Medicine and Pharmacology

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<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.

Abstract: Patients with inflammatory bowel disease (IBD) require long-term immunosuppressive therapy, raising concerns about treatment associated malignancy risk. The comparative ma-lignancy profiles of biologic and advanced small-molecule therapies remain incompletely characterized. A systematic review was conducted following PRISMA guidelines. PubMed, Embase, Cochrane Library, and Web of Science were searched from inception through June 2025, with supplementary screening via Google Scholar. Eligible studies included randomized controlled trials and observational cohort studies evaluating malignancy outcomes in adult IBD patients receiving anti-tumor necrosis factor (TNF) agents, anti-integrin therapies, anti-interleukin (IL)-12/23 and IL-23 inhibitors, Janus kinase (JAK) inhibitors, or sphingosine-1-phosphate (S1P) receptor modulators. Studies evaluating thiopurines alone or in combination with biologic therapy were included when malignancy risk was specifically assessed. The Newcastle-Ottawa Scale was used for quality assessment of observational studies and the Cochrane risk-of-bias tool for randomized trials. A formal quantitative meta-analysis was not performed due to heterogeneity in study designs, populations, comparators, outcome definitions, and follow-up durations. Twenty-eight studies met the inclusion criteria. Thiopurines showed the most consistent malignancy association, including lymphoma (pooled SIR 4.92; 95% CI, 3.10–7.78), NMSC, acute myeloid leukemia/myelodysplastic syndrome, and urinary tract cancers. Anti-TNF monotherapy showed no significant increase in overall cancer incidence but carried a modest lymphoma risk (aHR 2.41; 95% CI, 1.60–3.64). Combination anti-TNF plus thiopurine therapy was associated with the highest lymphoma risk (aHR 6.11; 95% CI, 3.46–10.8). Vedolizumab and ustekinumab showed no increased malignancy risk, including in patients with prior cancer. JAK inhibitor data from rheumatoid arthritis (ORAL Surveillance: HR 1.48; 95% CI, 1.04–2.09 for tofacitinib vs. TNF inhibitors) have not been replicated in IBD-specific studies through 9.2 years of follow-up. S1P receptor modulators showed low malignancy rates (0.4 per 100 patient years over 10 years for ozanimod). Malignancy risk with IBD therapies is heterogeneous and drug class dependent. Thiopurines and combination therapy carry the highest risk. Gut-selective agents (vedolizumab, ustekinumab) have the most favorable safety profiles and are preferred in patients with prior malignancy. JAK inhibitor and S1P modulator data in IBD are reassuring but require continued long-term surveillance.

Abstract: Background/Objectives: Endoscopic electroporation — including electrochemotherapy, calcium electroporation, irreversible electroporation and pulsed-field ablation — is an intended non-thermal, configuration-dependent platform increasingly applied to selected colorectal neoplasms. Early experience suggests roles in palliative haemostasis, luminal symptom control and local disease management, but the field is heterogeneous and methodologically immature, and uncontrolled diffusion is a real risk. Methods: We performed a narrative review of the mechanistic, preclinical and clinical literature on electroporation-based therapies relevant to colorectal neoplasia, with emphasis on endoscopic delivery, and synthesised the governance and reporting requirements for responsible adoption. Results: Mechanistically, reversible electroporation underpins electrochemotherapy and calcium electroporation, while irreversible electroporation and pulsed-field ablation produce drug-free, predominantly non-thermal cell death; these modes are not interchangeable. Across published colorectal cohorts the most consistent signal is for palliative haemostatic and symptom-control use; salvage, local-control and complex-polyp applications are less mature, and organ-preservation, immune-priming and neoadjuvant uses remain investigational. A recurring weakness is that effect depends on a configuration of patient, lesion and procedural parameters that current reporting frequently omits, so that “treatment delivered” is an inadequate unit of analysis. To address this, we propose SENTAL (Special Endoscopic Non-Thermal Ablation Therapy) as a service model: a two-axis classification (clinical intent first, timing/role modifier second), a six-domain minimum dataset with structured CTCAE and Clavien–Dindo safety grading that distinguishes “none” from “not recorded”, denominator-disciplined outcome reporting, and a four-layer governance cycle. Conclusions: Endoscopic electroporation should be adopted as a controlled clinical-learning process rather than diffused on the basis of favourable anecdotes. A configuration-dependent bioelectric therapy requires a configuration-aware clinical service, disciplined vocabulary and registry-linked governance to generate evidence adequate for health-technology appraisal.

Abstract: The gastrointestinal and respiratory tracts are closely connected through a bidirectional network known as the gut–lung axis, in which microbiota serve as key mediators of inter-organ communication. This axis involves both the extensively studied gut microbiota and the low-biomass lung microbiota, once considered to be sterile. Through regulation of in-nate and adaptive immune responses and production of bioactive metabolites, microbiota contribute to local and systemic immune homeostasis. Disruption of microbial composi-tion or function, known as dysbiosis, may contribute to disease initiation and progression. However, the mechanisms underlying gut-to-lung and, particularly, lung-to-gut commu-nication remain incompletely defined. This review summarizes existing evidence on the composition and physiological roles of gut and lung microbiota, including their effects on epithelial barrier integrity, immune maturation, pathogen resistance, and microbi-al-derived metabolite production. It further discusses how gut microbiota, their derived metabolites, and immune-cell regulation support pulmonary defense and modulate air-way inflammation. Conversely, it examines how pulmonary conditions may disrupt in-testinal barrier function, alter gut microbial communities, and promote intestinal inflam-mation. Overall, this review highlights the importance of bidirectional microbial and im-munological crosstalk in maintaining local and systemic health and influencing disease susceptibility across both organ systems.

Abstract:

Purpose: This study aimed to investigate the association between the C-reactive protein (CRP)/high-density lipoprotein cholesterol (HDL-C) ratio and the occurrence of advanced colorectal adenoma (ACA). Methods: A retrospective case analysis was conducted; enrolling 712 patients with colorectal adenoma (CRA) who underwent colonoscopy. The patients were divided into an ACA group and a non-ACA group based on the definition of ACA. Clinical data were compared between the two groups; and we needed to calculate the CRP/HDL-C ratio. We performed multivariate logistic regression analysis to identify risk factors for ACA; and evaluated the predictive efficacy of the CRP/HDL-C ratio using the receiver operating characteristic (ROC) curve. Results: Finally; 712 subjects were included; with 401 cases in the non-ACA group and 311 cases in the ACA group. The CRP/HDL-C ratio level in the ACA group was significantly higher than that in the non-ACA group (2.91±1.38 vs. 1.93±0.82; p<0.001). After grouping according to the quartiles of the CRP/HDL-C ratio; the prevalence of ACA showed a clear increasing trend with rising quartiles (Q1: 14.6%; Q2: 33.7%; Q3: 59.5%; Q4: 70.2%, p<0.001). Multivariate logistic regression analysis showed that after adjusting for covariates; the risks of ACA in Q2; Q3; and Q4 were significantly higher compared with Q1; with values of (OR=3.089; 95% CI: 1.474–6.473; P=0.003); (OR=7.204; 95% CI: 3.487–14.882; P<0.001); and (OR=13.773; 95% CI: 6.476–29.289; P<0.001); respectively. Multivariate logistic regression also indicated that the CRP/HDL-C ratio (OR=3.375; 95% CI: 2.512–4.535; P<0.001) was an independent risk factor for the prevalence of ACA. The area under the ROC curve (AUC) of the CRP/HDL-C ratio for predicting ACA was 0.799 (95% CI: 0.756–0.841). Conclusion: The CRP/HDL-C ratio is significantly positively correlated with the risk of developing advanced colorectal adenoma (ACA); exhibits good clinical predictive value; and can serve as a potential biomarker for the early screening of ACA.

Abstract: Background and Aims; Metabolic dysfunction–associated steatotic liver disease (MASLD) is closely linked to systemic cardiometabolic dysfunction. Resting heart rate (RHR), a marker of autonomic and metabolic stress, has been associated with metabolic syndrome and cardiovascular disease, though its relationship with MASLD remains incompletely characterized. We evaluated the association between RHR and liver-related outcomes in a nationally representative U.S. cohort. Materials and Methods; We analyzed adults aged 20–79 years from NHANES 2017–2020 with valid vibration-controlled transient elastography (VCTE) measurements. Participants with significant alcohol use, viral hepatitis, pregnancy, beta-blocker use, or missing key data were excluded. Liver outcomes included elevated alanine aminotransferase (ALT), advanced steatosis (CAP ≥290 dB/m), FIB-4 fibrosis category, and VCTE-defined fibrosis. Multivariable regression models adjusted for demographic and metabolic covariates were used to evaluate associations between RHR and liver-related outcomes. Results; A total of 3,567 adults were included. Each 1 beat-per-minute increase in RHR was independently associated with elevated ALT (OR 1.025, 95% CI 1.002–1.050, p=0.026) and advanced steatosis (OR 1.036, 95% CI 1.001–1.073, p=0.033). No significant association was observed between RHR and higher FIB-4 category (OR 1.025, 95% CI 0.992–1.060, p=0.150) or VCTE-defined fibrosis (OR 0.990, 95% CI 0.961–1.021, p=0.511). Associations with ALT and steatosis were attenuated after adjustment for glycemic and lipid parameters. Conclusions; Higher RHR was associated with steatosis-related and metabolic liver outcomes, but not fibrosis, in a nationally representative cohort. These findings suggest that RHR may reflect underlying autonomic and metabolic dysfunction relevant to early MASLD pathogenesis rather than advanced fibrotic disease.

Abstract: Background/Objectives: Ulcerative colitis (UC) has a higher risk of developing colorectal polyps and colorectal cancer (CRC) than non-UC individuals. The aim of the study was to explore the risk factors for coexisted colorectal polyps in patients with UC, especially for coexisted colorectal adenoma. Methods: Patients diagnosed with UC who were admitted to our hospital between January 1, 2015, and December 31, 2022 were enrolled in the study. Patients’ data including demographic data, smoking history, alcohol consumption history, disease related parameters, were retrospectively collected through the Electronic Medical Record System. Results: A total of 549 patients with UC were enrolled, among whom, 261 patients were with colorectal polyps. Within the polyp group, 54 patients had adenomatous polyps. Seven patients were diagnosed with CRC. Multivariate logistic regression revealed age ≤ 40 years, disease duration &gt;10 years, severe disease activity, and non-biologic treatment were risk factors for colorectal polyps in patients with UC; while age &gt; 40 years, disease duration &gt; 10 years, a chronic relapsing disease course, and larger polyps size were risk factors for adenomatous polyps in UC patients; and age &gt; 40 years, disease duration &gt; 10 years, and the presence of polyps were risk factors for CRC in patients with UC. Conclusions: UC patients with a junior age, long disease duration, severe disease activity, and non-biologic treatment are likely to have colorectal polyps. While patients with a senior age, long disease duration, a chronic relapsing disease course, and larger polyp size should be screened for adenomatous polyps, and with senior age, long disease duration, and the presence of polyps should be screened for CRC.

Abstract: We propose a new clinical entity termed recovery-phase viral pancreatitis (RVP), characterized by acute pancreatitis arising during the recovery phase of viral infection. RVP frequently develops after apparent symptom improvement or hospital discharge. Although acute pancreatitis associated with viral infections, particularly coronavirus disease 2019 (COVID-19), has been increasingly recognized, most previous studies have focused on pancreatic injury occurring during the acute infectious phase. However, accumulating reports have described pancreatic inflammation and acute pancreatitis arising during apparent clinical recovery and even after hospital discharge. These manifestations are difficult to explain solely by direct viral cytopathic injury during acute infection and instead suggest the presence of a distinct recovery-associated inflammatory process. We performed a focused narrative literature review to identify cases of acute pancreatitis arising during the recovery phase of viral infections. Representative cases demonstrated a reproducible temporal pattern in which pancreatitis developed approximately 1–3 weeks after the onset of viral illness, frequently during convalescence or after hospital discharge. Similar acute pancreatitis during recovery-phase patterns were observed not only in SARS-CoV-2 infection but also in dengue virus, Epstein–Barr virus, and hepatitis A virus infections. Potential mechanisms may involve transient immune suppression during acute viral infection, permitting pancreatic viral infection and antigen persistence. Recovery-associated immune responses may subsequently trigger pancreatic inflammation and acute pancreatitis during the recovery phase or after hospital discharge. Although RVP shares certain conceptual similarities with immune reconstitution inflammatory syndrome (IRIS), it differs in that it appears to arise during the natural course of viral infection without external immune manipulation or profound baseline immunodeficiency. We therefore propose that RVP should be distinguished from classical IRIS.Because RVP may arise even after apparent recovery or hospital discharge, its association with preceding viral infection may be overlooked, leading to potential misclassification as conventional acute pancreatitis. Recognition of RVP may improve clinical awareness of post-viral pancreatic complications.

Abstract: Chronic liver disease (CLD) constitutes a major global health burden, with high morbidity and mortality, limited treatment options for several etiologies, and an urgent need for novel therapeutic targets. Fibroblast growth factor 1 (FGF1) is a unique member of the FGF family capable of binding all four FGFR subtypes, thereby regulating multiple signaling pathways including PI3K/AKT, Ras/MAPK, and PLCγ, which are involved in metabolism, cell survival, proliferation, and tissue repair. Emerging evidence highlights the multifaceted and context-dependent roles of FGF1 in CLD. In drug-induced liver injury (DILI) caused by anti-tuberculosis drugs, acetaminophen, or doxorubicin, FGF1 exerts protective effects by restoring bile acid homeostasis, reducing oxidative stress, inflammation, and apoptosis. In metabolic-associated fatty liver disease (MAFLD), FGF1 ameliorates hepatic steatosis, oxidative injury, and insulin resistance through downregulation of SREBP1, upregulation of PPARα, and activation of Nrf2-mediated antioxidant responses. Conversely, in primary sclerosing cholangitis (PSC), FGF1 aggravates ductular reaction, biliary senescence, and liver fibrosis via upregulation of SASP and TGF-β1, suggesting that inhibition of the FGF1/FGFR axis may be therapeutic. For alcohol-related liver disease (ALD), although direct experimental evidence is lacking, FGF1 is hypothesized to confer protection given its known activities against oxidative stress, lipid dysregulation, and cell death. Despite its promise, the mitogenic potential of FGF1 raises safety concerns; however, N-terminally modified FGF1 analogs (e.g., FGF1Δ) retain metabolic benefits with reduced proliferative activity. Collectively, FGF1 represents a versatile and disease-dependent regulator in CLD, warranting further mechanistic studies, safety evaluations, and development of targeted analogs as a novel therapeutic strategy for difficult-to-treat liver diseases.

Abstract: Background/Objectives: Celiac disease is an immune-mediated enteropathy with heterogeneous gastrointestinal and extraintestinal manifestations. Psychiatric symptoms, arthralgia, thyroid comorbidity, anemia, and abnormal liver tests can obscure recognition in primary care. Methods: We report a de-identified reflective case from routine family medicine practice, structured in accordance with CARE case-report principles. Results: A woman in her early sixties with hypothyroidism and glaucoma presented with new low mood, anhedonia, somnolence, generalized anxiety, increased alcohol intake, poor appetite, weight loss, abdominal bloating, diarrhea, flatulence, and polyarthralgia. Investigations showed mild anemia, markedly elevated ferritin and liver enzymes, uncontrolled hypothyroidism, and strongly positive tissue transglutaminase IgA (>250 kIU/L; reference 0.0-14.9). Radiographs showed mild osteoarthritis and osteopenia without erosive arthropathy. CT abdomen/pelvis excluded malignancy but showed severe diffuse hepatic steatosis and mild pancreatic atrophy. The patient declined gastroenterology referral and confirmatory endoscopy with duodenal biopsy. A working diagnosis of probable celiac disease was made; she commenced a gluten-free diet, received alcohol-cessation advice, had levothyroxine adjusted, and was followed in the community. Most symptoms improved within six months. Conclusions: Celiac serology should be considered in adults with anxiety or depressive symptoms accompanied by gastrointestinal symptoms, weight loss, arthralgia, autoimmune thyroid disease, or unexplained liver-test abnormalities. The case also highlights diagnostic uncertainty, and follow-up needs when biopsy is declined.

Abstract: Background: Hepatocellular carcinoma (HCC) is one of the most common and deadliest cancers worldwide. Alpha-fetoprotein (AFP), a widely used and accessible tumoral marker, has limited performance in the early detection of HCC among high-risk populations. This study aims to evaluate the potential added value of ccfDNA (circulating cell-free DNA), alone or in combination with AFP, using accessible, feasible ccfDNA analysis. Methods: A prospective cohort of 125 patients with chronic liver disease was analyzed. Patients with incomplete clinical or laboratory data and patients without cirrhosis were excluded from the final analysis. Nonparametric tests, logistic regression and ROC curve analysis were performed. ccfDNA concentration was assessed by fluorimetry and fragment size was measured using on-chip electrophoresis. Results: ccfDNA fragment size was significantly lower in the cirrhosis-HCC subgroup compared to the cirrhosis-only subgroup (p< 0.001). While AFP remains an independent predictor of HCC among cirrhosis patients, ccfDNA fragment size did not prove to be an independent predictor in this cohort. However, AUROC (Area Under the Receiver Operating Characteristic Curve) analysis revealed that a combined model of AFP and ccfDNA fragment size showed modest additional discriminatory value between the two groups, compared to either ccfDNA peak size or AFP alone. Conclusions: ccfDNA fragment size may provide modest complementary value within multimarker panels. However, the marker needs further validation in a larger cohort, and adequate assessment of potential confounders such as severity of liver dysfunction and age.

Abstract: The Warburg effect is a metabolic phenomenon observed in cancer cells and is characterized by aerobic glycolysis instead of mitochondrial oxidative phosphorylation as the primary mechanism of cellular energy generation. The exact benefit of such a metabolic switch is poorly understood, as aerobic glycolysis is thermodynamically more inefficient than mitochondrial oxidative phosphorylation. Here, we present a case of a 40-year-old male with advanced stage 4 hepatocellular carcinoma with chronically low glucose levels measured in the 20s to 40s and completely asymptomatic. Upon examination, findings of sympathetic hyperactivity in the setting of hypoglycemia were absent, and mentation was completely intact. This occurred in the absence of any states or medications known to induce hypoglycemia; concurrently, the patient demonstrated hyperphagia, suggesting increased metabolic demand in the setting of an immense, overwhelming tumor burden. During these hypoglycemic intervals, the patient's coagulation profile, including PT and international normalized ratio, remained within normal limits, suggesting sufficient residual hepatic parenchyma and glucogenic capacity. The patient's glucose remained extremely low, refractory to correction with multiple dextrose, D5, and D10 administrations. This suggests chronic systemic habituation to malignant cell consumption of serum glucose leading to adaptations to this hypoglycemia in highly metabolically active organs, such as the brain, heart, liver, and kidneys. This report highlights the clinical utility of recognizing this metabolic state in the setting of advanced-stage malignancy with significant tumor burden and how it affects hospital glucose management. Its early recognition will lead to improvements in meeting the patient's metabolic demands while avoiding paradoxical exacerbation of lactic acidosis when providing guideline-directed oncological treatment. This metabolic state may function as a surrogate marker, in conjunction with serum markers and imaging studies, for clinical identification of advanced stage malignancies and for treatment escalation.