Tang NSY, Teng MLP, Selvakumar A
… +17 more, Ng CWH, Sasikumar NA, Lim MP, Ko D, Lee HT, Kow A, Danpanichkul P, Muthiah MD, Wijarnpreecha K, Choi WM, Fujii H, Ng CH, Syn N, Patidar KR, Tsochatzis EA, Siddiqui MS, Tan EX
BACKGROUND: Following therapeutic advancements, recompensation has gained increasing recognition in patients on waitlist for liver transplantation (LT). Identifying key predictors of waitlist removal because of improveme...BACKGROUND: Following therapeutic advancements, recompensation has gained increasing recognition in patients on waitlist for liver transplantation (LT). Identifying key predictors of waitlist removal because of improvement can enhance prognostication and resource allocation. We hence examined predictors of improvement-related waitlist removal using a machine learning-based approach with data from the United Network for Organ Sharing database. METHODS: In this retrospective cohort study, adult LT waitlist candidates from 2000 to 2025 in the United Network for Organ Sharing registry were included. A random survival forest model was applied to examine key predictors associated with improvement-related waitlist removal, while accounting for death and LT as competing risks. Variable importance (VIMP) measure and minimal depth were used to guide variable selection. Model performance was evaluated using the concordance index, Brier scores, and time-dependent area under the curve. RESULTS: The cohort included 127 978 individuals listed for LT. Eight thousand four hundred ninety-three (6.6%) were delisted because of clinical improvement. The random survival forest model demonstrated strong performance and discriminatory ability overall at 1, 5, and 15 y (concordance index was 0.777, 0.771, and 0.781; time-dependent area under the curve was 0.78, 0.78, and 0.80). Brier scores were reduced relative to the reference. Strong predictors of recovery highlighted in both VIMP and minimal depth-based assessments of VIMP included diagnosis, age, and serum albumin. CONCLUSIONS: Identified variables could inform the development of robust predictive models to guide individualized decision-making for LT. With further validation and integration into clinical workflows, such models could enhance prognostication of patient trajectory on the LT waitlist and facilitate appropriate resource allocation.
Lombardi P, Ramon-Gil E, Raja RQ
… +52 more, Brunetti L, Manfredi GF, Zhou Z, Merces G, Cappuyns S, Fulgenzi CAM, D'Alessio A, Torkpour A, Celsa C, Stefanini B, Yang H, Crowley F, Marron TU, Saeed A, Pinter M, Scheiner B, Huang YH, Lee PC, Nishida N, Po-Ting Lin R, Dalbeni A, Vivaldi C, Masi G, Rohlen N, von Felden J, Kaseb A, Galle PR, Kudo M, Hsu WF, Rimassa L, Parisi A, Kelley RK, Toyoda H, Pirisi M, Jabar F, Rakaee M, Cabibbo G, Cammà C, Piscaglia F, Hwang S, Shin DJ, Li M, Dekervel J, Guerra N, Meyer T, Reeves HL, Bengsch B, Daniele G, Mann DA, Chon HJ, Leslie J, Pinato DJ
BACKGROUND: Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation fol...BACKGROUND: Despite improved outcomes with atezolizumab plus bevacizumab (A+B) in hepatocellular carcinoma (HCC), primary refractoriness (PRef), characterised by early progression or short-lived disease stabilisation following treatment, remains a significant challenge. METHODS: We analysed 1296 patients with HCC treated with frontline A+B (AB-real) and validated findings in 645 trial participants recruited to IMbrave150 and GO30140. PRef was defined by Society for the Immunotherapy of Cancer (SITC) criteria. We performed a multi-parametric analysis of pre-treatment tumour tissue, including machine learning-based quantification of tumour-infiltrating lymphocytes, imaging mass cytometry (IMC) and RNA sequencing (RNAseq) to evaluate differences in the tumour microenvironment (TME) of PRef versus responding patients. Two independent cohorts were further used to refine the TME characterisation through single-cell RNA sequencing (n=20) and IMC (n=16). We employed conditional inference tree analyses to provide a hierarchical organisation of PRef determinants. RESULTS: Among 677 AB-real and 378 trial patients evaluable by SITC criteria, PRef identified inferior median OS in comparison with responding patients (AB-real: 7.3 vs. 31.5 months,p<0.001; Trials: 10.8 vs. NR, p<0.001). PRef patients exhibited higher baseline systemic inflammation (NLR≥3), a distinctively immunosuppressive TME enriched in CD163 tumour-associated macrophages, vascular cancer-associated fibroblasts, a higher T/T ratio, and pro-tumour supportive cellular interactions. RNAseq of tumour tissue confirmed lower intrinsic immunogenicity in PRef samples with elevated myeloid infiltration. Conditional inference tree analysis identified IFN-γ signature downregulation combined with NLR≥3 as the strongest contributor of PRef. CONCLUSIONS: PRef to A+B identifies a distinct biological entity characterised by unopposed systemic inflammation, myeloid infiltration and T-cell depletion. Targeting myeloid-mediated immunosuppression, particularly in patients with low IFN-γ signature expression and elevated NLR might enhance responsiveness to A+B. IMPACT AND IMPLICATIONS: Atezolizumab plus bevacizumab represents the standard first-line treatment for unresectable HCC, yet the biological basis of early treatment failure remains poorly understood. In this multi-cohort translational study, we show that approximately 40% of patients exhibit primary refractoriness according to SITC criteria - clinically validated here for the first time in HCC - and identify a distinct immunomolecular profile of primary refractory tumours characterised by IFN-γ pathway repression, unfavourable myeloid polarisation, and a distinct spatial immune architecture. These findings provide a biological framework that may inform the design of biomarker-stratified trials and rational combination strategies to overcome primary resistance to first-line immunotherapy.
JMIR Form Res
· 2026 Jun · PMID 42296541
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BACKGROUND: The mortality rate from liver disease among people with type 2 diabetes mellitus (T2DM) increased by 20% between 2001 and 2018. There are marked racial and ethnic differences among people with T2DM at risk of...BACKGROUND: The mortality rate from liver disease among people with type 2 diabetes mellitus (T2DM) increased by 20% between 2001 and 2018. There are marked racial and ethnic differences among people with T2DM at risk of metabolic dysfunction-associated steatotic liver disease (MASLD) and related complications. OBJECTIVE: We aimed to investigate the distribution of individual-level social determinants of health (SDOH) in people living with both T2DM and MASLD. METHODS: In this small cross-sectional study, patients (N=50) were recruited from a tertiary care general hepatology clinic to complete a survey that assessed potential determinants of health. We sought to oversample Black and Hispanic patients to better understand the prevalence of SDOH. Electronic health records were reviewed to determine stage of liver disease, and these data were linked to survey results to identify the distribution of individual-level determinants of health in patients with cirrhosis. RESULTS: Black and Hispanic respondents were more likely to report more experiences of racial discrimination, worries about being discriminated against, and group-based medical mistrust, especially regarding unsupportive health care providers. Cirrhosis groups tended to have lower incomes and less coverage from private health insurance. However, no substantial trends were observed in the distribution of health literacy, discrimination, and diabetes stigma among patients with and without cirrhosis. CONCLUSIONS: These findings will inform a future study aimed at assessing and developing interventions to address the combined impact of individual- and neighborhood-level SDOH on health-related outcomes in patients with T2DM and MASLD.
OBJECTIVES: SARS-CoV-2 infection causes an innate immune response that is activated through pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like recep...OBJECTIVES: SARS-CoV-2 infection causes an innate immune response that is activated through pattern-recognition receptors (PRRs), including Toll-like receptors (TLRs) and retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs). Endosomal TLR7/8 detects viral ssRNA, while TLR3 also recognizes dsRNA formed during viral replication. Both RIG-I and MDA5 recognize SARS-CoV-2 RNA in the cytoplasm of infected cells. PRR pathways recruit essential downstream adapter proteins to induce type I interferons (IFNs) and inflammatory cytokines. While genetic variations in host may influence SARS-CoV-2 infection, immune response, and COVID-19 severity, their specific role in triggering these processes remains unclear. This study analyzes the frequency of specific polymorphisms within genes in COVID-19 patients to evaluate their impact on disease severity. METHODS: We genotyped ten polymorphisms in 261 individuals, including 166 patients hospitalized for COVID-19, and evaluated their associations with clinical parameters and serum cytokine profiles. Single-nucleotide polymorphisms (SNPs) of (rs3775290 and rs3775291), (rs179008, rs3853839, and rs5741880), (rs3764879 and rs3764880), rs1990760, and rs73479410 were genotyped using qPCR allelic discrimination, while rs3775296 was analyzed by PCR-RFLP. Cytokine concentrations were quantified using MILLIPLEX Magnetic Bead Panels and Luminex xMAP technology. RESULTS: In this case-control study, the recessive G/G genotype of the rs3853839 SNP was associated with an increased risk of hospitalization. The presence of at least one recessive T allele for the rs179008 SNP was associated with lower cytokine levels (IP-10, IL-10, TNF-α) and a decreased risk of severe symptoms in hospitalized patients. CONCLUSIONS: Our findings suggest that the rs3853839 SNP may represent a genetic risk factor for severe COVID-19, whereas the missense rs179008 SNP (Q11L) may contribute to less severe symptoms among these patients.
OBJECTIVES: To characterise the clinical, microbiological and economic burden of hospital-admitted, injection-related infections among incarcerated people who inject drugs. STUDY TYPE: Retrospective observational cohort...OBJECTIVES: To characterise the clinical, microbiological and economic burden of hospital-admitted, injection-related infections among incarcerated people who inject drugs. STUDY TYPE: Retrospective observational cohort study. SETTING: Secure unit of the Princess Alexandra Hospital, Brisbane, Australia. PARTICIPANTS: Adults incarcerated in Queensland prisons who were admitted to hospital with an injection-related infection between 1 July 2019 and 30 June 2023. MAIN OUTCOME MEASURES: Types of injection-related infection, microbiological findings, requirement for surgical or radiological source control, hospital length of stay and inpatient healthcare costs. RESULTS: There were 321 hospital admissions for injection-related infection among 265 patients, accounting for 282 unique infections. Most patients were male (241; 90.9%), with a mean age of 33 years (standard deviation [SD], 7.4 years), and 76 (28.7%) identified as First Nations. The most frequent infections were soft tissue infections (77/282; 27.3%), acute hepatitis C (64/282; 22.7%) and cellulitis (43/282; 15.2%). Surgical or radiological source control was required in 95 infections (34.0%), and infectious diseases consultation occurred in 130 infections (46.1%). Among 39 true-positive blood cultures, Staphylococcus aureus was identified in 17 (43.6%), Burkholderia species in 10 (25.6%) and non-tuberculous Mycobacterium species in 3 (7.7%). Among the 218 non-acute hepatitis C infections, 50 (22.9%) were hepatitis C virus (HCV) RNA positive. Overall, HCV RNA was present in 114 of 282 infections (40.4%). The total inflation-adjusted inpatient cost was $8.39 million, with a median cost per infection of $11,602 (interquartile range, $7426-$34,544). CONCLUSION: Injection-related infections among incarcerated people who inject drugs were associated with substantial morbidity and healthcare costs in this large hospital cohort. A wide clinical spectrum was observed, including atypical pathogens, and clinically overt acute hepatitis C requiring hospital admission. These findings describe a significant burden of preventable disease in custodial settings and support the introduction of established primary prevention and harm-reduction interventions in prisons.
Hernández-Rosiles V, Carias-Domínguez A, Baules de Arrocha G
… +20 more, Garcés-Camacho JF, Fisberg M, Bages-Mesa MC, Higuera-Carillo M, Daza-Carreño W, Ho J, Alfaro-Hurtado M, Taquez-Castro CL, Silva-Weffort V, Peredo MS, Peña-Hernández S, Sanabria MC, Escobedo-Berumen L, Ladino L, Sanjuanelo-Camargo S, Pazmiño AM, Zambrano-Rivas A, Goday PS, Vázquez-Frias R, Feeding Difficulties Working Group of the Latin American Society of Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN)
INTRODUCTION AND AIMS: Feeding difficulties (FDs) in childhood are highly prevalent and a common reason for medical consultation. Historically, clinical approaches have been fragmented. The Pediatric Feeding Disorder (PF...INTRODUCTION AND AIMS: Feeding difficulties (FDs) in childhood are highly prevalent and a common reason for medical consultation. Historically, clinical approaches have been fragmented. The Pediatric Feeding Disorder (PFD) model provides a comprehensive framework that incorporates medical, nutritional, feeding skill, and psychosocial dimensions. Our aims were to (1) describe the current definitions of FDs in children, (2) identify their main risk factors and existing classifications, and (3) propose a clinical algorithm to guide the diagnostic and therapeutic approach from an interdisciplinary perspective. MATERIALS AND METHODS: A narrative review was carried out by the Feeding Difficulties Working Group of the Latin American Society of Pediatric Gastroenterology, Hepatology and Nutrition (LASPGHAN), reviewing the literature published between January 2000 and April 2025 from the PubMed, Scopus, SciELO, and LILACS databases. RESULTS: Three classification systems were identified: sensory-based, medical/nutritional, and functional. Risk factors included prematurity, gastrointestinal and neuromotor diseases, negative feeding experiences, inadequate feeding practices, and psychosocial factors. A comprehensive and interdisciplinary clinical algorithm was developed. CONCLUSIONS: Pediatric FDs require an interdisciplinary and family-centered approach, adapted to the Latin American context. Terminology standardization and clinical criteria harmonization are key steps for optimizing diagnosis, treatment, and research in the region. The development of a clinical algorithm outlining their approach is a first step toward this goal.
INTRODUCTION: Gastroparesis (GP) is a chronic gastrointestinal motility disorder that imposes a substantial clinical and economic burden. For patients with refractory GP, gastric peroral endoscopic myotomy (G-POEM) and b...INTRODUCTION: Gastroparesis (GP) is a chronic gastrointestinal motility disorder that imposes a substantial clinical and economic burden. For patients with refractory GP, gastric peroral endoscopic myotomy (G-POEM) and botulinum toxin injection (BTI) are emerging therapies with differing efficacy profiles and procedural costs. Given these differences, we evaluated the cost-effectiveness of G-POEM versus BTI for refractory GP. METHODS: We conducted a cost-effectiveness analysis using a decision tree model informed by randomized trial data from a US health care system perspective over 3- and 12-month time horizons. Procedural costs, adverse events, and repeat BTI sessions were incorporated. Quality-adjusted life-years (QALYs) were estimated from the Gastrointestinal Quality of Life Index (GIQLI) and from Short Form-12 (SF-12) scores. Cost-effectiveness was assessed using incremental cost-effectiveness ratios (ICERs) at a willingness-to-pay (WTP) threshold of $100,000/QALY. RESULTS: The base-case analysis was modeled on a 48.1-year-old patient with refractory GP-defined as persistent symptoms despite 6 months of medical therapy and a GP Cardinal Symptom Index score >2. At 3 months, G-POEM was associated with higher costs and marginally greater effectiveness than BTI (ICER $288,341/QALY), making BTI the cost-effective strategy in the short term. At 12 months, incorporating repeat BTI, G-POEM became the cost-effective option, with BTI yielding an ICER of $334,046/QALY relative to G-POEM. Sensitivity analyses identified clinical success rates and procedural costs as primary cost-effectiveness drivers. At 12 months, the cost-effectiveness acceptability curve showed G-POEM was cost-effective in most simulations at lower WTP thresholds, with BTI favored only at thresholds near $335,000/QALY. CONCLUSION: While BTI is more cost-effective in the short term, the cumulative costs of repeat sessions make G-POEM the more economically favorable strategy over 12 months. Improving clinical success rate by optimizing patient selection and refining procedural techniques could further improve cost-effectiveness profiles.
Fibrosis in Crohn's Disease (CD) occurs when there is continuous inflammation and repair mechanisms, which may lead to fibrotic strictures and ultimately intestinal surgical resection. There are limited non-invasive biom...Fibrosis in Crohn's Disease (CD) occurs when there is continuous inflammation and repair mechanisms, which may lead to fibrotic strictures and ultimately intestinal surgical resection. There are limited non-invasive biomarkers for monitoring CD activity, particularly for detecting fibrosis. Thus, we set out to identify biomarkers that could be monitored for the detection and treatment of fibrosis. We used multiplex protein arrays to examine cytokines and pro-fibrotic factors in the serum of CD patients and analyzed their reliability to predict fibrosis. These markers were confirmed in tissues and the role of cytokines in upregulating fibrotic factors was examined. Collagen 1A1, Fibronectin, MMP9, and Timp-1 in patient serum were identified as strong predictors of fibrosis. IL-1β, MCP-1 and TNFα were identified as major regulators of fibrosis factors in human tissues. Overall, we identified four serum markers that are strong indicators of fibrosis and provided some novel insight into the impact of cytokines on fibrotic factors. Taken together, these findings may lead to earlier detection of fibrosis, and improved monitoring and treatment for CD patients.
Koch V, Gockel I, Reingruber J
… +22 more, Kreuser N, Bigge J, Venerito M, Alakus H, May A, Gerges C, Thieme R, Heider D, Hillmer AM, Ebigbo A, Bruns CJ, Lang H, Messmann H, Rösch T, Wissniowski TT, Müller M, Denzer UW, Nöthen MM, Vieth M, Thrift AP, Maj C, Schumacher J
United European Gastroenterol J
· 2026 Jun · PMID 42272320
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BACKGROUND: Esophageal adenocarcinoma (EAC) represents one of the most increasing malignancies in Western countries. The disease is multifactorial, involving modifiable risk factors and genetic susceptibility variants. T...BACKGROUND: Esophageal adenocarcinoma (EAC) represents one of the most increasing malignancies in Western countries. The disease is multifactorial, involving modifiable risk factors and genetic susceptibility variants. These variants can be aggregated to a polygenic risk score (PRS) that reflects individual genetic risk. Investigation of the effects of lifestyle factors, PRS, and co-medication on EAC age at onset (AAO) is critical for shaping prevention strategies. METHODS: A detailed questionnaire was used to assess pre-diagnostic exposure to lifestyle factors and clinical information from a large German EAC cohort. Linear regression analysis was performed to identify factors associated with EAC AAO in 1742 EAC patients. PRS was available for 1190 patients. Subgroup analyses were conducted to estimate the effects of the analyzed factors on AAO according to age group (early vs. late onset), sex, and prior diagnosis of Barrett's esophagus (BE). RESULTS: Earlier AAO was significantly associated with gastroesophageal reflux (GER), smoking and a higher PRS, whereas later AAO was associated with physical activity and higher consumption of fish and fruits. Among co-medication, combined use of proton pump inhibitors (PPIs) and acetylsalicylic acid (ASA) showed the most significant effect on AAO, whereas the use of PPIs and ASA alone showed weaker effects. DISCUSSION: This study represents the largest questionnaire-based analysis to date investigating factors influencing EAC development. Our findings show that the combined use of PPIs and ASA, both cost-effective medications, is associated with delayed EAC onset. In addition, lifestyle and genetics contribute to EAC AAO.
Alcohol-related hepatitis (AH) is a complex disease associated with numerous unmet needs, particularly in diagnosis and treatment. The epidemiology of AH has evolved in recent years, reflecting changes in alcohol consump...Alcohol-related hepatitis (AH) is a complex disease associated with numerous unmet needs, particularly in diagnosis and treatment. The epidemiology of AH has evolved in recent years, reflecting changes in alcohol consumption during the COVID-19 pandemic and the increasing incidence of AH following bariatric surgery. Advances have also been made in the non-invasive diagnosis of AH, helping to reduce the need for liver biopsy, as well as in the management of infection. Several novel therapeutic strategies have been evaluated, including faecal microbiota transplantation, IL-1 receptor antagonists, oxysterols, and reduced exposure to corticosteroids or antibiotics. Although the results of these trials have been relatively disappointing, they have helped identify promising directions for future research. In patients with the most severe form of AH, particularly those who do not respond to corticosteroids, several studies have suggested that the indications for early liver transplantation could be expanded. Overall, developments over recent years have generated increased optimism regarding the management of patients with severe AH.