Fecal incontinence (FI) affects up to 8% of adults and substantially impairs quality of life. Surgical options carry higher risk and cost, and evidence for minimally invasive alternatives, such as anal inserts, is limited. To determine whether a novel anal insert achieves a clinically meaningful reduction in FI severity compared with usual care. This multicenter, open-label, randomized clinical superiority trial was conducted from May 26, 2021, to August 1, 2024, with 8 weeks of treatment and 4 weeks of follow-up at 2 outpatient hospital clinics in the Netherlands. Participants were individuals aged 16 to 90 years with FI (Rome IV criteria) with at least 1 FI episode during a 14-day run-in period. Data were analyzed from August 2 to December 20, 2024. A single-use anal insert compared with usual care alone. The primary outcome was proportion of participants achieving a reduction of at least 3 points in the St Mark's incontinence score from baseline to 8 weeks. Secondary outcomes included FI-specific quality of life, anxiety, depression, adverse events, and weekly FI episodes (post hoc outcome). A total of 73 participants were screened and 72 were randomized (60 [83.3%] female; mean [SD] age, 67.3 [9.8] years]), with 35 participants receiving the insert and 37 receiving usual care. There was no significant difference in reduction in St Mark's score (9 participants [25.7%] in the insert group vs 7 participants [18.9%] in the control group; relative risk, 1.36 [95% CI, 0.57 to 3.25]). Coping (mean between-group difference, 0.19 [95% CI, 0.03 to 0.35]) and depression (mean between-group difference, 0.15 [95% CI, 0.01 to 0.30]) domains of the quality-of-life assessment improved more with the insert group, whereas lifestyle and embarrassment domains of the quality-of-life assessment, anxiety, and overall depression showed no between-group differences. The insert reduced FI episodes (estimated mean difference, -3.09 [95% CI, -4.39 to -1.75] episodes per week) and increased the proportion achieving more than 50% reduction in FI episodes. No serious adverse events occurred; device-related adverse events were common but mild. In this randomized clinical trial, the primary outcome of achieving a reduction of at least 3 points in St Mark's incontinence score was not met; however, the anal insert improved selected FI-specific quality-of-life domains. These findings suggest that the device may provide a minimally invasive option for selected patients. ClinicalTrials.gov Identifier: NCT04657588.
Metabolic dysfunction-associated steatotic liver disease (MASLD) affects approximately 32% of the US adult population. The present study aimed to utilize the All of Us electronic health record-linked large cohort to assess seven metabolic risk factors (MRFs) simultaneously, the impact by ethnicity and age, and clinical presentations of MASLD. This study included a MASLD group (n = 15,060) and a frequency-matched control group (n = 75,300). Multivariable analyses were performed to compare the frequencies of MRFs and clinical outcomes between the two groups. Type 1 diabetes was not included in the multivariable analysis. Subgroup analyses were conducted according to race and ethnicity, as well as age. The overall frequency of MASLD was 6.0%. Compared with the control group, individuals with MASLD had significantly higher independent frequencies of obesity (66.1% vs. 41.3%), type 2 diabetes (39.5% vs. 16.9%), hypertension (64.3% vs. 38.6%), hyperlipidemia (59.8% vs. 37.3%), obstructive sleep apnea (28.9% vs. 13.4%), and hypothyroidism (21.2% vs. 13.4%). Obesity was identified as the strongest independent MRF among Asians, Whites, and Hispanics, particularly in individuals younger than 50 years, whereas hypertension was the strongest independent MRF in Blacks. MASLD was also associated with significantly higher frequencies of cardiac events, including coronary artery disease (17.1% vs. 9.4%) and myocardial infarction (7.1% vs. 4.2%); hepatic events, including cirrhosis (7.5% vs. 1.1%) and hepatocellular carcinoma (0.5% vs. 0.1%); and elevated liver enzymes, including alanine aminotransferase (27.7% vs. 10.1%), aspartate aminotransferase (18.0% vs. 6.4%), and alkaline phosphatase (19.8% vs. 13.1%), compared with the control group. Our study demonstrated that obesity, hypertension, hyperlipidemia, type 2 diabetes, obstructive sleep apnea, and hypothyroidism were independent MRFs for MASLD overall, but the ranking of these MRFs by odds ratios could vary by ethnicity and age. MASLD presents with significantly higher rates of alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase elevation, as well as cardiac and hepatic events.
Background and Objectives: In recent years, frailty has emerged as a prognostic factor in inflammatory bowel diseases (IBD), particularly among patients with active disease. However, evidence regarding its reversibility after treatment optimization remains limited. This study aimed to assess frailty in active IBD and determine whether frailty status improved after 6 months of clinical management and the achievement of clinical remission. Materials and Methods: This prospective, single-center, observational cohort study included adults with active IBD requiring escalation to advanced therapy who achieved clinical remission at the 6-month follow-up. Patients were evaluated at baseline and after 6 months using a modified Fried frailty phenotype. Quality of life was assessed using the Short Inflammatory Bowel Disease Questionnaire (SIBDQ), and depressive symptoms were assessed using the Center for Epidemiologic Studies Depression (CES-D) scale. Univariate and multivariate logistic regressions were utilized to identify independent factors associated with frailty improvement. Results: The analysis included 54 patients (61.1% male; 42.6% with Crohn's disease). At baseline, 20.4% were classified as frail, 72.2% as pre-frail, and 7.4% as robust. Following 6 months of clinical management and the achievement of clinical remission, a 100% resolution of frailty was observed, with the robust cohort expanding to 42.6%. Significant improvements occurred across clinical parameters, including handgrip strength, 400 m walk times, and median SIBDQ scores (increasing from 4.4 to 5.9, p < 0.001) alongside a substantial decline in CES-D scores (p = 0.017). Multivariate logistic regression revealed that severe disease at baseline (aOR = 4.51, 95%CI: 1.26-16.18, p = 0.020), anti-TNF therapy initiation (aOR = 3.69, 95%CI: 1.04-13.18, p = 0.044), and higher baseline CES-D scores (aOR = 1.06, 95%CI: 1.00-1.13, p = 0.038) were independently associated with higher odds of frailty improvement. Conclusions: Among patients who achieved clinical remission, frailty and pre-frailty demonstrate substantial short-term improvement following advanced therapy. Functional and psychological recoveries are associated with successful control of baseline disease severity and systemic inflammation.
Information on childhood cancer burden is crucial for effective cancer policy planning. Unfortunately, observed paediatric cancer data are not available in every country, and previous global burden estimates have not discretely reported several common cancers of childhood. We aimed to inform efforts to address childhood cancer burden globally by analysing results from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, which now include nine additional cancer causes compared with previous GBD analyses. GBD 2023 data sources for cancer estimation included population-based cancer registries, vital registration systems, and verbal autopsies. For childhood cancers (defined as those occurring at ages 0-19 years), mortality was estimated using cancer-specific ensemble models and incidence was estimated using mortality estimates and modelled mortality-to-incidence ratios (MIRs). Years of life lost (YLLs) were estimated by multiplying age-specific cancer deaths by the standard life expectancy at the age of death. Prevalence was estimated using survival estimates modelled from MIRs and multiplied by sequelae-specific disability weights to estimate years lived with disability (YLDs). Disability-adjusted life-years (DALYs) were estimated as the sum of YLLs and YLDs. Estimates are presented globally and by geographical and resource groupings, and all estimates are presented with 95% uncertainty intervals (UIs). Globally, in 2023, there were an estimated 377 000 incident childhood cancer cases (95% UI 288 000-489 000), 144 000 deaths (131 000-162 000), and 11·7 million (10·7-13·2) DALYs due to childhood cancer. Deaths due to childhood cancer decreased by 27·0% (15·5-36·1) globally, from 197 000 (173 000-218 000) in 1990, but increased in the WHO African region by 55·6% (25·5-92·4), from 31 500 (24 900-38 500) to 49 000 (42 600-58 200) between 1990 and 2023. In 2023, age-standardised YLLs due to childhood cancer were inversely correlated with country-level Socio-demographic Index. Childhood cancer was the eighth-leading cause of childhood deaths and the ninth-leading cause of DALYs among all cancers in 2023. The percentage of DALYs due to uncategorised childhood cancers was reduced from 26·5% (26·5-26·5) in GBD 2017 to 10·5% (8·1-13·1) with the addition of the nine new cancer causes. Target cancers for the WHO Global Initiative for Childhood Cancer (GICC) comprised 47·3% (42·2-52·0) of global childhood cancer deaths in 2023. Global childhood cancer burden remains a substantial contributor to global childhood disease and cancer burden and is disproportionately weighted towards resource-limited settings. The estimation of additional cancer types relevant in childhood provides a step towards alignment with WHO GICC targets. Efforts to decrease global childhood cancer burden should focus on addressing the inequities in burden worldwide and support comprehensive improvements along the childhood cancer diagnosis and care continuum. St Jude Children's Research Hospital, Gates Foundation, and St Baldrick's Foundation.
The long-term clinical outcomes of patients with hepatitis B virus (HBV)-related cirrhosis receiving nucleos(t)ide analog (NA) therapy according to virological response patterns remain inadequately defined. This study aimed to investigate the association between virological response patterns and clinical outcomes in a large, long-term, real-world cohort. This retrospective-prospective cohort study enrolled patients with HBV-related cirrhosis receiving NA therapy from 2009 to 2019. According to the serum HBV DNA levels during the initial two years of antiviral treatment, patients were categorized as having a complete (CVR) or partial virological response (PVR). Patients with CVR were further stratified according to their dynamic HBV DNA changes during follow-up into maintained virological response (MVR) or virological breakthrough (VBT) patterns. The primary clinical outcomes included hepatocellular carcinoma (HCC), acute-on-chronic liver failure, and liver-related death. Secondary endpoints included recompensation and progression to decompensation. Cox proportional hazards regression was used to assess the association between virological response patterns and clinical endpoints. In total, 1,869 patients were enrolled. During a median follow-up of seven years, the MVR, VBT, and PVR rates were 65.4%, 26.5%, and 8.1%, respectively. The cumulative serum hepatitis B surface antigen (HBsAg) clearance rate was 9.8%. Moreover, 34.9% of patients with HBsAg < 100 IU/mL at baseline experienced HBsAg clearance. Compared with patients with VBT and PVR, those with MVR had a lower five- and ten-year cumulative incidence of HCC in both the compensated (five-year: 10.1% vs. 17.0%; ten-year: 14.2% vs. 33.6%; P < 0.001) and decompensated cirrhosis subgroups (five-year: 19.5% vs. 36.7%; ten-year: 25.7% vs. 49.7%; P < 0.001). Similarly, patients with MVR also had a lower cumulative incidence of liver-related death. Additionally, a higher hepatic recompensation rate was observed in patients with MVR than in those with VBT (34.1% vs. 22.5%, P < 0.001). Importantly, patients achieving HBsAg clearance and undetectable serum HBV DNA levels ("functional cure" during ongoing NA therapy) had the lowest five- and ten-year cumulative incidence of HCC (3.9% and 8.7%, respectively). Patients with long-term MVR exhibited a lower incidence of HCC and liver-related death in both compensated and decompensated HBV-related cirrhosis subgroups, especially those achieving "functional cure." However, more than 30% of patients experienced PVR or VBT during long-term NA antiviral therapy. These findings highlight the importance of long-term, rigorous monitoring after initial CVR to optimize outcomes and support clinical decision-making.
Metabolic dysfunction-associated steatotic liver disease (MASLD) and chronic kidney disease (CKD) have shown a significant increase in comorbidity on a global scale due to the prevalence of metabolic syndrome. In 2023, a number of academic societies formally proposed the concept of MASLD, superseding the previous terminology of "non-alcoholic fatty liver disease" and "metabolic dysfunction-associated fatty liver disease". The diagnostic criteria have been revised to place greater emphasis on the association between hepatic steatosis and cardiometabolic risk factors. MASLD constitutes an independent risk factor for CKD, with this risk potentially increasing in line with the severity of fatty degeneration and the progression of hepatic fibrosis. CKD may represent a potential risk factor for the progression of fibrosis in patients with MASLD. The interaction between the two conditions may accelerate the occurrence of cardiovascular events and increase the risk of all-cause mortality. MASLD and CKD may share core pathophysiological mechanisms, including genetic variants, insulin resistance, lipid metabolism disorders, chronic inflammation, oxidative stress, and gut microbiota dysbiosis. However, the bidirectional causal relationship between the two conditions and the molecular dialogue between organs remains unclear. Furthermore, there are significant gaps in clinical prediction tools and targeted treatment strategies for comorbidities. This paper reviews common pathophysiological mechanisms in MASLD and CKD, the epidemiological and clinical evidence linking MASLD to the risk of CKD, biomarkers and clinical prediction models for coexisting conditions, and potential therapeutic strategies. Our aim is to provide a theoretical basis for early identification, mechanism exploration, and clinical treatment of comorbidities.
Dubin-Johnson syndrome (DJS) and Rotor syndrome (RS) are rare, autosomal recessive disorders that result in chronic, predominantly conjugated hyperbilirubinemia without cholestasis or hepatocellular injury. Although both conditions are benign and non-progressive, they reflect distinct molecular defects in hepatocellular transport pathways. DJS arises from mutations in the ABCC2 gene encoding the canalicular transporter multidrug resistance-associated protein 2, leading to impaired biliary excretion of conjugated bilirubin and organic anions. In contrast, RS results from combined deficiencies of the sinusoidal transporters OATP1B1 and OATP1B3, encoded by SLCO1B1 and SLCO1B3 genes, respectively, which mediate hepatic reuptake of conjugated bilirubin from the sinusoidal blood. These defects explain the characteristic biochemical and clinical distinctions between the syndromes, including the black hepatic pigmentation and markedly elevated urinary coproporphyrin I fraction in DJS, and the absence of pigmentation with moderate coproporphyrin I predominance in RS. Recent studies have expanded the understanding of how these transporters influence not only bilirubin handling but also the hepatic disposition of various drugs and endogenous metabolites. Recognition of DJS and RS is essential to prevent misdiagnosis of cholestatic or hepatocellular disease, avoid unnecessary investigations, and anticipate altered pharmacokinetics in affected individuals. This review synthesizes current evidence from molecular, biochemical, and clinical studies to highlight how these syndromes illuminate broader principles of hepatic transporter physiology and its relevance to inherited and acquired disorders of bilirubin metabolism.
Individuals with cirrhosis frequently require Emergency Department (ED) care, with some experiencing repeated ED use, yet little is known about the patient and caregiver perspectives driving decisions to visit the ED. We aimed to explore perspectives of including high ED utilizers with cirrhosis and their caregivers to identify drivers of ED use and opportunities to optimize care. Using human-centered design methods, we conducted an in-person group engagement session with 7 adults with cirrhosis and their caregivers, recruited from recent ED encounters. A custom board-game activity facilitated the discussion. Data were analyzed using snippet extraction, affinity mapping, and affinity concept modeling. Seven major themes emerged: (1) Mindset around symptoms, which includes fear, uncertainty, and caregiver burden. (2) Informational needs, including reliance on variable-quality online resources and lack of trusted education. (3) Day-to-day cirrhosis management, particularly challenges related to medications and symptom monitoring. (4) Symptom-driven ED triggers, with some prompting, urgent visits. (5) Decision-making factors, including limited alternatives to ED care and prior experiences, and mismatched patient-caregiver thresholds for seeking care. (6) Expectations of ED care, focused on pain relief and return to baseline health. (7) Challenges during ED care, including long wait times, misdiagnosis concerns, and stigma related to pain treatment. Concept modeling revealed that ED decision-making is a dynamic journey shaped by symptom severity, emotional states, logistical considerations, and evolving patient-caregiver-provider roles. Pain, uncertainty about symptom severity, and lack of accessible real-time clinical support were major drivers of ED utilization in cirrhosis. Interventions addressing these specific needs may reduce avoidable ED use. These findings provide a patient-informed foundation for care delivery redesign in cirrhosis.
Gastrointestinal symptom-specific anxiety (GSA) is increasingly recognized as an important construct in the disease experience of inflammatory bowel diseases (IBD). However, it remains unclear to what extent GSA overlaps with general anxiety in the IBD population, and whether it is associated with disability beyond general anxiety and other clinical and demographic variables. First, we examined how many patients with elevated GSA do or do not experience general anxiety, and vice versa. Second, we assessed the unique contribution of GSA to variance in IBD-related disability, keeping general anxiety, disease activity, and other variables constant. In a cross-sectional survey study, over 1000 IBD patients completed questionnaires on general anxiety (the anxiety subscale of the Hospital Anxiety and Depression Scale [HADS]), GSA (the Visceral Sensitivity Index [VSI]), IBD-related disability (the IBD Disk), and self-reported clinical disease activity (Patient-Reported Outcomes [PRO] and Manitoba IBD Index [MIBDI]) alongside a set of general demographic and clinical questions. GSA and general anxiety frequently co-occurred, but 38.0% of patients reported GSA without general anxiety. Additionally, GSA was significantly associated with IBD-related disability (P < .001) even when general anxiety, disease activity, and other variables were controlled for. Although general anxiety showed the strongest association with disability (β = .27), the association for GSA (β = 0.22) was stronger than for clinical disease activity (β = .18) and other demographic and clinical variables. Overall, this highlights the clinical significance of GSA beyond general anxiety and disease activity in IBD.
Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a predominant cause of chronic liver disease, underscoring the demand for accessible, non-invasive diagnostic tools. Tongue diagnosis in Traditional Chinese Medicine provides a distinctive perspective on systemic health, though it remains largely subjective. This study aimed to develop an interpretable multimodal deep learning model for MAFLD screening by integrating quantitative tongue image features with routine clinical data. From 904 screened candidates, 477 subjects (157 healthy, 320 MAFLD) were included and randomly allocated to training, validation, and test sets in an 8:1:1 ratio. All participants underwent standardized tongue imaging (International Commission on Illumination L*a*b color features) and comprehensive clinical evaluation. We constructed a dual-stream deep learning model, combining a ConvNeXt-Tiny network for tongue images and a multilayer perceptron for clinical variables. Feature fusion was achieved via a Dynamic Affine Feature Transformation module, and the model was trained using weighted cross-entropy loss. MAFLD patients showed significant metabolic abnormalities compared to healthy controls. A progressive decrease in tongue yellowness (b* value) was observed with advancing fibrosis. On an independent test set (n = 48), the multimodal model achieved 97.92% accuracy, Quadratic Weighted Kappa of 0.9538, and 96.88% sensitivity, and 100% specificity, outperforming single-modality and serological models. Interpretability analyses confirmed the model's focus on clinically relevant tongue regions and key metabolic drivers. We developed an accurate and interpretable multimodal model that synergizes tongue image features with metabolic indicators for MAFLD screening. This approach presents a promising, low-cost tool potentially well-suited for resource-limited settings.
Metabolic dysfunction-associated steatotic liver disease (MASLD) is increasing rapidly, yet regional differences in burden and care quality remain unclear. This study aimed to compare regional incidence, mortality, and disability; evaluate care quality; identify key determinants; and project future incidence. We analyzed the Global Burden of Disease 2023 estimates of MASLD incidence, deaths, and disability-adjusted life years from 1990 to 2023 by age, sex, country, and region. Age-standardized rates were assessed using joinpoint regression. A composite Quality of Care Index (QCI) was derived through principal component analysis. Gradient boosting models with SHapley Additive exPlanations interpretation identified key predictors, and Bayesian age-period-cohort models generated incidence projections. In 2023, South and East Asia had the largest numbers of new cases, while North Africa and the Middle East and Andean Latin America recorded the highest age-standardized incidence, mortality, and disability rates. Eastern Europe and Andean Latin America showed sustained increases in mortality and disability despite moderate incidence growth. QCI values were lowest in South Asia, Western Sub-Saharan Africa, and Eastern Europe. High body mass index and fasting plasma glucose were prominent contributors in comparative risk attribution analyses, and machine learning models identified age and calendar year as the strongest predictors of modeled burden patterns. Incidence is projected to continue increasing through 2050, particularly in India and China. MASLD burden and care quality vary widely across regions. Low-QCI regions show higher mortality and disability, unfavorable metabolic risk profiles, and delayed detection patterns. Strengthening prevention, early case finding, fibrosis assessment, and treatment access may slow MASLD progression.
Hepatic encephalopathy (HE) is a neurologic complication of advanced liver disease (e.g., cirrhosis) resulting in impaired functioning and reduced quality of life. This condition is associated with a substantial burden for patients and their caregivers and carries a poor prognosis and increased risk of hospitalization and mortality. This narrative review discusses the burden of HE, precipitating risk factors, and clinical considerations for reducing the risk of overt HE (OHE) recurrence in adults with cirrhosis. Key precipitating factors include certain medications, constipation, dehydration, uncontrolled diabetes mellitus, electrolyte imbalances, gastrointestinal bleeding, infection, and sarcopenia, among others. Identification and treatment of precipitating factors are critical steps in the management of HE. Components of ongoing care include patient and caregiver education, nutritional supplementation and sleep management, pharmacotherapy, and nonpharmacologic interventions (e.g., spontaneous portosystemic shunt embolization and liver transplantation in appropriate patients). Clinical guidelines recommend lactulose therapy as secondary prophylaxis after an initial episode of OHE. Rifaximin is recommended as add-on therapy to lactulose when an additional OHE episode occurs. Polyethylene glycol has been investigated as an alternative to lactulose in patients with acute HE and in those with chronic HE and a poor response to lactulose. Oral L-ornithine-L-aspartate may reduce the risk of OHE recurrence in patients with cirrhosis. Investigational agents include nitazoxanide, fecal microbiota transplantation, and the use of artificial intelligence, app-based technology, and wearable devices to facilitate acute and prophylactic management of HE.
We assessed whether baseline endoscopic and clinical scores of diverticular disease (DD) may predict the severity of acute diverticulitis (AD), hospital admission and length of hospital stay (HS). We conducted a 3-year, multicentre, prospective cohort study involving 2215 patients. DD was scored according to the Diverticular Inflammation and Complication Assessment (DICA) classification and the Combined Overview on Diverticular Assessment (CODA) score. Higher baseline DICA and CODA scores were associated with increased risk of complicated AD [relative risk ratio (RRR) = 5.57; 95% confidence interval (CI): 3.42-9.09 and RRR = 5.17; 95% CI: 3.01-8.88, respectively]. An average HS of 4.62 days (95% CI: 2.93-6.27) for DICA 1, 5.57 days (95% CI: 4.29-6.85) for DICA 2 and 6.73 days (95% CI: 5.81-7.64) for DICA 3 was recorded; an average HS of 4.14 days (95% CI: 2.32-5.96) for CODA A, 5.12 days (95% CI: 3.67-6.56) for CODA B and 6.32 days (95% CI: 5.35-7.30) for CODA C was recorded. DICA and CODA scores may predict the severity of AD and the length of the HS.
With guidelines recommending earlier advanced therapy (AT) use after 5-ASA failure for patients with moderately-to-severely active ulcerative colitis (UC), it is important to explore treatment preferences at the point of escalation to first-line AT. A web-based discrete choice experiment (DCE) survey was administered to AT-naïve patients with moderately-to-severely active UC and gastroenterologists in 5 European countries. Treatment attributes included time until symptom improvement, probability of remission and corticosteroid-free remission, risks of cancer, serious infection, and major adverse cardiovascular events (MACE), and mode of administration. Preference weights, relative attribute importance (RAI), and maximum acceptable risk were estimated. A latent class analysis explored preference heterogeneity. Probability of remission at 1 year was the most important attribute for patients (N = 514; RAI = 45.3%) and gastroenterologists (N = 397; RAI = 48.5%). Five-year cancer risk was the second most important attribute for patients (RAI = 11.8%) and third for gastroenterologists (RAI = 10.9%). RAI of MACE was higher for patients than gastroenterologists (10.6% vs. 6.8%). Both were willing to accept risks for increased probability of remission. Latent class analysis identified 4 groups of patients and 2 groups of gastroenterologists with distinct preferences. The relative importance of efficacy was higher compared with safety in latent classes representing 80% of patients. Clinical remission was most important to patients and gastroenterologists, and both were willing to accept some risk in exchange for the benefits of AT. However, some heterogeneity in preferences was observed. To support patient-centered, guideline-concordant care, gastroenterologists should discuss escalation to AT with patients not well-controlled on conventional therapy, incorporating individual preferences through shared decision-making.
Antimitochondrial antibody (AMA)-negative primary biliary cholangitis (PBC) is a rare presentation of PBC that comprises 5%-10% of all PBC patients. The pathogenesis of AMA-negative PBC appears to be similar to that of AMA-positive PBC. AMA-negative PBC presents similarly to AMA-positive PBC, with symptoms of cholestasis, fatigue, and pruritus most commonly reported. Defective bicarbonate production, resulting in acidification of bile and bile acids, has been proposed as the primary mechanism of damage to bile ducts and hepatocytes and is reflected in elevations of alkaline phosphatase and aminotransferases. Chronic damage can lead to the development of cirrhosis. The diagnosis is made by the finding of AMA negativity by ELISA or assays of similar sensitivity and a positive PBC-specific antinuclear antibody (ANA; anti-glycoprotein 210 and anti-speckled 100 kDa protein) test. In cases in which anti-glycoprotein 210 and anti-speckled 100 kDa protein assays are also negative, a liver biopsy is required to make the diagnosis after exclusion of other causes of cholestasis by magnetic resonance cholangiopancreatography or endoscopic retrograde cholangiopancreatography. Treatment for AMA-negative PBC is the same as for AMA-positive cases, with ursodeoxycholic acid as the first-line treatment. Current treatment is most effective in early stages, where it slows but does not eliminate progression. Risk stratification by validated tools such as the GLOBE and UK-PBC scores remains useful in AMA-negative PBC.
Insulin resistance is a common extrahepatic manifestation of hepatitis C virus (HCV) infection (HCVi), but its mechanism is poorly understood. While systemic insulin resistance is documented, portal insulin dynamics, a key regulator of hepatic metabolism, remain unexplored. This study aimed to investigate the relationship between insulin, the gut-liver axis, and immunometabolic changes in patients with HCV. HCV patients were evaluated before (HCVi; n = 29) and after sustained virologic response (SVR) achieved with sofosbuvir/velpatasvir treatment (SVR, n = 23) (NCT02400216). Liver biopsies, portal blood, and peripheral blood were collected at both phases. Statistical analyses were conducted using Wilcoxon rank-sum tests, Mann-Whitney tests, and Pearson's correlation coefficients to assess differences and associations across insulin, glucose, cytokines, metabolites, immune cells, and hepatic liver transcriptomics to elucidate impaired insulin homeostasis in HCVi. HCV patients had significantly reduced portal insulin compared to SVR (p = 0.02), while peripheral insulin, portal glucose, and peripheral glucose remained unchanged. Portal insulin correlated positively with proinflammatory cytokines and vascular injury markers and negatively with CD8/CD62L/CD45RA/CD3 cells (naive cytotoxic T-cells) and non-standard nucleotides. Hepatic transcriptomic analysis revealed portal insulin correlated positively with immune and negatively with amino acid pathways, reflecting insulin's role in the perturbations of immunometabolism during HCVi. Lower portal insulin during HCVi is associated with changes consistent with altered pancreatic insulin secretion and decreased hepatic insulin extraction. The observed correlations support a potential relationship between the immune response and insulin dynamics, indicating an interplay between the immune system, metabolism, and insulin in HCVi, with clinical implications for the management of dysglycemia.
Fatigue affects 60%-80% of patients with cirrhosis, yet no universally effective pharmacologic therapy exists. Taurine, an amino sulfonic acid with antioxidant and membrane-stabilizing properties, may address metabolic mechanisms underlying fatigue. We hypothesized that L-taurine supplementation would significantly reduce fatigue severity compared to standard care in patients with decompensated cirrhosis. This single-center, parallel-arm, open-label randomized controlled trial enrolled adults with decompensated cirrhosis (Child-Turcotte-Pugh score 7-13) and clinically significant fatigue (Fatigue Assessment Scale score >22) at a tertiary care center in South India. Participants were randomized via block randomization to L-taurine (1000 mg/d) plus standard care or standard care alone for 12 weeks. The primary outcome was the change in the Fatigue Assessment Scale score. Analysis of covariance examined treatment-by-anaemia interactions. Effect sizes were calculated using Cohen's d. Of 220 randomized patients, 202 completed the study (standard care: n=100; taurine: n=102). The mean FAS change was -6.83±8.70 (standard care) versus -8.08±7.95 (taurine), with no significant difference (mean difference -1.25; 95% CI: -3.55 to 1.05; p=0.288; Cohen's d=-0.15). However, a significant treatment-by-anemia interaction was observed (p=0.009). In patients without anemia (n=41), taurine produced a large treatment effect (-11.90±4.04 vs. -4.57±9.23; p=0.002; Cohen's d=-1.02), whereas patients with anemia (n=161) showed no benefit (p=0.832). Adverse events occurred in 11.8% of patients treated with taurine, all of which were mild. L-taurine did not improve fatigue in unselected patients with decompensated cirrhosis. A post hoc subgroup analysis suggested potential benefit in patients without anemia; however, given the open-label design, small subgroup size, post hoc nature of the analysis, and the inherent limitations of unblinded patient-reported outcomes, this finding should be considered hypothesis-generating. A confirmatory, placebo-controlled trial enrolling patients without anemia is warranted (Clinical Trials Registry India number CTRI/2023/06/054455).
Radiomics holds promise for extracting quantitative biomarkers from CT images of hepatocellular carcinoma (HCC), but its clinical translation is hampered by poor reproducibility caused by variations in image acquisition, manual segmentation and feature extraction. This multicenter study assessed the reproducibility of both segmentation and radiomic features in patients with early, intermediate and advanced HCC. Forty-five patients (15 per centre; 5 per tumor stage) from three institutions underwent contrast-enhanced CT. Three radiologists independently delineated lesion and perilesion regions on arterial (HAP) and portal venous phases (PVP) using 3D‑Slicer. Segmentation quality was assessed with the Jaccard index; masks with < 25% concordance were manually revised. Using the SlicerRadiomics module, 851 features per phase were extracted, and reproducibility was measured via the generalized concordance correlation coefficient (GCCC) before and after revision. Median Jaccard values were 0,40, 0,56and 0,74, between center 1 and 2, between center 1 and center 3, and between center 2 and 3, respectively. Twenty-seven segmentations underwent manual revision based on Jaccard index. After manual revision Lesion features (mean GCCC 0,65) were more reproducible than perilesional ones (0,52), and PVP produced slightly higher concordance than HAP. Before revision, mean GCCC ranged from 0.45 to 0.68 (median 0.48-0.77); early-stage lesions had the highest reproducibility and advanced-stage the lowest. After revision, lesion mean GCCC improved to 0.71 (HAP) and 0.67 (PVP), with larger gains in intermediate-stage tumours, while perilesional concordance improved modestly. Radiomic feature reproducibility depends on HCC stage and region. Early HCC lesions yield more reproducible features compared to advanced tumours. Manual revision enhances concordance, particularly for lesion regions, but defining peritumoral tissue remains challenging.
Selective inhibition of interleukin (IL)-23 through antagonism of the IL-23p19 subunit has demonstrated clinical efficacy in inflammatory bowel disease, but the molecular changes underlying the efficacy outcomes have not yet been described. Here, we provide a detailed evaluation of the cellular and molecular changes associated with guselkumab treatment in patients with moderately to severely active ulcerative colitis (UC) from the QUASAR Phase IIb induction study. In this double-blind, placebo-controlled, dose-ranging induction study, patients (n=313) were randomised (1:1:1) to receive intravenous guselkumab 200 or 400 mg or placebo at weeks 0, 4, and 8. Colon biopsy samples were collected at weeks 0 and 12, enabling molecular profiling by bulk RNA sequencing (RNA-seq, n=257), single-cell RNA sequencing (n=52), and flow cytometry (n=30). Serum proteomic profiling was also performed at weeks 0, 4, and 12 (n=302). Guselkumab treatment significantly reduced pro-inflammatory serum proteins by week 4 with continued decline through week 12, compared with placebo. Unsupervised analysis of tissue gene modules revealed significant changes in transcriptional states related to pro-inflammatory and epithelial repair pathways, which were most pronounced in patients who achieved histological-endoscopic mucosal improvement (HEMI) at week 12, an important tissue-based end point. Single-cell analyses supported a decrease in the cellular abundance of pro-inflammatory and an increase in mucosal cell types in tissue following treatment. This analysis of guselkumab in UC demonstrated changes in key pathways and cell types that are associated with achieving important clinical end points including HEMI at week 12. NCT04033445.
The Asia-Pacific region accounts for a larger share of the hepatitis B burden than any other regions of the world, presenting a challenge to meeting the World Health Organization (WHO) 2030 elimination targets. In this study, we aimed to quantify the burden of chronic hepatitis B (CHB) and project its trends through 2030 using the Global Burden of Disease 2023 framework, thereby identifying gaps and priorities for the Asia-Pacific region to achieve WHO 2030 targets. Using data from the Global Burden of Disease Study 2023, we analyzed CHB prevalence, mortality, and disability-adjusted life years. We evaluated temporal trends (1990-2023) using average annual percent changes and projected the 2024-2030 burden using Bayesian age-period-cohort models. In 2023, the Asia-Pacific region accounted for 63% of global CHB cases (178.0 million), 66% of deaths (259.1 thousand), and 65% of disability-adjusted life years (8.4 million). Regional prevalence and mortality rates exceeded global averages, although childhood (<5 years) prevalence was comparatively lower (590.3 vs. 1,325.3 per 100,000). East Asia bore the highest absolute burden (99.2 million cases), and South Asia had the largest pediatric caseload. Between 1990 and 2023, Western Asia showed the steepest decline in adult prevalence (-1.99%), whereas Southeast and Central Asia exhibited upward mortality trends. Projections indicate that the Asia-Pacific region is off track to meet the WHO 2030 disease elimination targets, as the prevalence rate in children under five years remains above the 0.1% target threshold and absolute mortality is projected to increase. The Asia-Pacific region continues to contribute the largest share of the global CHB burden and now faces persistent gaps despite progress. Although substantial progress has been made in reducing prevalence through immunization, the region is currently off track to meet the WHO 2030 targets for both incidence and mortality.