The impact of acute-on-chronic liver failure (ACLF), a deadly form of decompensated cirrhosis characterized by the presence of organ failures, has not been well characterized, largely due to the lack of a code for ACLF in the International Classification of Diseases (ICD). We used ICD codes for extrahepatic organ failure to assess the burden of cirrhosis with extrahepatic organ failures (EHOFs) on European health care systems. The authors have searched national healthcare system databases from Germany for the period 2005-2020 and matched the data with that from France, Italy, and Denmark for admissions between 2017 and 2020, specifically for cases with an ICD diagnosis of cirrhosis combined with kidney, brain, respiratory, or circulatory failure. During the 4-year period, 1,599,680 hospital admissions for cirrhosis, which included 329,093 (20.6%) admissions with at least 1 EHOF, were recorded across the 4 countries. The most frequent failing organs were kidneys (52.9%) and respiration (41.2%). The annual number of admissions for cirrhosis decreased over time (from 414,093 to 375,112), whereas the percentage of admissions with EHOF rose from 19.9% to 21.5%. Overall, the in-hospital mortality rate of patients with a diagnosis of EHOF was high (29.2%), markedly exceeding the mortality of those with a diagnosis of cirrhosis (7.9%). The proportion of estimated total healthcare claims of all hospital admissions of EHOF from cirrhosis was 44.9%. This study reveals that the burden of cirrhosis with EHOF was high in the 4 European countries, with a substantial impact on patient mortality. Crucially, these findings underscore the significant economic strain placed on healthcare systems by EHOF in cirrhosis patients. This should motivate all stakeholders to take action aiming at reducing this burden.
Since the publication of the first European Society for the Study of Coeliac Disease (ESsCD) guidelines in 2019, substantial advances have been made in understanding the management and complex disease courses of coeliac disease (CeD) in adults. These 2025 updated guidelines aim to integrate new evidence, refine management strategies, and promote a personalised and multidisciplinary approach to care. The ESsCD convened a multidisciplinary panel of experts to revise the 2019 guidelines using the Appraisal of Guidelines for Research and Evaluation II (AGREE II) framework. Evidence was appraised and graded according to the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) methodology. Statements and recommendations were draughted within working groups and finalised through a structured Delphi consensus process. The updated guidelines are presented in two parts. Part 1, which has already been published, addresses the diagnostic approach to CeD in adults, whereas Part 2 focuses on disease management, structured follow-up, and the evaluation and treatment of persistent symptoms despite a gluten-free diet or refractory disease. New or expanded sections include guidance on the safe inclusion of oats, use of low-FODMAP diets in patients with persistent symptoms, management of exocrine pancreatic insufficiency, recognition of functional asplenia and related vaccination recommendations, and stratified bone-health screening. The guidelines also discuss nutritional and psychosocial support, digital models of care, and structured transition from paediatric to adult services. Updated therapeutic strategies for refractory CeD are provided, including immunosuppressive and novel pharmacologic options. These updated guidelines offer a comprehensive, evidence-based framework for the management and follow-up of adults with CeD. By integrating recent scientific advances with pragmatic, patient-centred recommendations, they seek to optimise clinical outcomes, quality of life, and long-term health in individuals with CeD.
The REBECCA project taps into the potential of using real-world data (RWD) for supporting groundbreaking clinical research on complex chronic conditions as a complement to Randomised Controlled Trials. REBECCA moves beyond the analysis of clinical data from Electronic health records, by combining it with detailed monitoring data from multiple wearables, online behaviour and self-reported data to monitor patients's quality of life in terms of their functional and emotional status. The project focuses on the detection of cancer-related fatigue, developed during breast cancer recovery, using digital biomarker profiles for early detection of the disease and assessing the value of detailed and longitudinal patient monitoring as a means of improving patient care. The project also demonstrates the extensibility of REBECCA monitoring to other forms of cancer, such as prostate cancer. We describe the three clinical trials being conducted in Norway and the use of the REBECCA platform, capable of detailed monitoring and privacy preserving federated cross-country data analysis. The RWD will be analyzed in the context of data from questionnaires (Patient Reported Outcome Measures) and results from analysis of biological samples. Through this approach we expect that the REBECCA project will produce new knowledge on clinical management of cancer patients and contribute to new biological knowledge on cancer-related fatigue. Status and perspectives: The REBECCA project is ongoing, and patient follow-up will be completed during February 2026. The initial analyses of RWD, PROMs and biological samples have started together with the partners in the REBECCA consortium. The REBECCA trials are approved by the Regional Ethics Committee of the Western Health Authority (REK Vest) under the IDs 225,855 (REBECCA-1), 242,088 (REBECCA-2) and 619,903 (REBECCA-3). All trials have also been registered at clinicaltrials.gov (NCT05587777, NCT06120595 and NCT06435091). Trial registration: NCT05587777, Retrospectively registered 19th of October 2022, https://clinicaltrials.gov/study/ NCT05587777; NCT05587777, Retrospectively registered 6th of November 2023, https://clinicaltrials.gov/study/ NCT06120595; NCT05587777, Retrospectively registered 23rd of May 2024, https://clinicaltrials.gov/study/ NCT06435091.
Metabolic dysfunction-associated steatotic liver disease (MASLD) has been linked to an increased risk of serious infection, but the impact of in utero exposure to maternal MASLD on the risk of infection in offspring remains unknown. This nationwide cohort study included all singleton live born offspring exposed in utero to maternal biopsy-proven MASLD (1992-2017) in Sweden. Offspring born to mothers with MASLD (N = 239) were matched with up to five reference offspring (N = 1131) of mothers without MASLD by maternal age at delivery, calendar year of delivery, and parity. We used multivariable Cox regression to estimate adjusted hazard ratios (aHRs) for incident serious infection up until 2023. Results were also stratified by maternal histological severity of MASLD (simple steatosis vs. severe MASLD including steatohepatitis, any stage of liver fibrosis or cirrhosis). Over a median of 16.7 years of follow-up, 56 incident serious infections occurred in MASLD offspring (incidence rate [IR] 15.8/1000 person-years) and 140 incident serious infections occurred in reference offspring (IR 7.4/1000 person-years), which corresponded to an aHR of 1.81 (95% CI 1.23-2.68). The aHRs for incident serious infection were similar to offspring of mothers with simple steatosis and severe MASLD (1.97 vs. 1.70). This association was primarily explained by early-life infections (1-year aHR 3.11, 95% CI 1.74-5.58), with severe MASLD potentially being a major factor in the observed association during the first year. Results remained consistent across subgroups. Maternal MASLD, even simple steatosis, is associated with a higher hazard of serious offspring infection, highlighting the need for closer monitoring.
In the last decades, the world of hepatology has widely changed. Although relevant advances have be achieved (e.g. the way toward eradication of hepatitis C virus), many challenges are far to be won. Patients with liver disease continue to face noteworthy barriers to early diagnosis and effective disease management. In response to these tasks, the Italian Association for the Study of the Liver formed a multidisciplinary commission to address the unmet needs of people affected by liver diseases. We analyzed the state of the art of the following consolidated unmet needs: stigma (with particular attention to alcohol-related disease and obesity), specific criticisms of elderly, socioeconomic barriers that patients with liver disorders can face, gender gap in many aspects of liver disease and, finally, the complex issue of quality of life. For each unmet need, we proposed a key-message task and some concrete future perspectives. Preserving a holistic vision and using both multidisciplinary and interdisciplinary method, represent the only effective approach to take on the many unmet needs of patients with liver disorders.
The SANO trial demonstrated that active surveillance after neoadjuvant chemoradiotherapy (nCRT) has non-inferior 2-year overall survival compared with standard surgery in patients with locally advanced oesophageal cancer. This aim of this study was to compare health-related quality of life (HRQoL) in both groups. Patients with a cCR after nCRT were included and randomized within the stepped-wedge cluster-randomized SANO trial to active surveillance or surgery. HRQoL was measured using the European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Core 30 (QLQ-C30) and the EORTC Quality of Life Questionnaire-Oesophago-Gastric Module (QLQ-OG25) before nCRT (baseline) and at 3 (before surgery), 6, 9, 12, 16, 20, and 24 months after nCRT. Predefined endpoints included dysphagia (QLQ-OG25), as well as dyspnoea, fatigue, physical functioning, and emotional functioning (all QLQ-C30). Repeated measures analysis was used to assess between-group differences. Cohen's d (CD) >0.5 was considered clinically relevant. A total of 274 patients were included, with a response rate of 85.4% (234 patients responded in total; 169 active surveillance patients and 65 standard surgery patients). At 6 months after nCRT, scores for dysphagia, dyspnoea, fatigue, and physical functioning were significantly better in the active surveillance group (CD of -1.09, -0.63, -0.70, and 0.77 respectively; all P ≤ 0.001). Dysphagia remained significantly better in the active surveillance group at 9, 12, and 24 months after nCRT (CD of -0.60 (P = 0.001), -0.46 (P = 0.015), and -0.79 (P < 0.001) respectively). No differences were found for other domains. Active surveillance patients experienced less dysphagia, dyspnoea, and fatigue, as well as better physical functioning, at 6 months after nCRT compared with standard surgery patients. Dysphagia remained improved at 2 years. These results support an active surveillance approach in patients with oesophageal cancer who attain a cCR after nCRT. NTR-6803 (Netherlands Trial Register). Oesophageal cancer is often treated with chemotherapy and radiotherapy (nCRT), followed by surgery. The SANO trial evaluated whether active surveillance (watching and monitoring patients instead and doing surgery when indicated) could be as safe as surgery for patients who responded well to nCRT. The aim of this study was to compare the quality of life between patients who chose active surveillance and those who had surgery. A total of 274 patients were randomly assigned to either the active surveillance group or the surgery group. Their quality of life was measured at different times before and after treatment. The study focused on several areas: swallowing problems, shortness of breath, tiredness, physical health, and emotional health. Patients who chose active surveillance felt better in many ways in the short term compared with those who had surgery. They had less trouble swallowing, less shortness of breath, felt less tired, and had better physical health at 6 months. The improvement in swallowing lasted for up to 2 years. This suggests that active surveillance could be a good option for patients with oesophageal cancer who respond well to treatment, offering them a better quality of life without needing surgery.
INTRODUCTION: Most European transplant centres require patients to abstain from alcohol consumption for at least 6 months to be listed for liver transplantation, even though delayed transplantation is associated with increased mortality. This study examined the effects of a shorter duration of alcohol abstinence before placement on the waiting list for liver transplantation on post-transplant survival and quality of life. This article contributes to the ongoing debate on whether patients with less than 6 months of alcohol abstinence should be categorically excluded from transplantation. This retrospective cohort study analysed patients at the University Hospital Zurich who underwent liver transplantation for any indication between 2011 and 2019. Patients younger than 18 years and those with acute liver failure were excluded. The follow-up period was 3 years. The outcomes were post-transplant survival and quality of life in patients with less than (group 1) or more than (group 2) 6 months of abstinence before being listed for liver transplantation. Survival was compared using log-rank tests, and quality of life (scored from 0 to 100) was compared using multivariate ANOVA with repeated measures. Of the 206 included patients, 50 (24%) had abstained from alcohol for less than 6 months before being listed for liver transplantation (group 1). The cohort had a median (IQR) age at transplantation of 59 (53-64) years, and 155 (75%) were men. Three-year survival was similar in patients with less than or more than 6 months of alcohol abstinence before listing (76% [95% CI, 62%; 86%] vs 78% [95% CI, 70%; 83%]). No significant differences in quality-of-life scores were observed between groups (F(2,244) = 0.814, p = 0.435), and no significant changes in quality of life over time were found within each group (F(1,133) = 0.346, p = 0.557). The median (IQR) quality of life score at 36 months after transplantation was 80 (56-92) in patients with less than 6 months of abstinence before listing versus 78 (63-90) in those with more than 6 months of abstinence. Post-transplant survival and quality of life did not differ between patients with less than 6 months and those with more than 6 months of alcohol abstinence before being listed for liver transplantation. These findings suggest that the strict 6-month abstinence requirement for inclusion on the waiting list should be reconsidered to prevent patients from being denied access to life-saving transplantation solely because of a shorter abstinence duration.
Breast cancer is a leading cause of mortality and morbidity among females worldwide. As part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023, we provided an updated comprehensive assessment of the epidemiological trends, disease burden, and risk factors associated with breast cancer globally, regionally, and nationally from 1990 to 2023. Breast cancer incidence, mortality, prevalence, years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) were estimated by age and sex for 204 countries and territories from 1990 to 2023. Mortality estimates were generated using GBD Cause of Death Ensemble models, leveraging data from population-based cancer registration systems, vital registration systems, and verbal autopsies. Mortality-to-incidence ratios were calculated to derive both mortality and incidence estimates. Prevalence was calculated by combining incidence and modelled survival estimates. YLLs were established by multiplying age-specific deaths with the GBD standard life expectancy at the age of death. YLDs were estimated by applying disability weights to prevalence estimates. The sum of YLLs and YLDs equalled the number of DALYs. Breast cancer burden attributable to seven risk factors was examined through the comparative risk assessment framework. The GBD forecasting framework was used to forecast breast cancer incidence and mortality from 2024 to 2050. Age-standardised rates were calculated for each metric using the GBD 2023 world standard population. In 2023, there were an estimated 2·30 million (95% uncertainty interval [UI] 2·01 to 2·61) breast cancer incident cases, 764 000 deaths (672 000 to 854 000), and 24·1 million (21·3 to 27·5) DALYs among females globally. In the World Bank low-income group, where a low age-standardised incidence rate (ASIR) was estimated (44·2 per 100 000 person-years [31·2 to 58·4]), the age-standardised mortality rate (ASMR) was the highest (24·1 per 100 000 [16·8 to 31·9]). The highest ASIR was in the high-income group (75·7 per 100 000 [67·1 to 84·0]), and the lowest ASMR was in the upper-middle-income group (11·2 per 100 000 [10·2 to 12·3]). Between 1990 and 2023, the ASIR in the low-income group increased by 147·2% (38·1 to 271·7), compared with a 1·2% (-11·5 to 17·2) change in the high-income group. The ASMR decreased in the high-income group, changing by -29·9% (-33·6 to -25·9), but increased by 99·3% (12·5 to 202·9) in the low-income group. The increase in age-standardised DALY rates followed that of ASMRs. Risk factors such as dietary risks, tobacco use, and high fasting plasma glucose contributed to 28·3% (16·6 to 38·9) of breast cancer DALYs in 2023. The risk factors with a decrease in attributable DALYs between 1990 and 2023 were high alcohol use and tobacco. By 2050, the global incident cases of breast cancer among females were forecast to reach 3·56 million (2·29 to 4·83), with 1·37 million (0·841 to 2·02) deaths. The stable incidence and declining mortality rates of female breast cancer in high-income nations reflect success in screening, diagnosis, and treatment. In contrast, the concurrent rise in incidence and mortality in other regions signals health system deficits. Without effective interventions, many countries will fall short of the WHO Global Breast Cancer Initiative's ambitious target of achieving an annual reduction of 2·5% in age-standardised mortality rates by 2040. The mounting breast cancer burden, disproportionately affecting some of the world's most vulnerable populations, will further exacerbate health inequalities across the globe without decisive immediate action. Gates Foundation, St Jude Children's Research Hospital.
Gastric cancer continues to impose a substantial health burden in Europe. The European Council Recommendations have called for consideration of implementing measures aimed at reducing gastric cancer-related mortality. This manuscript reviews current gastric cancer prevention initiatives in Europe. The GISTAR study in Latvia has been enrolling participants from the general population for Helicobacter pylori screen-and-treat intervention together with serological testing for pepsinogens. The EUROHELICAN study was the first to evaluate an H. pylori screen-and-treat strategy in young adults, which has been expanded within the TOGAS project. In addition, TOGAS has addressed stakeholder perspectives, the cost-effectiveness of screen-and-treat strategies, and the prevalence of gastric precancerous conditions among individuals participating in colorectal cancer screening. The GISTAR cohort has also enabled the assessment of long-term outcomes following H. pylori eradication. The EUGastScreen project, carried out within the EUCanScreen Joint Action, aims to evaluate the feasibility of simultaneous screening for H. pylori infection and colorectal cancer using a stool-based test. The European Registry on H. pylori Management (Hp-EuReg) supports the collection of important clinical data from routine clinical practice. Furthermore, the development of European guidelines for gastric cancer prevention has been initiated as part of the European Commission Initiative on Gastric Cancer and is expected to continue until 2027. The recently published 5th edition of the European Code Against Cancer includes recommendations on H. pylori management for the first time. Ongoing initiatives will provide important evidence to support the future implementation of gastric cancer prevention strategies, including data on feasibility, acceptability among the general population and stakeholders, and cost-effectiveness. However, additional implementation studies for gastric cancer prevention will be required.
Several studies have suggested that naldemedine may reduce opioid-induced constipation (OIC) as well as opioid-induced nausea and vomiting (OINV). This study aimed to investigate prophylactic effects of naldemedine on OINV in patients initiating regular, oral, strong opioids for cancer pain. In this preplanned secondary analysis of a multicenter, double-blind, randomized, placebo-controlled trial investigating the preventive effects of naldemedine on OIC, eligible patients were randomized in a 1:1 ratio to receive either naldemedine 0.2 mg or placebo once daily for 14 days. The primary endpoint was the complete response (CR) rate, defined as the proportion of patients with no vomiting episodes and no use of rescue antiemetics within the first three days of opioid initiation. The secondary endpoint was the nausea and vomiting score of the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 15 Palliative Care (EORTC QLQ-C15-PAL). Of the 103 patients, 48 and 47 patients in each group started protocol treatment, respectively. The CR rate was significantly higher in the naldemedine group than in the placebo group (81.3% vs 38.3%, P < .001). Nausea and vomiting scores on the QLQ-C15-PAL at weeks 1 and 2 were significantly better in the naldemedine group (means 7.1 and 6.4) versus placebo (means 44.6 and 35.3; both P < .001). Within the total effect of naldemedine on the QLQ-C15-PAL nausea and vomiting scores at week 2, the proportion mediated through OIC reduction was 21.9%. Naldemedine may have intrinsic antiemetic potency to prevent both OIC and OINV. https://jrct.niph.go.jp/ (Japan Registry of Clinical Trials) Identifier: jRCTs031200397.
The term 'gut health' is increasingly used as a catch-all phrase by many stakeholders, including scientists, health-care professionals, industry and the general public, to describe a wide range of health-related concepts. Despite its widespread use, particularly in relation to studies on diet, fermented foods, biotics and the gut microbiome, it remains unclear what the term gut health means. Therefore, an expert panel was convened by the International Scientific Association for Probiotics and Prebiotics to address the current state of scientific and clinical knowledge on the physiology, manifestation, application and measurement of the concept of gut health. The panel evaluated the term in the context of the central role of the gastrointestinal tract in health and overall well-being and proposed a definition of gut health as "a state of normal gastrointestinal function without active gastrointestinal disease and gut-related symptoms that affect quality of life". The definition was developed mindful of the functional, subjective and extrinsic domains that contribute to gut health. In this Consensus Statement, clinically relevant and accessible metrics to assess these domains are reviewed and a comprehensive approach to gut health is proposed that is relevant to clinical practice as well as to studies of dietary and biotic interventions.
Pancreatic ductal adenocarcinoma (PDAC) remains a deadly malignancy owing to its late presentation and the limited sensitivity of current serum biomarkers and imaging for early detection. Extracellular vesicles (EVs), which carry proteins, nucleic acids, and lipids that reflect tumor-stromal interactions, have emerged as promising biomarkers for early diagnosis, disease monitoring, and treatment response. Several EV-derived proteins, microRNAs, long noncoding RNAs, and DNA alterations linked to early carcinogenesis and therapeutic resistance have been identified. However, variability in pre-analytical handling and analytical platforms has hindered reproducibility. Global standardization efforts, such as European Liquid Biopsy Society (ELBS), The Blood Profiling Atlas in Cancer (BloodPAC), International Liquid Biopsy Standardization Alliance (ILSA), and Minimal information for studies of extracellular vesicles (MISEV), are currently helping to unify methodologies for EV isolation and molecular profiling. Advances in analytical technologies have shifted the field from bulk EV measurements to high-resolution single-vesicle approaches. Techniques, such as nanoflow cytometry, super-resolution imaging, Raman spectroscopy, and surface-enhanced Raman scattering, enable the detection of rare, mutation-bearing, or functionally distinct EV subpopulations, which may enhance diagnostic precision. In gastroenterology, a major opportunity lies in integrating single-EV analytics with the endoscopic sampling of tumor-proximal fluids. EVs obtained from pancreatic juice, bile, duodenal fluid, or portal venous blood via endoscopic retrograde cholangiopancreatography (ERCP) or endoscopic ultrasound (EUS) provide spatially enriched molecular information beyond peripheral blood. Combining endoscopic access with particle-level EV characterization may allow real-time, mechanism-informed assessment of tumor biology and premalignant lesions, offering a promising strategy for early detection and risk stratification in PDAC. Together, these developments have positioned EV-based liquid biopsy as a rapidly maturing field with strong translational potential.
Genetic variants near LYPLAL1 are associated with Metabolic dysfunction-Associated Steatotic Liver Disease (MASLD) in humans, but their impact on LYPLAL1 function is unknown. We identified LYPLAL1 loss-of-function variants from UK BioBank (UKBB) whole-exome sequencing data that had AlphaMissense or GPN-MSA scores in the top 20% of LYPLAL1 variants for being disruptive. We aggregated these variants and carried out burden analysis for effects on MRI Proton Density-Fat Fraction (MRI-PDFF) and ICD-based MASLD in UKBB. Rare loss-of-function LYPLAL1 variants were associated with reduced MRI-PDFF and ICD diagnosed MASLD across sexes. We used CRISPR to knockout and overexpress LYPLAL1 in human hepatoma cells (HuH-7), measuring lipid content, lipid uptake/export, and changes in de novo lipogenesis and mitochondrial β-oxidation. LYPLAL1 subcellular localization was determined by overexpressing LYPLAL1-HA tagged protein. We purified GST tagged human LYPLAL1 protein and conducted in vitro tests for esterase and depalmitoylase activity. Knocking out LYPLAL1 reduced triglycerides biochemically as well as lipid intensity after oleic (18:1, n-9) acid treatment. LYPLAL1 KO cells had increased expression of PPARα and MLXIPL, increased mitochondrial β-oxidation, and reduced capacity to both import fatty acids (FAs) and export lipoproteins. Overexpression of LYPLAL1 increased lipid droplet accumulation and decreased PPARα and MLXIPL. LYPLAL1-HA is partly localized to mitochondria when treated with oleic acid. Biochemical analyses showed that LYPLAL1 has strong esterase activity but lacks depalmitoylase activity. Reduction of LYPLAL1 esterase function likely increases β-oxidation of FAs in mitochondria through PPARα and MLXIPL and decreases FA import to protect against lipid accumulation in human liver cancer cells. Together, our results indicate that LYPLAL1 loss-of-function protects against MASLD in Europeans and in vitro, LYPLAL1 is an esterase for short-chain substrates which is involved in the regulation of mitochondrial β-oxidation and uptake of fatty acids, influencing lipid accumulation in the liver.
No medications are currently approved for the prevention of recurrent acute pancreatitis. This trial evaluated whether naldemedine, a peripherally acting μ-opioid receptor antagonist, reduces the risk of acute pancreatitis in patients with recurrent acute pancreatitis. This was a multicentre, double-blinded, placebo-controlled randomised trial conducted at four Danish pancreatitis referral centres. Participants aged 18-75 years with recurrent acute pancreatitis, both with and without a diagnosis of chronic pancreatitis, were randomised to receive naldemedine 0.2 mg or a matching placebo daily for up to 12 months. The primary outcome was acute pancreatitis recurrence, defined by the revised Atlanta Criteria. Secondary outcomes included pain flares, gastrointestinal symptoms, and quality of life. At the end of follow-up, the participant's global impression of change, safety and tolerability outcomes, new-onset diabetes and pancreatic exocrine insufficiency were assessed. 74 participants (mean age: 46 years; 41% female) were randomised to naldemedine (n = 36) or placebo (n = 38). During a median follow-up time of 365 days (IQR, 352-370), participants in the naldemedine group had a numerically lower risk of acute pancreatitis compared to placebo (HR 0.54; 95% CI, 0.29-1.01; p = 0.05). No differences were observed between the groups for secondary efficacy, safety, and tolerability outcomes. Participants treated with naldemedine for at least 1 year had a lower risk of acute pancreatitis (HR 0.49; 95% CI, 0.24-0.97; p = 0.04). Treatment with naldemedine was safe and well-tolerated and may reduce the risk of recurrent acute pancreatitis. A larger confirmatory trial is needed to verify these findings. ClinicalTrials.gov Identifier: PAMORA-RAP: NCT04966559.
The clinical presentation of chronic pancreatitis (CP) is highly variable and determined by the presence of pancreatic and extrapancreatic complications that occur with varying prevalence and severity. The Scandinavian and Baltic Pancreatic Club (SBPC) Forum of Excellence is a forum for clinicians from the Nordic and Baltic countries with specific knowledge on pancreatic diseases. In 2016, the forum established a database for patients with CP, which became the largest database on this patient population. This paper provides an insight into the 14 studies published from the SBPC database. The cohort grew over the years, and finally, a total of 2608 patients were entered into the database. Smoking and alcohol were leading aetiologies and these are both associated with pain, pancreatic exocrine insufficiency and structural changes. Cluster analysis revealed distinct complication profiles. Imaging findings correlated with clinical outcomes, and enzyme therapy adherence was suboptimal. Chronic pancreatitis is associated with reduced quality of life compared to controls. Endoscopic procedures (EP) were common while surgery was rare and usually preceded by EPs. The SBPC's research offers valuable insights into the aetiology, treatment and complications of CP, with significant implications for patient management. Future studies should aim to expand the evidence base for acute on chronic pancreatitis and explore the long-term outcomes of pancreatic enzyme replacement therapy adherence and invasive interventions in diverse populations. To address these problems, a new prospective register was started that is fully compliant with the current European Union legislation.
Although the current strategy in ulcerative colitis (UC) focuses on achieving endoscopic healing to improve long-term outcomes, patients with persistent microscopic inflammation or intestinal barrier dysfunction remain at increased risk of relapse. We evaluated whether structural and functional abnormalities of the ileal and colonic mucosa assessed by probe-based Confocal laser Endomicroscopy (pCLE) could predict the loss of therapeutic targets. The prospective single-center study included 81 UC patients in clinical and endoscopic remission monitored for 24 months. At baseline, barrier dysfunction and histological inflammation (HI) were assessed through colonoscopy with pCLE and targeted biopsies from the terminal ileum, ascending colon, sigmoid, and rectum. Clinical evaluations were performed every 3 months. The main predictors of loss of endoscopic remission were altered colonic permeability (Odds ratio OR = 3.85, 95% confidence interval CI 1.25-11.77, p = 0.018) and HI detected by pCLE (OR = 6.04, 95% CI 1.89-19.31, p = 0.002). Survival analysis demonstrated an increased risk of clinical relapse in patients with an altered barrier in the terminal ileum (Hazard ratio HR = 6.01, 95% CI 3.08-16.38, p < 0.001) or colon (HR = 6.51, 95% CI 2.08-17.21, p < 0.001). Persistent microscopic inflammation (Enhance index > 1) was significantly associated with unfavorable clinical outcome (HR = 3.39, 95% CI 1.23-8.38, p = 0.018). None of the 29 patients diagnosed with triple healing (histological healing associated with intact ileal and colonic permeability) at inclusion experienced relapse. Morphological and functional evaluation using pCLE offers superior prognostic value and is emerging as a possible therapeutic target for the prevention of clinical and endoscopic relapses in UC.
Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. The higher incidence and earlier onset of HCC in sub-Saharan Africa suggest a potential role for a genetic predisposition. This study evaluated the association of TERT-rs2242652-(A), a variant linked to lower HCC risk, with HCC in populations from Ghana, Nigeria, and Cameroon, compared with a population from the United States. The study included 537 patients with HCC: United States (n = 348), Ghana (n = 79), Nigeria (n = 43), and Cameroon (n = 67). The control group had 2,872 cancer-free individuals: United States (n = 2,399), Ghana (n = 323), Nigeria (n = 85), and Cameroon (n = 65). Whole-exome sequencing was conducted using germline DNA, and data for TERT-rs2242652 were analyzed. Odds ratios (ORs) and 95% CIs were calculated using unconditional logistic regression. Chi-square tests assessed protective allele frequencies. In the US cohort, TERT-rs2242652 was significantly associated with lower HCC risk (OR, 0.75 [95% CI, 0.58 to 0.96]; P = .02), with an allele frequency of 18.8% (15.4% in HCC cases v 19.3% in controls). In the combined sub-Saharan African population, no significant association was observed, but there was a trend toward decreased HCC risk (OR, 0.80 [95% CI, 0.53 to 1.22]; P = .29), with an allele frequency of 12.2% (10.6% in HCC cases v 12.9% in controls). Separate analyses of Ghanaian, Nigerian, and Cameroonian populations showed similar nonsignificant trends. The protective allele frequency in the combined African populations was significantly lower than in the US cohort (P < .0001). In sub-Saharan African populations, there was a lower frequency of the HCC protective allele TERT-rs2242652 compared with European Americans. These findings underscore the importance of multiethnic genetic studies in understanding population differences in HCC risk and developing prevention strategies.
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.
Whether patients with metabolic dysfunction-associated steatotic liver disease (MASLD) cirrhosis can achieve recompensation is still a subject of debate. This study aimed to evaluate the incidence and factors associated with recompensation in patients with decompensated MASLD cirrhosis. Cohort study across 4 university hospitals in Barcelona (Spain), enrolling individuals with MASLD cirrhosis at their initial decompensating event. Liver recompensation (Baveno VII) was defined as the absence of clinical decompensation after discontinuation of specific treatment, along with sustained improvement in liver function. Competing-risk regression models were used to identify predictors of recompensation. Among 124 patients [mean age: 69 years (IQR 62-73), 53% males], 59% had obesity, 74% type 2 diabetes, 66% arterial hypertension, and 47% dyslipidemia. Most patients were Child-Pugh B (61%) with a median MELD-Na score of 11 (IQR 10-16). After a median follow-up of 2.1 years (IQR 0.97-4.53), the 2-year cumulative incidence of recompensation was 24%. Factors associated with recompensation included MELD-Na (aSHR 0.891 [95% CI 0.833-0.953]; p=0.001), albumin (aSHR 1.894 [95% CI 1.008-3.297]; p=0.024, ascites (aSHR 0.475, [95% CI 0.268-0.841]; p=0.011), and multiple decompensation (aSHR 0.151 [94% CI 0.033-0.698]; p=0.015) as a first decompensation event. Although a substantial proportion of patients initially achieved recompensation, this was frequently transient, and its apparent survival benefit did not persist after adjustment for liver function and accounting for time-dependence. Liver recompensation in MASLD cirrhosis occurs in 24% of patients within 2 years after first decompensation and is mainly dependent on basal liver function. However, frequent further decompensation limits its prognostic impact on survival.
Meningitis remains the leading infectious cause of neurological disabilities globally, disproportionately affecting children younger than 5 years and populations in the African meningitis belt. Whereas previous global estimates focused on ten pathogen categories, this study presents the most comprehensive analysis to date, assessing the meningitis burden attributable to 17 causative pathogens based on the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 framework. GBD is a systematic, scientific effort aimed at quantifying the comparative magnitude of health loss caused by diseases, injuries, and risk factors across age groups, sexes, and geographical locations over time. We estimated meningitis mortality using the Cause of Death Ensemble model (CODEm) and morbidity using DisMod-MR 2.1, incorporating data from vital registration, verbal autopsy, surveillance, hospital data, and systematic reviews. Aetiology-specific estimates were generated with pathogen-linked case-fatality ratios and splined binomial regression models. Risk factor attribution was based on established risk-outcome pairs and population attributable fractions. In 2023, there were 259 000 (95% uncertainty interval 202 000-335 000) global deaths and 2·54 million (2·20-2·93) incident cases of meningitis. Children younger than 5 years accounted for more than a third of deaths (86 600 [53 300-149 000]). Streptococcus pneumoniae, Neisseria meningitidis, non-polio enteroviruses, and other viruses were the leading causes of death, while non-polio enteroviruses caused the most cases. The four WHO-defined preventable meningitis pathogens of interest (S pneumoniae, N meningitidis, Haemophilus influenzae, and Group B streptococcus) contributed to 98 700 deaths (77 000-127 000) and 594 000 cases (514 000-686 000). Low birthweight, short gestation, and household air pollution were the top risk factors for meningitis-related mortality. Although mortality and incidence have declined significantly since 1990, progress is insufficient to meet WHO 2030 targets. Despite marked progress in reducing bacterial meningitis via global vaccination campaigns, a substantial meningitis burden persists, attributable both to common pathogens such as S pneumoniae and N meningitidis and to emerging non-bacterial pathogens such as Candida spp and drug-resistant fungi. Achieving WHO goals will require sustained investment in surveillance, vaccination, maternal screening, and health-system strengthening, especially in high-burden settings. Gates Foundation, Wellcome Trust, and UK Department of Health and Social Care.