BACKGROUND: Throat and airway symptoms are common, but only a small proportion are reflux-related. The term "laryngopharyngeal reflux" has variable definitions in the literature and has been used to describe symptomatic...BACKGROUND: Throat and airway symptoms are common, but only a small proportion are reflux-related. The term "laryngopharyngeal reflux" has variable definitions in the literature and has been used to describe symptomatic patients with or without objective reflux, often leading to prolonged/unnecessary treatment trials. PURPOSE: The San Diego consensus introduced the term laryngopharyngeal symptoms (LPS) to describe upper aerodigestive symptoms with potential relationship to reflux physiology, including cough, regurgitation, throat pain, throat clearing, excess phlegm, and hoarseness/voice change. This review describes presentation, health care burden and risk stratification of throat and airway symptoms in light of the San Diego consensus definitions and clinical approach. Laryngopharyngeal reflux disease (LPRD) requires objective evidence of pathologic reflux in addition to LPS. Importantly, LPS alone do not predict LPRD. While various validated patient-reported outcome instruments are available, only some are LPS/LPRD-specific, and all lack specificity for making a diagnosis of LPRD. These instruments may have value in tracking symptoms over time and post-treatment. Concurrent typical reflux symptoms may prompt empiric anti-reflux medication trials as initial therapy. Risk stratification scores have been developed for the purpose of directing upfront therapy for high-risk patients and investigation for intermediate/low-risk patients, but their clinical use needs further validation. Objective diagnosis of LPRD provides confidence in escalation of reflux interventions. Life-threatening long-term sequelae are infrequent in LPS/LPRD, although impact on quality of life and healthcare burden can be profound.
Chronic hepatitis delta (CHD) is the most severe form of viral hepatitis and is associated with accelerated progression to cirrhosis and liver failure. Bulevirtide has shown promising results in trials, but real-world da...Chronic hepatitis delta (CHD) is the most severe form of viral hepatitis and is associated with accelerated progression to cirrhosis and liver failure. Bulevirtide has shown promising results in trials, but real-world data on its effectiveness, safety and impact on patient-reported outcomes (PROs) remain limited. To evaluate the effectiveness, safety, and PROs (quality-of life-QoL; adherence) of bulevirtide therapy in CHD patients undergoing a dedicated pharmacist-led patient-education program (PEP). A prospective observational study enrolled 31 consecutive CHD patients receiving bulevirtide 2 mg daily at a tertiary referral centre. Virological, biochemical and combined responses were assessed at weeks 24, 48 and 60. QoL (through EQ-5D-5L questionnaire), adherence (proportion of days covered), and adverse events were monitored during follow-up. Bulevirtide significantly reduced HDV-RNA by week 24 (p < 0.01), with further reductions at week 48 (p = 0.05) and 60 (p < 0.01). Liver tests improved significantly from baseline to week 24 (p < 0.01) and remained stable. Combined response was achieved in 43.7% of patients by week 60. QoL improved significantly (p = 0.03), and adherence was excellent (≥ 90%). Adverse events were mostly mild and transient. In real-world clinical practice, bulevirtide achieved sustained virological and biochemical improvements with favourable safety and quality-of-life outcomes, confirming its effectiveness in routine management of CHD. While the 60-week data (n = 16) are exploratory due to the sample size, these findings confirm its effectiveness and safety in routine management of CHD.
Tougeron D, Rivera F, Kanonnikoff TF
… +13 more, Le Malicot K, Guarssifi M, Fares N, Soularue E, Dos Santos M, Wagner M, Taieb J, Aparicio T, Laurent-Puig P, Hacker UT, Fernández Montes A, Al-Batran SE, Lordick F
BACKGROUND: Prognosis of metastatic oesogastric adenocarcinoma (mOGC) beyond second‑line therapy remains poor. Trifluridine/tipiracil monotherapy is recommended in later lines but provides limited survival benefits. Anti...BACKGROUND: Prognosis of metastatic oesogastric adenocarcinoma (mOGC) beyond second‑line therapy remains poor. Trifluridine/tipiracil monotherapy is recommended in later lines but provides limited survival benefits. Anti‑angiogenic drugs have demonstrated significant efficacy in mOGC. Fruquintinib is a selective VEGFR‑1, ‑2 and ‑3 inhibitor with demonstrated activity in refractory colorectal adenocarcinoma. This design paper reports the rationale and design of the academic ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS trial within the European network in gastro-intestinal oncology intergroup (ENGIC). METHODS: ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS is an international, multicentre, open‑label, randomized phase III trial comparing trifluridine/tipiracil plus fruquintinib versus trifluridine/tipiracil alone in patients with metastatic oesophageal, gastro-oesophageal junction or gastric adenocarcinoma previously treated with two or three treatment lines. Patients are randomized 1:1 and stratified by treatment line, time from metastatic diagnosis to randomization, WHO performance status and prior anti‑angiogenic exposure. The primary endpoint is overall survival. Secondary endpoints include progression‑free survival, time to progression, objective response rate, disease control rate, safety, quality of life and translational biomarker analyses. PERSPECTIVES: ENGIC 06 - PRODIGE 114 - FFCD 2401 - FRUQUITAS is designed to determine whether VEGFR inhibition with fruquintinib plus trifluridine/tipiracil can meaningfully improve survival outcomes in pre-treated mOGC. TRIAL REGISTRATION: EU CT number 2025‑522395‑92‑00.
Sunkesula V, Koo TH, Boppana SH
… +5 more, Kundrapu S, Waghray N, Husnain MG, Diwakar A, Shah B
Clin Res Hepatol Gastroenterol
· 2026 Jun · PMID 42107597
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BACKGROUND/OBJECTIVES: Hypoalbuminemia is common in severe acute pancreatitis (SAP) and is associated with poor outcomes. Early administration of human albumin has been proposed to improve outcomes by expanding the intra...BACKGROUND/OBJECTIVES: Hypoalbuminemia is common in severe acute pancreatitis (SAP) and is associated with poor outcomes. Early administration of human albumin has been proposed to improve outcomes by expanding the intravascular volume and correcting hypoalbuminemia. We performed a systematic review to evaluate whether early albumin infusion in patients with moderate SAP reduces the incidence of sepsis and improves clinical outcomes. METHODS: We searched the MEDLINE, EMBASE, and Cochrane CENTRAL databases from inception to January 15, 2026, for studies of albumin infusion in adult patients with moderate or SAP. Eligible studies included randomized controlled trials (RCTs) and cohort studies that compared early albumin infusion with no albumin or crystalloid-only therapy. The primary outcome was sepsis incidence. The secondary outcomes included in-hospital mortality, and A.P.-related complications. RESULTS: Six studies (one RCT and five retrospective cohorts studies) met the inclusion criteria. Albumin infusion protocols varied (5% albumin 30 g/day for 2-3 days in the RCT). Early albumin administration was associated with a significantly lower risk of sepsis in patients with SAP. However, their effects on mortality were inconsistent. One cohort study of patients with hypoalbuminemic SAP reported significantly lower in-hospital mortality with albumin therapy. However, the RCT showed no difference in the 60-day mortality between the albumin and control groups. None of the included studies reported a clear reduction in pancreatitis-specific complications attributable to albumin. CONCLUSIONS: Early albumin infusion in moderate to SAP was associated with a lower risk of sepsis across studies but yielded no clear improvement in overall mortality.
Kaul E, Thul J, Miller WC
… +6 more, Fate KR, Fisher J, Pruett TL, Nagel EM, Earthman CP, Teigen L
Clin Nutr ESPEN
· 2026 Aug · PMID 42107535
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BACKGROUND: Malnutrition is prevalent in liver transplant candidates and associated with poor outcomes. Computed tomography (CT)-derived skeletal muscle measures predict liver transplant outcomes, but their relationship...BACKGROUND: Malnutrition is prevalent in liver transplant candidates and associated with poor outcomes. Computed tomography (CT)-derived skeletal muscle measures predict liver transplant outcomes, but their relationship with malnutrition diagnoses remains unclear. We evaluated associations between The American Society for Parenteral and Enteral Nutrition and the Academy of Nutrition and Dietetics Indicators for Malnutrition (AAIM) and the Global Leadership Initiative on Malnutrition (GLIM) defined malnutrition and CT-derived muscle features. Additionally, we investigated whether incorporating muscle area or density measures alongside malnutrition assessments improves prediction of transplant outcomes. METHODS: Ninety-one patients who underwent CT within 90 days before liver transplant were assessed for malnutrition within 48 h of transplantation. Psoas muscle area indexed to height (psoas area index) and muscle density were captured. Stepwise regression evaluated associations between malnutrition, muscle measures, anthropometric measures, and whether muscle measures improved outcome predictions. RESULTS: Malnutrition was associated with lower psoas area index for both criteria (AAIM: p < 0.001; GLIM: p = 0.02), and psoas density with GLIM criteria (p < 0.01). Malnutrition weakly predicted length of stay (p = 0.02, R = 0.06; p = 0.14, R = 0.04) and discharge disposition (p < 0.01, R = 0.07; p = 0.17, R = 0.01). Adding muscle density substantially improved length of stay prediction (p < 0.0001, R = 0.19; p < 0.001, R = 0.17). CONCLUSION: Malnutrition criteria seem to better reflect CT-derived measures of psoas muscle area compared to density. Including muscle density measures alongside malnutrition assessments may improve clinical outcome predictions in liver transplant patients and allow for development of more targeted nutrition interventions.
BACKGROUND AND AIM: Postbiotics, preparations of inanimate microorganisms and/or their components with health benefits, may offer potential advantages in the management of IBS, but evidence remains limited. We conducted...BACKGROUND AND AIM: Postbiotics, preparations of inanimate microorganisms and/or their components with health benefits, may offer potential advantages in the management of IBS, but evidence remains limited. We conducted the first systematic review and meta-analysis to assess the efficacy and safety of postbiotics in adults with IBS. METHODS: PubMed, Scopus, Embase, and Web of Science were searched from inception to August 2025 for randomized controlled trials (RCTs) comparing postbiotics with placebo in adults diagnosed with IBS by Rome III or IV criteria. Primary outcomes were changes in the IBS Symptom Severity Scale (IBS-SSS) and achievement of ≥ 30% abdominal pain reduction. Secondary outcomes included quality of life (QoL) and treatment-emergent adverse events (TEAEs). Risk of bias was assessed using Cochrane RoB 2.0 and certainty of evidence using GRADE. Meta-analyses were conducted using RevMan 5.4. RESULTS: Four RCTs including 1062 participants were analyzed. Postbiotics significantly reduced IBS-SSS scores compared with placebo (standardized mean difference [SMD] - 1.36, 95% CI -1.75 to -0.97; p < 0.00001). Postbiotics increased the likelihood of achieving a clinically meaningful pain response (risk ratio [RR] 2.46, 95% CI 1.96-3.57; p < 0.00001). QoL improved with oral capsule formulations (SMD 0.84, 95% CI 0.67-1.01; I = 0%), but not when an enema-based study was included. TEAE rates were similar between groups (RR 0.68, 95% CI 0.34-1.35; p = 0.27). Heterogeneity was moderate to substantial. Certainty of evidence was low. CONCLUSIONS: Postbiotics may improve IBS symptom severity and abdominal pain, with oral formulations showing potential QoL benefits and comparable safety to placebo. Larger, standardized RCTs are required to confirm these findings.
BACKGROUND & AIMS: Patients at high risk for hepatocellular carcinoma (HCC) are recommended to undergo biannual abdominal ultrasound surveillance; however, ultrasound has low sensitivity for small HCC nodules and is asso...BACKGROUND & AIMS: Patients at high risk for hepatocellular carcinoma (HCC) are recommended to undergo biannual abdominal ultrasound surveillance; however, ultrasound has low sensitivity for small HCC nodules and is associated with poor adherence. To address these limitations, the multianalyte HelioLiver Dx blood test was developed to aid in the detection of HCC in patients with cirrhosis who are at high risk for HCC. METHODS: The performance of the HelioLiver Dx test and ultrasound for the detection of HCC in adults with cirrhosis was evaluated in a cross-sectional, prospective, blinded, multicenter validation study. All participants provided blood specimens for the HelioLiver Dx test and underwent ultrasound. All participants also underwent multiphasic MRI, which served as the reference standard for determining HCC status. RESULTS: Of 1,268 evaluable participants, 46 (3.6%) were considered to have HCC as determined by MRI, with many (46%) having small HCC lesions ≤2 cm in diameter. The HelioLiver Dx test had a sensitivity of 47.8% (95% CI 32.9-63.1) for all HCC lesions and 28.6% (95% CI 11.3-52.2) for HCC lesions ≤2 cm. In contrast, ultrasound demonstrated a lower sensitivity of 28.3% (95% CI 16.0-43.5) for all HCC lesions and failed to detect any (0%; 95% CI 0.0-16.1) HCC lesions ≤2 cm. The specificity of HelioLiver Dx and ultrasound were 87.6% (95% CI 85.6-89.4) and 93.9% (95% CI 92.5-95.2), respectively. The HelioLiver Dx test met prespecified co-primary endpoints for superior sensitivity and non-inferior specificity compared to ultrasound. CONCLUSION: Compared with ultrasound and alpha-fetoprotein, the HelioLiver Dx test identified more HCC lesions overall, including more small lesions. A convenient and accurate blood-based test may improve HCC surveillance by facilitating earlier detection and reducing patient barriers to testing. GOV IDENTIFIER: NCT03694600 IMPACT AND IMPLICATIONS: There is a significant, unmet clinical need for more sensitive and accessible methods for the early detection of hepatocellular carcinoma (HCC) in high-risk patient populations. The current study is the first blinded, multicenter, prospective study to evaluate the performance of a multianalyte blood test compared to abdominal ultrasound for the detection of HCC among patients with cirrhosis. The multianalyte HelioLiver Dx test met prespecified co-primary endpoints for superior sensitivity and non-inferior specificity compared to ultrasound for detection of HCC lesions. The availability of a more accessible, convenient and sensitive blood test to aid in the detection of HCC may improve utilization and consequently clinical outcomes for high-risk patients via reduction of care barriers and improved early HCC detection. CLINICALTRIALS: gov identifier: NCT03694600.
BACKGROUND: We previously reported the 10-year effects of colonoscopy screening on colorectal cancer incidence and mortality. Here, we report the effects after 13 years of follow-up. METHODS: In this multicountry, popula...BACKGROUND: We previously reported the 10-year effects of colonoscopy screening on colorectal cancer incidence and mortality. Here, we report the effects after 13 years of follow-up. METHODS: In this multicountry, population-based randomised controlled trial, 84 583 men and women aged 55-64 years at enrolment from Norway, Poland, and Sweden were randomly allocated (1:2) to colonoscopy screening or no screening and analysed. The primary outcomes were colorectal cancer incidence and mortality after 10-15 years of follow-up in intention-to-screen analyses, with first analysis after 10 years, and repeated every other year or at longer intervals. This trial is registered with ClinicalTrials.gov, NCT00883792, and is ongoing. FINDINGS: At 13 years of follow-up, colorectal cancer incidence was 375 colorectal cancers (1·46%) of 28 217 individuals in the screening group and 912 colorectal cancers (1·80%) of 56 366 individuals in the no-screening group. The risk ratio (RR) was 0·81 (95% CI 0·71-0·90) in intention-to-screen analyses and 0·55 (0·33-0·81) in per-protocol analyses. The risk for proximal colorectal cancer was 129 (0·51%) in the screening group versus 283 (0·56%) in the no-screening group (RR 0·91 [0·71-1·09]), and the risk for distal colorectal cancer was 224 (0·87%) in the screening group versus 563 (1·11%) in the no-screening group (RR 0·79 [0·65-0·89]; interaction p<0·0001). In men, the colorectal cancer risk was 214 (1·69%) of 14 154 in the screening group and 541 (2·19%) of 28 247 in the no-screening group (RR 0·77 [0·64 to -0·88]); in women, the risk was 161 (1·24%) of 14 063 in the screening group versus 371 (1·43%) of 28 119 in the no-screening group (RR 0·87 [0·70 to 1·02]; interaction p<0·0001). Colorectal cancer mortality was 106 (0·41%) of 28 217 in the screening group and 236 (0·47%) of 56 366 in the no-screening group (intention-to-screen RR 0·88 [0·68-1·08], per-protocol RR 0·70 [0·26-1·25]). The observed colorectal cancer mortality in the non-screening group (0·47%) was substantially lower than expected at the time of designing the trial (0·82%). INTERPRETATION: One colonoscopy significantly reduced colorectal cancer incidence but not mortality over 13 years. Colorectal cancer mortality was lower in both study groups than when the trial was designed. FUNDING: The Norwegian Research Council, the Nordic Cancer Union, the Norwegian Cancer Society, and the Health Fund of South-East Norway.
BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. Although genetic variants are linked to MASLD progression, whether their asso...BACKGROUND AND AIMS: Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease worldwide. Although genetic variants are linked to MASLD progression, whether their associations with fibrosis severity are consistent across clinical contexts remains unclear. METHODS: A cross-sectional analysis of 6446 individuals with MASLD from a community-based (n = 4477) and a tertiary-care hepatology population (n = 1969) was conducted. Fibrosis severity was assessed using the fibrosis-4 (FIB-4) index. Associations between MASLD-related genetic variants (PNPLA3 rs738409, TM6SF2 rs58542926, and MBOAT7 rs641738) and fibrosis were evaluated using multivariable logistic regression within each population. RESULTS: Advanced fibrosis was more prevalent in the tertiary-care population than in the community-based population (FIB-4 > 1.30: 34.5% vs. 41.2%; FIB-4 ≥ 3.25: 8.4% vs. 0.4%). PNPLA3 rs738409 showed consistent associations with fibrosis severity in both populations, with markedly stronger effects in the tertiary-care setting. In the community-based population, the GG genotype was associated with significant fibrosis (FIB-4 > 1.30; adjusted OR 1.28; 95% CI, 1.03-1.60; P for trend = 0.015), but not with higher thresholds. In contrast, in the tertiary-care population, the GG genotype was strongly associated with FIB-4 > 1.30 (OR 3.11; 95% CI, 2.23-4.34), and FIB-4 ≥ 3.25 (OR 4.17; 95% CI, 2.60-6.67; all P for trend < 0.001). TM6SF2 rs58542926 showed modest associations only in the community-based population, while MBOAT7 rs641738 was not associated with fibrosis severity. CONCLUSIONS: Genetic associations with fibrosis in MASLD appear to be context dependent. PNPLA3 rs738409 shows consistent but markedly greater effect sizes in tertiary-care settings, suggesting that clinical and metabolic context may play an important role in modulating genetic risk beyond ancestry alone.
BACKGROUND & AIMS: Dysregulation of hepatic cathepsins contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) by promoting inflammation, apoptosis, and fibrosis. However, the role of intestinal c...BACKGROUND & AIMS: Dysregulation of hepatic cathepsins contributes to metabolic dysfunction-associated steatotic liver disease (MASLD) by promoting inflammation, apoptosis, and fibrosis. However, the role of intestinal cathepsins in MASLD has not been investigated. Given the central role of the gut-liver axis in disease progression, this represents an important knowledge gap. METHODS: Faecal cathepsin B and S activity was measured in 95 patients with MASLD and 18 healthy controls. Cathepsin activity was correlated with liver disease severity, metabolic parameters, and gut microbiome composition. RESULTS: Faecal cathepsin B and S activity was higher in patients with MASLD than in healthy controls. Cathepsin B activity was further increased in patients with metabolic dysfunction-associated steatohepatitis. Cathepsin B and S activity correlated with serum transaminases and hepatic steatosis, while cathepsin B activity was additionally associated with liver stiffness. Cathepsin B and S activity correlated with adiposity but showed no associations with other metabolic dysfunction-related parameters. Moreover, gut microbiome composition differed between patients with low vs. high faecal cathepsin B or S activity, respectively. CONCLUSION: Increased faecal cathepsin B and S activity is associated with liver disease severity and adiposity in MASLD and is linked to alterations of the gut microbiome, suggesting a potential role of intestinal cathepsins in gut-liver axis dysfunction.
Expert Opin Drug Metab Toxicol
· 2026 May · PMID 42090424
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INTRODUCTION: drug-induced liver injury (DILI) is a poorly understood condition which can be caused by various medications, including herbals and anti-cancer drugs. A literature review of studies published 1995-2025 was...INTRODUCTION: drug-induced liver injury (DILI) is a poorly understood condition which can be caused by various medications, including herbals and anti-cancer drugs. A literature review of studies published 1995-2025 was conducted by searching PubMed and Google Scholar. Sex seems to play a role in the etiology of specific medications, as women are more prone to DILI due to certain drugs, whereas male sex is a risk factor of DILI due to other drugs. AREAS COVERED: The current article highlights new studies on sex regarding risk factors of DILI, prediction of liver injury, and predictors of severe outcomes. Studies on sex-related differences in pharmacokinetics and drug-specific differences of DILI are discussed. In addition, the differences in the incidence of DILI and severity in women are discussed. EXPERT OPINION: Although sex-related differences have been reported, the reasons for drug-specific risk factors for DILI are poorly characterized. A better understanding of drug vs. host-related factors in terms of sex is needed in order to predict the risk in women vs. men. Further studies are needed to determine if differences in different phenotypes and severity in women compared to men are due to hormonal and/or pharmacokinetics or other factors.
Tursi A, Piovani D, Brandimarte G
… +18 more, Di Mario F, Figlioli G, Dumitrascu DL, Oliveira EC, Papa V, Papagrigoriadis S, Stundiene I, Reichert MC, Regula J, Elisei W, Picchio M, Bassotti G, Bafutto M, Latella G, Maconi G, Bonovas S, Papa A, Danese S
Tech Coloproctol
· 2026 May · PMID 42086886
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BACKGROUND: 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). METHODS: We...BACKGROUND: 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). METHODS: 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. RESULTS: 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. CONCLUSIONS: DICA and CODA scores may predict the severity of AD and the length of the HS.
INTRODUCTION: An increase in cirrhosis-related hospitalizations has highlighted opportunities for improved patient care and standardization of practice. We created a cirrhosis admission order set with the goal of promoti...INTRODUCTION: An increase in cirrhosis-related hospitalizations has highlighted opportunities for improved patient care and standardization of practice. We created a cirrhosis admission order set with the goal of promoting guideline-directed care and improving patient outcomes. METHODS: We developed and implemented a cirrhosis order set that included dietary recommendations, diagnostic paracentesis orders and studies, common complications of portal hypertension and educational materials at time of discharge. We used a retrospective cohort design to compare post-intervention process measures and outcomes. RESULTS: The use of the order set resulted in a significant increase in low sodium diet (93% vs. 37%, p = 0.001), high protein diet (91% vs. 37%, p = 0.001) and diagnostic paracentesis (46% vs. 26%, p = 0.001) performed during admission. There was also a significant reduction in time to diagnostic paracentesis (460 min vs. 1210 min, p = 0.03) and less all-cause Emergency Department visits (32% vs. 46%, p = 0.006) in the order set group. There was no significant impact on length of stay, readmission rates or in-hospital mortality. DISCUSSION: The use of a standardized order set improves inpatient management of cirrhosis and encourages guideline-directed care. This order set could easily be replicated at other institutions or among non-cirrhotic patient populations. Future work should focus on further standardization of the discharge process with the goal of having a more tangible impact on length of stay and readmission rates.
INTRODUCTION: Pediatric functional constipation is a highly prevalent disorder associated with significant morbidity and impaired quality of life. Despite widespread use of osmotic and stimulant laxatives, a substantial...INTRODUCTION: Pediatric functional constipation is a highly prevalent disorder associated with significant morbidity and impaired quality of life. Despite widespread use of osmotic and stimulant laxatives, a substantial proportion of children remain symptomatic, highlighting an unmet need for novel therapies. AREAS COVERED: This review provides an overview of the mechanism of action, pharmacokinetics, safety, and clinical efficacy of linaclotide for the treatment of functional constipation in children. Evidence from phase 2 dose-finding studies, a pivotal phase 3 randomized controlled trial, and real-world data is summarized. Prior pediatric experience with other prosecretory and prokinetic agents is discussed to contextualize the current therapeutic landscape. A focused literature review was conducted using PubMed/MEDLINE and regulatory sources (U.S. Food and Drug Administration [FDA]), prioritizing pediatric clinical trials and observational studies evaluating linaclotide in functional constipation. EXPERT OPINION: Linaclotide may represent a mechanism-based therapeutic option for pediatric patients with functional constipation who remain symptomatic despite optimized conventional therapy. By targeting guanylate cyclase-C-mediated epithelial secretion, linaclotide is associated with improvements in bowel habits and a predominantly gastrointestinal safety profile. However, the pediatric evidence base remains relatively limited, and further studies are needed to define long-term outcomes, predictors of response, and its role within treatment algorithms.
Miarka M, Smyk W, Bodys-Pełka A
… +4 more, Gibiński K, Główczyńska R, Figiel W, Raszeja-Wyszomirska J
Adv Clin Exp Med
· 2026 Jun · PMID 42083488
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BACKGROUND: Sarcopenia, characterized by the loss of skeletal muscle mass, strength, and function, is a prevalent and severe complication of liver cirrhosis, irrespective of its etiology. Despite its early onset in cirrh...BACKGROUND: Sarcopenia, characterized by the loss of skeletal muscle mass, strength, and function, is a prevalent and severe complication of liver cirrhosis, irrespective of its etiology. Despite its early onset in cirrhosis, the impact of sarcopenia on liver transplantation (LT) outcomes is often underestimated. OBJECTIVES: This study evaluates the role of both static and dynamic assessments of sarcopenia in LT recipients, focusing on cardiopulmonary performance and the likelihood of prolonged ICU stays. MATERIAL AND METHODS: We studied 54 LT recipients (median age: 53.5 years, 59% female patients) at a single center. The L3 skeletal muscle index (L3SMI) was measured using computed tomography (CT) scans, while exercise tolerance was evaluated with the 6-minute walk test (6MWT). Cardiac output (CO) was recorded in liters per minute. RESULTS: The median Model for End-Stage Liver Disease (MELD) score was 14.4, with 37% of patients classified as Child-Pugh class C. Major LT indications included autoimmune liver diseases (46.3%) and alcohol-related liver disease (ALD; 31.5%). Sarcopenia was present in 60.4% of patients. No significant differences in L3SMI were found related to underlying liver disease, gender, body mass index (BMI), or ammonia levels. However, patients with ALD covered significantly shorter distances in the 6MWT (p = 0.02). Sarcopenic patients had significantly higher CO than non-sarcopenic patients (p < 0.01). Intensive care unit (ICU) stay ≥3 days was observed in 77.8% of recipients, with no clear risk factors identified. CONCLUSIONS: Sarcopenia linked to end-stage liver disease (ESLD) correlates with cirrhotic cardiomyopathy, as evidenced by increased CO. Further studies are required to clarify the role of 6MWT and CO in post-LT risk stratification.
BACKGROUND AND AIMS: Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has...BACKGROUND AND AIMS: Deficiency of adenosine deaminase 2 (DADA2) is caused by mutations in the ADA2 gene and results in an auto-inflammatory state. Hepatosplenomegaly, with or without abnormalities in liver enzymes, has been reported in DADA2. Anti-tumour necrosis factor (anti-TNF) therapy is the standard of care for the prevention of recurrent ischemic strokes and reduction of inflammatory burden. However, little is known about the extent of hepatic involvement and the utility of non-invasive tools for identifying liver disease and monitoring treatment response. METHODS: Retrospective analysis was performed on a prospective cohort of 70 patients with DADA2. Patients underwent baseline and annual laboratory testing, abdominal imaging and transient elastography. Hepatomegaly and splenomegaly were assessed on imaging, with splenomegaly defined using the spleen-to-height (SH) ratio. Liver biopsy and esophagogastroduodenoscopy were performed when indicated. RESULTS: At baseline, elevated ALT was uncommon (29%). Hepatomegaly and splenomegaly were present in 36% and 58%, respectively. Liver biopsies were performed in 12 patients, 8 of whom showed porto-sinusoidal vascular disease (PSVD). Over a median follow-up of 4.5 years, 40% demonstrated persistently elevated ALT levels. Clinically evident portal hypertension was present in 14%, and decompensation events, such as ascites and variceal bleeding, occurred in 5%. Anti-TNF therapy resulted in resolution of splenomegaly in 28% and a reduction in mean SH ratio across the entire cohort. Patients who underwent haematopoietic cell transplantation (HCT) appeared to be at risk for complications such as hepatic graft versus host disease and veno-occlusive disease. CONCLUSIONS: DADA2 vasculopathy appears to affect intrahepatic portal veins and result in PSVD. SH ratio shows significant promise in identifying liver involvement and monitoring treatment response. The improvement in SH suggests that PSVD may be reversible with treatment in this setting. Hepatic evaluation at baseline is encouraged for all patients, and pre-HCT liver biopsy should be considered, as there can be clinically silent liver disease that could potentially cause transplant-related complications.
Chen R, Li X, Zhu P
… +19 more, Yi X, Wang T, Chen H, Huang X, Ye G, Jiang J, Ong M, Jiang L, Li Y, Zhong S, He Y, Fan R, Zhang B, Li H, Cai J, Zheng S, Xu Q, Ling Q, Zhang H
BACKGROUND & AIMS: Endothelial cell (EC) damage is an initiating event in acute cellular rejection after liver transplantation (LT). However, the origin and characteristics of post-transplant neonatal ECs remain controve...BACKGROUND & AIMS: Endothelial cell (EC) damage is an initiating event in acute cellular rejection after liver transplantation (LT). However, the origin and characteristics of post-transplant neonatal ECs remain controversial. We aimed to uncover the mechanisms underlying EC-T cell interactions after transplantation and to develop an EC-targeted strategy to alleviate transplant rejection. METHODS: Leveraging single-cell RNA sequencing from 13 human and 4 murine liver allografts, we mapped the functional atlas of ECs. Allogeneic orthotopic LT in CAG;R26-tdTomato and Cd34-CreER;R26-tdTomato mice confirmed the cellular origin of ECs. We used CellChat, multiplex immunohistochemistry, and in vitro co-culture models to investigate the mechanism of EC-T cell interactions. Using a platelet-based bio-delivery system, we achieved targeted delivery of a CXCL12 monoclonal antibody (αCXCL12). RESULTS: ECs in transplanted livers exhibited a dual origin, being derived from both donor and recipient cells. Recipient-derived ECs were characterized by high CD34 expression, high stemness, and pro-inflammatory characteristics. Using genetic lineage-tracing mice combined with an orthotopic LT model, we found that recipient CD34 cell-derived ECs peaked at 2 weeks post-LT and declined by 4 weeks, consistent with the temporal pattern of rejection. We further identified that CD34 ECs recruit and potentiate Th1 and cytotoxic CD8 T cells via the CXCL12-CXCR4 axis and co-stimulatory molecules. In turn, cytotoxic CD8 T cells induced pyroptosis of CD34 cell-derived ECs through the Caspase1-GSDMD pathway. Platelets loaded with αCXCL12 specifically targeted ECs in the transplanted liver, reducing T-cell infiltration and mitigating rejection. CONCLUSIONS: We identified a population of recipient-derived CD34 ECs that exacerbates acute rejection by activating T cells through the CXCL12-CXCR4 axis. We further developed a platelet-based delivery strategy that precisely targets EC-derived CXCL12 and effectively prevents acute cellular rejection. IMPACT AND IMPLICATIONS: We integrated single-cell transcriptomic data from human and murine liver allografts to delineate the dual cellular origins and functional atlas of endothelial cells. Using lineage-tracing mice in an allogeneic orthotopic liver transplantation model, we tracked the fate of CD34 cells and demonstrated the contribution of recipient-derived CD34-lineage endothelial cells to liver allograft angiogenesis. These CD34-lineage endothelial cells recruited T cells through the CXCL12-CXCR4 axis and activated them via co-stimulatory molecules. Furthermore, a platelet-based biological delivery strategy targeting CXCL12 in CD34-lineage endothelial cells alleviated T cell-mediated rejection. This study provides an endothelial cell-centered perspective and proposes a potential novel immunosuppressive strategy for liver transplantation.