Search Results (984)

Background: Metastatic pancreatic adenocarcinoma carries a dismal prognosis, and treatment options after progression on standard chemotherapy remain limited. We report a metabolic response in a patient with drug-resistant disease treated with a combined multimodal regimen that paired dose-reduced (“activated”) multi-agent chemotherapy with targeted agents and metabolic/microenvironmental support, set against an unusually long overall survival. Case Presentation: A 46-year-old man was diagnosed with inoperable, locally advanced/stage IV pancreatic adenocarcinoma in June 2023 and maintained disease control for approximately 2.5 years on a combined multimodal regimen, termed here metabolically controlled oncologic therapy (MCOT): dose-reduced chemotherapy given with regional hyperthermia, hyperbaric oxygen, and a carbohydrate-restricted diet. In February 2026 he developed local recurrence and diffuse liver metastases, and by May 2026 had deteriorated rapidly, with ¹⁸F-FDG PET/CT showing a peak SUVmax of 18.2 and CA 19-9 of 2788 U/mL. His regimen was intensified to a low-dose, multi-agent “activated” chemotherapy protocol combined with lenvatinib, everolimus, hyperthermia, and hyperbaric oxygen. Clinical Findings and Outcomes: One month later, his performance status had recovered from ECOG PS 2 to PS 0, CA 19-9 was 31 U/mL, and follow-up PET/CT showed a 63.7% decrease in SUVmax (from 18.2 to 6.6). Treatment-related adverse events included Grade 1 nausea, Grade 1 vomiting, and thrombocytopenia; no Grade 2 or higher non-hematological toxicity was observed. Conclusions: In selected patients who are considered to have exhausted standard options, a combined multimodal regimen pairing dose-reduced chemotherapy with metabolic and microenvironmental support may produce a well-tolerated metabolic response. As a single, uncontrolled observation, these findings cannot establish causality and require confirmation in prospective, controlled studies. Full article

Monascus yellow pigments, including monascin, ankaflavin, and the derivative monascinol, are azaphilone secondary metabolites produced by Monascus species. They have attracted attention as candidate functional-food ingredients because experimental studies indicate activity in pathways relevant to lipid and glucose metabolism. Available evidence, however, is heterogeneous and is derived predominantly from in vitro and animal studies; the human evidence is limited to small, short-term studies of Monascus-fermented preparations rather than isolated pigments. Reported associations with PPAR-α/γ and AMPK signaling, and with gut–liver-axis outcomes, should therefore be interpreted as mechanistic or preclinical observations. Monascus yellow pigments may offer a promising safety profile relative to monacolin K-containing preparations, but their long-term efficacy, dose standardization, and safety require confirmation in adequately powered human trials. Monascus-fermented products are being investigated beyond their traditional use as colorants and sources of monacolin K, partly because monacolin K has statin-like safety concerns. This review summarizes the structural diversity, biosynthetic pathways, and reported pharmacological activities of monascin, ankaflavin, and monascinol. Preclinical studies suggest that these azaphilones may influence PPAR-α/γ-, AMPK-, oxidative-stress-, and inflammation-related pathways and may affect lipid and glucose metabolism. Evidence for gut-microbiota modulation by monascinol is currently derived mainly from animal and mechanistic studies. Human data remain limited, including a small, short-duration trial of a Monascus-fermented preparation enriched in monascin and ankaflavin; these findings support short-term investigation but do not establish long-term clinical efficacy or comparative safety. Accordingly, Monascus yellow pigments should be regarded as promising candidate functional ingredients whose composition, bioavailability, dose, long-term safety, and clinical applicability require further rigorous evaluation. Full article

Background: Short-term variation in the Fibrosis-4 index (FIB-4) may identify people who warrant further liver assessment. We evaluated longitudinal FIB-4 changes and associated metabolic factors in people with HIV (PWH) and metabolic dysfunction-associated steatotic liver disease (MASLD). Methods: This retrospective cohort included 683 PWH with ultrasound-defined MASLD who underwent routine clinical and laboratory assessments approximately every three months. A prespecified FIB-4 increase required both a ≥20% rise and crossing to ≥1.3 among participants with baseline FIB-4 < 1.3, or a ≥20% rise among those with baseline FIB-4 ≥ 1.3. Results: Of 683 enrolled participants, 655 were analyzed longitudinally. Over a median follow-up of 12.0 months, 59 (9.0%) met the FIB-4 increase definition, corresponding to 8.8 events per 100 person-years. Weight gain was associated with this outcome (adjusted hazard ratio 1.19 per 1% increase, 95% CI 1.14–1.24), whereas HIV- and antiretroviral therapy-related variables were not. Transition from non-obesity to obesity was associated with the outcome (odds ratio 8.45, 95% CI 3.57–20.02). Weight change also correlated with concurrent changes in total cholesterol, triglycerides, fasting glucose, and liver enzymes (all p < 0.01). Conclusions: Weight gain was associated with short-term FIB-4 increase and with concurrent metabolic change in PWH with MASLD. Full article

Background: Although advances in critical care have improved short-term outcomes, sepsis survivors continue to face substantial chronic morbidity and impaired long-term survival. Conventional threshold-based tools such as the Sequential Organ Failure Assessment (SOFA) and Modified Early Warning Score (MEWS) show moderate and variable discrimination across cohorts. Reported areas under the receiver operating characteristic curve (AUROCs) must therefore be interpreted in relation to the population, prediction horizon, and outcome used in each study rather than as direct head-to-head comparisons. Objectives: This review evaluates how artificial intelligence (AI) could be linked with dynamic plasma metabolites, particularly citrulline and β-hydroxybutyrate (3-HB), to support biologically informed sepsis phenotyping, while critically examining mechanistic evidence, clinical limitations, and translational readiness. Data Synthesis: Machine-learning and natural language processing architectures have shown promising discrimination in many early-detection studies, with pooled AUROCs near 0.87 and reported prediction windows extending to 48 h. However, performance estimates vary with cohort composition, outcome definition, and validation design, and they should not be ranked against unrelated biomarker studies. Human sepsis studies generally associate low or persistently low citrulline with impaired intestinal function and organ injury, but no sepsis-specific decision cutoff has been externally validated. For 3-HB, an AUROC of 0.8429 for septic liver injury was derived from a cohort of 57 patients and has not been shown to add value beyond routine liver tests or illness-severity measures. Murine experiments provide mechanistic hypotheses for ketone-mediated organ protection, but model-specific and sometimes opposing nutritional effects limit direct translation. These metabolites are therefore best considered candidate longitudinal features for multimodal phenotyping rather than stand-alone clinical triggers. Conclusions: Biologically informed algorithmic surveillance is a promising direction, but clinical implementation requires prospective serial sampling, explicit adjustment for renal, hepatic and nutritional confounders, head-to-head comparison with routine markers, and external validation of calibration and clinical utility. Until these requirements are met, citrulline and 3-HB should support research phenotyping rather than direct treatment selection. Full article

Per- and polyfluoroalkyl substances (PFAS) are environmental contaminants associated with higher serum lipids, although primarily in cross-sectional studies, limiting causal inference. We aim to determine whether there is a causal relationship between PFAS and serum lipid levels by emulating a target trial of a hypothetical PFAS-reduction intervention using observational data. The target trial would enroll adults aged ≥20 years without prior cardiovascular, kidney, or liver disease, diabetes, or use of related medications. Participants would be randomly assigned to either PFAS-reduction counseling or no counseling, with adherence evaluated after 10 years, and then followed up after 10 years to assess effects on serum lipids. To emulate the target trial, we will use data from the Copenhagen City Heart Study on three successive clinical visits: baseline, follow-up, and outcome assessment visit, 10 years apart. Eligible participants meet the target trial criteria, have available blood samples for PFAS quantification at follow-up, and information on serum lipids at the outcome assessment. Intervention strategies will be evaluated based on observed reductions in PFAS concentrations between baseline and follow-up visit. Serum lipids are assessed at the outcome assessment visit. The emulation assumes exchangeability by adjusting for baseline and time-varying confounders using G-computation. This protocol explores applying the target trial emulation framework to improve causal inference in environmental epidemiology. Full article

In the biosynthesis of heme the tetrapyrrole hydroxymethylbilane is converted enzymatically to uroporphyrinogen III whereas conversion to uroporphyrinogen I occurs spontaneously. Both are substrates for uroporphyrinogen decarboxylase (UROD) but only the III isomer is a precursor of heme. These porphyrinogens are easily oxidised to the respective uroporphyrins and trace amounts occur in the urine of healthy humans and animals. Large quantities of uroporphyrins I and III, as well as other oxidation products, occur in the liver and urine of patients with some porphyrias and after poisoning of people and animals by chemicals, such as hexachlorobenzene (HCB) and 2,3,7,8-tetrachorodibenzo-p-dioxin (TCDD). In the acquired disorder sporadic porphyria cutanea tarda (sPCT) and chemical-induced porphyria, hepatic UROD is inhibited, ostensibly by a partially oxidised uroporphyrinogen. The processes leading to oxidation of the uroporphyrinogens are interactions of a variety of external, internal and genetic factors. In some experimental systems, cytochrome P450 1A2 is implicated in the oxidation of uroporphyrinogens and uroporphyria and many patients and in vivo studies demonstrate the influence of iron. The article reviews the present state of knowledge of uroporphyrinogen oxidation, susceptibility and outcomes, and illustrates areas that require further exploration to explain fully the mechanisms of sPCT and the related uroporphyria caused by chemicals of toxic concern. Full article

Background/Objectives: In cirrhotic patients, guidelines generally recommend maintaining mean arterial pressure (MAP) ≥ 65 mmHg, but the prognostic impact of MAP in transplant candidates is unclear. This study aimed to evaluate the association between MAP and waitlist mortality and cirrhosis-related complications in patients listed for liver transplantation. Methods: We conducted a retrospective cohort study of 103 adults (age ≥ 18 years) with cirrhosis listed for liver transplantation (MELD 20–24) at a single center (2019–2023). Patients with hepatocellular carcinoma were excluded. The primary outcome was death on the transplant waitlist (n = 9 events). Logistic regression was used to assess the association of MAP (per 1 mmHg) with mortality. Continuous variables were compared using the t-test, and categorical variables were compared using the chi-square test; p < 0.05 was considered significant. Results: Mean MAP at listing was significantly higher in survivors than non-survivors (83.2 ± 9.4 vs. 76.9 ± 8.7 mmHg; p = 0.04). In logistic regression, higher MAP was associated with lower odds of waitlist death (unadjusted odds ratio [OR] per 1 mmHg increase = 0.94; 95% confidence interval [CI] 0.89–0.99; p = 0.041). Subgroup analysis showed a significant inverse association between MAP and hepatorenal syndrome (HRS) (OR per 1 mmHg = 0.94; 95% CI 0.89–0.98; p = 0.011), whereas MAP was not significantly associated with hepatic encephalopathy, ascites, or variceal bleeding (all p > 0.2). Conclusions: Among the cirrhotic patients listed for transplantation, lower MAP at baseline is associated with waitlist mortality and hepatorenal syndrome. These findings should be interpreted cautiously given the small number of events and require validation in larger cohorts. Full article

Background/Objectives: Gallbladder emptying is primarily regulated by postprandial cholecystokinin release. In proteinuric glomerular diseases, renal loss of peptide hormones, hormone-binding proteins, or related regulatory proteins may affect biliary motility. However, gallbladder function has not been adequately investigated in individuals with proteinuric glomerular disease. This study evaluated the association between proteinuria and gallbladder emptying in patients with preserved kidney function and biopsy-proven glomerular disease. Methods: This single-center ultrasonographic case–control study with prospective participant enrollment and data collection included 106 participants: 52 patients with biopsy-proven proteinuric glomerular disease and 54 healthy controls without proteinuria. The proteinuric patient group consisted of individuals diagnosed with primary glomerulonephritis or amyloid A (AA) amyloidosis. Acute kidney injury, estimated glomerular filtration rate <60 mL/min/1.73 m², cholelithiasis, liver disease, diabetes mellitus, previous upper gastrointestinal surgery, pregnancy, oral contraceptive use, and recent rapid weight loss were considered exclusion criteria. After an overnight fast of at least 8 h, fasting gallbladder volume was measured by ultrasonography and recorded as baseline volume (V0). Gallbladder volume was measured again 45 min after stimulation with a standardized 40 g chocolate meal and recorded as postprandial volume (V45). Gallbladder volume was calculated using the ellipsoid formula, and gallbladder ejection fraction (GBEF) was calculated as [(V0 − V45)/V0] × 100. GBEF <40% was used as a predefined clinical threshold for impaired gallbladder emptying. In the primary analysis, the association between proteinuria status and GBEF as a continuous outcome was evaluated using a multivariable linear regression model adjusted for age, sex, body mass index, and family history of gallstones. Impaired gallbladder emptying, operationally defined as GBEF <40% for the supportive secondary binary outcome, was examined using multivariable logistic regression model adjusted for the same covariates. Results: Compared with controls, proteinuric patients had significantly higher postprandial gallbladder volume at 45 min: 15,614.04 ± 9148.35 mm³ versus 10,346.89 ± 5254.17 mm³ (p = 0.0003). GBEF was significantly lower in the proteinuria group than in healthy controls: 41.76% ± 19.64 versus 53.10% ± 20.22; mean difference, −11.34 percentage points (95% confidence interval, −19.02 to −3.66; p = 0.0042). Impaired gallbladder emptying was more frequently observed in the proteinuria group: 48.1% versus 27.8% (p = 0.031). In unadjusted analysis, the presence of proteinuria was associated with a 2.41-fold increase in the odds of impaired gallbladder emptying. This association remained statistically significant after adjustment for age, sex, and body mass index: adjusted odds ratio, 2.95 (95% confidence interval, 1.17–7.47; p = 0.022). Among proteinuric patients, GBEF did not differ significantly according to nephrotic versus non-nephrotic proteinuria, serum albumin level, serum total protein level, or histopathological diagnostic subgroup. Conclusions: In individuals with preserved kidney function and biopsy-proven glomerular disease, proteinuria was associated with impaired postprandial gallbladder emptying, and this association persisted after multivariable adjustment. These findings suggest that gallbladder dysmotility may represent a potentially relevant functional feature of proteinuric kidney disease; however, its biological basis and clinical consequences remain to be established. Prospective studies incorporating cholecystokinin measurements, duration of proteinuria, and longitudinal clinical follow-up are needed to clarify these issues. Full article

Background/Objectives: Cardiac comorbidities are increasingly common among liver transplant candidates, particularly those with metabolic dysfunction-associated steatohepatitis (MASH)-related cirrhosis. Although the Liver Transplant Comorbidity Index identifies coronary artery disease (CAD) as a predictor of post-transplant mortality, the impact of overall cardiac comorbidity burden on early outcomes after liver transplantation remains unclear. We evaluated the association between pre-transplant cardiac comorbidities and early post-transplant outcomes, with emphasis on MASH-related cirrhosis. Methods: We performed a retrospective cohort study using the TriNetX US Collaborative Research Network. Adults undergoing first-time isolated liver transplantation through May 2026 were included. Pre-transplant CAD, heart failure (HF), and atrial fibrillation (AF) documented within 12 months before transplantation were identified using ICD-10-CM codes. Patients were categorized by cardiac comorbidity burden (0–3 conditions). Recipients with any cardiac comorbidity underwent 1:1 propensity score matching to those without cardiac disease using 16 baseline demographic, clinical, and laboratory variables, including MELD-Na. The estimand was the average treatment effect in the treated patients. Primary outcomes comprised 30- and 90-day all-cause mortality. Secondary outcomes included a prespecified restricted major adverse cardiac event (MACE) composite, limited to hard endpoints (death, myocardial infarction, cardiac arrest, ischemic stroke), and a broader composite, i.e., acute kidney injury, prolonged mechanical ventilation, vasopressor requirement, renal replacement therapy, ICU and hospital length of stay, and 90-day readmission. Results: Among 5124 recipients, 986 (19.2%) exhibited at least one cardiac comorbidity. After matching, 974 patients remained in each group. Pre-transplant cardiac comorbidity was associated with higher 30- and 90-day mortality and increased risks of all secondary outcomes. The association with MACE persisted but was attenuated when restricted to hard endpoints (90-day RR 1.55; 95% CI 1.19–2.03) when compared with the broad composite (RR 1.75; 95% CI 1.40–2.18). MASH recipients with cardiac comorbidities experienced numerically higher event rates than did non-MASH recipients, but interaction estimates were imprecise and non-significant. In separate matched analyses, AF was most strongly associated with MACE, whereas CAD showed the strongest association with mortality. Conclusions: Pre-transplant cardiac comorbidity burden is associated with worse early post-transplant outcomes. Although MASH-cirrhosis recipients experienced numerically higher event rates, exploratory subgroup analyses did not demonstrate statistically significant differences from the non-MASH recipients. These findings may help refine cardiac risk prediction and perioperative planning, but they do not establish that intensified cardiac risk stratification or perioperative optimization improve outcomes. Prospective studies incorporating detailed cardiac, donor, operative, frailty, and medication data are needed to validate these associations and determine whether targeted risk-stratification and perioperative strategies can improve post-transplant outcomes. Full article

Vitamin A plays an important role in multiple homeostatic functions such as vision, immunity, epithelial cell integrity and differentiation, cell signaling, pulmonary function, reproduction, growth, and development. Vitamin A deficiency was described in people with cystic fibrosis (pwCF) due to a multitude of causes, such as suboptimally managed exocrine pancreatic insufficiency, advanced cystic fibrosis-related liver disease (aCFLD), and a history of intestinal resection, and is generally rare in contemporary practice. Apart from true vitamin A deficiency, low vitamin A levels may also be noted in various inflammatory states, as vitamin A is a negative acute-phase reactant. In the current era of cystic fibrosis (CF) transmembrane-conductance regulator (CFTR)-directed therapies, there is a paradigm shift in vitamin A status, with deficiency statuses becoming rarer, and instead higher serum vitamin levels (in some cases, even in the hypervitaminosis range) are increasingly reported. People with aCFLD, renal insufficiency, post-lung transplantation, and pregnancy are prone to vitamin A toxicity. Hence, CF clinicians should be proactive in evaluating these abnormalities and proficient in managing both deficiency and toxicity, as both these conditions can be associated with adverse outcomes. In this review, we detailed the basics of vitamin A metabolism, manifestations of both vitamin A deficiency and excess, and their clinical implications in pwCF. Full article

Obesity is a heterogeneous chronic disease for which safe, scalable adjuncts to lifestyle and clinical care remain needed. Tea derived from Camellia sinensis contains catechins, caffeine, theaflavins, thearubigins, theabrownins, polysaccharides, and other constituents whose abundance is shaped by withering, fixation, partial oxidation, full oxidation, and post-fermentation. This review integrates processing-dependent composition with molecular mechanisms, gut–liver signaling, human evidence, safety, and real-world preparation. Evidence is strongest for modest effects of green-tea catechin–caffeine preparations on energy metabolism and selected anthropometric or lipid outcomes, whereas inhibition of adipogenesis, activation of AMP-activated protein kinase, browning of white adipose tissue, and many appetite-related pathways remain supported mainly by cell and rodent studies. A recent meta-analysis in women with overweight or obesity estimated mean reductions of −1.23 kg in body weight and −3.46 cm in waist circumference, with intervention durations across the included trials typically ranging from 4 to 24 weeks, though most of the evidence derives from short- to medium-term interventions (generally ≤12 weeks); heterogeneity was moderate to high and the average weight effect remained below conventional clinical thresholds. Partially oxidized oolong tea and fully oxidized or post-fermented teas provide distinct profiles of caffeine, oxidized polyphenols, and microbial metabolites; their metabolic effects are promising but are less consistently tested in adequately powered human trials. Across tea types, convergent mechanisms include reduced digestive-enzyme activity, increased fatty-acid oxidation, modulation of thermogenesis, reinforcement of the intestinal barrier, and microbiota-dependent production of short-chain fatty acids and bile-acid signals. Translation is constrained by low systemic polyphenol exposure (i.e., limited bioavailability of intact catechins and their metabolites in circulation due to poor intestinal absorption, extensive phase-II metabolism, and rapid clearance), non-standardized doses and products, short intervention periods, interindividual variability, and limited direct comparisons among tea types. Available clinical data do not support tea as a primary treatment for obesity; rather, unsweetened tea or standardized preparations may serve as adjuncts to evidence-based dietary, physical activity, behavioral, and medical management. Priority areas include physiologically relevant dosing, standardized reporting of brewed-tea composition, long-term trials, and microbiome-informed personalization. Full article

Background/Objectives: Interferon-free direct-acting antiviral (DAA) therapy cures chronic hepatitis C virus (HCV) infection, but its short-term effects on health-related quality of life (HRQoL) are captured differently by generic and disease-specific instruments. We examined longitudinal changes in utility scores and HRQoL in a multicenter Japanese cohort. Methods: Adults with chronic HCV completed the EuroQol 5-Dimension 5-Level questionnaire (EQ-5D-5L), the 8-Item Short-Form Health Survey (SF-8), and the Chronic Liver Disease Questionnaire (CLDQ) at baseline and at 12, 24, and 36 weeks after treatment initiation; 48-week data were included when available. Complete-case panels were analyzed for each instrument (SF-8, n = 112; CLDQ, n = 131; EQ-5D-5L, n = 128). Domain trajectories were summarized and compared with baseline. Results: By week 36, SF-8 general health improved significantly from 50.42 to 52.47, whereas vitality (50.73 to 52.55) and mental health (51.02 to 53.05) showed nonsignificant numerical increases. CLDQ showed improvements in worry (5.21 to 5.82) and total score (5.21 to 5.47). EQ-5D-5L utility values remained high and largely stable (0.913 to 0.920), suggesting ceiling effects in patients with relatively good baseline health status. External real-world evidence also suggested better on-treatment HRQoL with ribavirin-free regimens. Conclusions: In Japanese patients with HCV, interferon-free DAA therapy was associated with early improvements in symptom-proximal and mental domains of HRQoL. Generic utility scores changed little over the short term, indicating that disease-specific patient-reported outcome (PRO) instruments and utility measures should be used together for patient-centered assessment and cost–utility modeling. Full article

Background: Chronic liver disease (CLD) represents a substantial global health challenge, with significant morbidity and mortality worldwide. Biological aging may be involved in CLD-related outcomes, but the associations of diverse DNA methylation (DNAm) aging algorithms with CLD phenotypes and long-term mortality remain incompletely characterized. Methods: Using a US nationally representative cohort, we analyzed 12 DNAm aging algorithms in 2522 adults aged ≥50. CLD was classified into viral, alcohol-related, metabolic syndrome (MetS)-related liver disease, or uncharacterized groups. Advanced fibrosis was defined by AST-to-platelet ratio index ≥0.7. Associations of algorithms with CLD and all-cause mortality (followed through 2019) were assessed using multivariable-adjusted regression and logistic regression models and Cox models, accounting for complex sampling. Results: Among participants with CLD, DNAm aging algorithms showed only nominal associations with APRI-defined advanced fibrosis. GrimAgeMortAcc, GrimAge2MortAcc, HannumAgeAcc, PhenoAgeAcc, DunedinPoAm, and HorvathTelo were significantly associated with all-cause mortality. GrimAge-based measures and PhenoAgeAcc showed the strongest associations with all-cause mortality across CLD-related phenotypes (HRs ranged from 1.31 to 1.82). HorvathTelo was inversely associated with mortality risk (HR = 0.71, 95% CI: 0.62–0.82). Conclusions: DNAm aging algorithms, particularly GrimAge-based measures, are strongly associated with long-term all-cause mortality among individuals with CLD-related phenotypes. Although associations with fibrosis-related outcomes varied according to fibrosis definitions, DNAm aging algorithms may provide additional biological information for mortality risk stratification among individuals with CLD-related phenotypes. Full article

Chronic hepatitis B virus (HBV) and hepatitis C virus (HCV) infection remain leading causes of cirrhosis and hepatocellular carcinoma (HCC) worldwide, and continue to represent a major challenge despite the growing contribution of alcohol-related and metabolic dysfunction-associated steatotic liver disease. Direct-acting antivirals now cure most patients with chronic HCV infection, while nucleos(t)ide analogues durably suppress HBV replication, producing a rapidly expanding population of treated and cured patients. Many nonetheless retain residual fibrosis, portal hypertension and long-term cancer risk, creating a need for non-invasive long-term liver assessment. Multiparametric ultrasound (MPUS) integrates the evaluation of morphology, fibrosis, steatosis, haemodynamics and perfusion within a single examination. This narrative review summarises the evidence supporting MPUS in chronic viral hepatitis, covering elastographic fibrosis assessment, Baveno VII liver and spleen stiffness criteria for clinically significant portal hypertension, contrast-enhanced ultrasound characterisation of focal liver lesions, and emerging techniques such as microvascular and viscosity-sensitive imaging. Particular attention is given to the confounding effect of inflammatory activity on liver stiffness. MPUS is presented here as a proposed evaluation framework for organising complementary measurements within a single examination, and not as an approach of demonstrated clinical superiority: no comparative or outcome-based study has yet shown that acquiring these parameters together improves clinical decisions relative to the individual techniques applied according to current guidelines. Within this framework, the most plausible role of MPUS in the elimination era is longitudinal assessment of the treated liver, a proposition that requires prospective validation against clinical endpoints. Full article

Oleanolic acid is a naturally occurring pentacyclic triterpenoid with broad preclinical promise in inflammation, oxidative stress, liver injury, metabolic disorders, cancer-related models, skin disease, and wound repair. Its further development, however, is constrained by poor aqueous solubility, low and variable bioavailability, limited barrier transport, crystallinity, and strong dependence of biological response on the formulation used. These properties make oleanolic acid a useful example of a hydrophobic natural compound whose pharmacological performance is inseparable from delivery design. This review examines polymeric nanocarriers and polymer-assisted delivery platforms developed for oleanolic acid delivery. Polymeric nanocarriers discussed in the review include biodegradable PLA/PLGA nanoparticles, PEGylated polymeric nanoparticles, polymeric micelles, nanogels, hyaluronic-acid-based nanoprodrugs, and selected polymer-assisted hybrid nanostructures. Hydrogels, polymeric fiber membranes, local depots, and microneedle systems are included as route-enabling delivery platforms when the polymeric matrix directly contributes to OA incorporation, carrier stabilization, local retention, barrier bypass, or release control. Non-polymeric delivery systems are discussed only as comparators or when their performance depends on integration with a polymeric component. Rather than treating these carriers only as solubility enhancers, the review evaluates how polymer composition, carrier architecture, drug physical state, release behavior, and route of administration affect oleanolic acid exposure. Particular attention is given to controlled release, local retention, disease-oriented delivery, and critical quality attributes such as particle size, loading, encapsulation efficiency, solid-state form, stability, residual solvent, sterility, and batch-to-batch reproducibility. Representative quantitative data on carrier size, drug loading, encapsulation efficiency, release, stability, tissue exposure, and biological outcomes are compared to illustrate both formulation-specific performance and the substantial methodological heterogeneity of the available studies. The available evidence indicates that increased apparent solubility, increased biological exposure, and improved therapeutic response should be treated as related but distinct outcomes. The most realistic near-term opportunities may lie in local and tissue-targeted applications, including inflammatory skin disease, wound healing, dermal delivery, and osteoarthritis, where sustained target-site exposure may be more relevant than systemic bioavailability. Future progress will depend on demonstrating that each formulation provides reproducible, safe, and route-appropriate OA exposure, together with a measurable advantage over simpler delivery approaches. Full article