label studies and a single randomized trial of bezafibrate for cholestatic pruritus. SEFA-6179, a structurally engineered medium-chain fatty acid analogue acting through GPR84, PPARα, and PPARγ, has shown promise in preclinical models of intestinal failure-associated liver disease (IFALD) and is entering phase II clinical development. This narrative review synthesizes the molecular pharmacology of PPAR isoforms, the available clinical and preclinical evidence for mono-, dual-, and pan-PPAR agonists, and their therapeutic applications across MASLD/MASH, ALD, PBC, PSC, IFALD, and advanced chronic liver disease (ACLD). The evolution from single isoform to multi-isoform PPAR agonism reflects the recognition that overlapping pathogenic mechanisms in liver diseases may require broader receptor coverage for optimal therapeutic efficacy.