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.
The 2023 iteration of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) estimated prevalence, incidence, and health burden for 375 diseases and injuries, including 12 mental disorders. We assess past, current, and emerging trends in the prevalence and burden of mental disorders across sexes and age groups, for 21 regions, 204 countries and territories, and by Socio-demographic Index (SDI) quintile, from 1990 to 2023. Mental disorders included in GBD 2023 were anxiety disorders, major depressive disorder, dysthymia, bipolar disorder, schizophrenia, autism spectrum disorders, conduct disorder, attention-deficit hyperactivity disorder, anorexia nervosa, bulimia nervosa, idiopathic developmental intellectual disability, and a residual category of other mental disorders. A literature review identified epidemiological data for each disorder. These were analysed via a Bayesian meta-regression to estimate prevalence by disorder, sex, age, location, and year. Disorder-specific prevalence was multiplied by disability weights representing the severity of health loss associated with each disorder to estimate years lived with disability (YLDs). Deaths due to anorexia nervosa were assessed with a Cause of Death Ensemble modelling strategy to estimate deaths by sex, age, location, and year, and then multiplied by the standard life expectancy at age of death to estimate years of life lost (YLLs). YLDs equalled disability-adjusted life-years (DALYs) for all mental disorders except anorexia nervosa (the only mental disorder considered as an underlying cause of death in GBD), for which DALYs represented the sum of YLDs and YLLs. We presented prevalence, deaths, YLDs, YLLs, and DALYs as counts, age-specific rates per 100 000 population, and age-standardised rates per 100 000 population. We estimated 1·17 billion (95% uncertainty interval 1·06-1·31) prevalent cases of mental disorders globally in 2023, equivalent to an age-standardised prevalence rate of 14 210·7 cases (12 849·5-15 940·1) per 100 000 population. These estimates represented a 95·5% (75·0-121·2) increase in prevalent cases and 24·2% (11·4-41·4) increase in age-standardised prevalence rate between 1990 and 2023. All mental disorders showed increases in prevalent cases between 1990 and 2023, while notable increases were seen in age-standardised prevalence rates for anxiety disorders, major depressive disorder, dysthymia, anorexia nervosa, bulimia nervosa, schizophrenia, and conduct disorder. There were an estimated 171 million (127-228) DALYs due to mental disorders globally across sex and age in 2023, equivalent to an age-standardised DALY rate of 2070·5 DALYs (1519·1-2750·5) per 100 000 population. Mental disorders contributed to 6·1% (4·8-7·6) of all-cause DALYs in 2023, making them the fifth leading cause of global DALYs (up from 12th in 1990). DALYs were almost entirely composed of YLDs. Mental disorders were the leading cause of YLDs in 2023 (up from second in 1990), explaining 17·3% (14·8-20·6) of all-cause global YLDs. Leading causes of mental disorder DALYs were anxiety disorders (ranked 11th among the 304 diseases and injuries at Level 4 of the GBD cause hierarchy), major depressive disorder (15th), and schizophrenia (41st). Globally in 2023, mental disorder age-standardised DALY rates were higher among females (2239·6 [1643·7-3014·1] per 100 000) than among males (1900·2 [1399·8-2510·8] per 100 000), and peaked in the 15-19 years age group (2617·3 [1850·6-3696·8] per 100 000). All locations showed increased mental disorder DALY rates in 2023 compared with 1990, ranging across countries and territories from 1302·4 (952·7-1683·7) per 100 000 in Viet Nam to 3555·8 (2661·9-4715·0) per 100 000 in the Netherlands. Across SDI quintiles, DALY rates ranged from 1853·0 (1352·1-2469·3) per 100 000 for middle SDI to 2184·1 (1606·1-2890·3) per 100 000 for high SDI. A significant health burden was imposed by mental disorders in all countries and territories in 2023, irrespective of the health resources available. In some instances, this burden has increased over time and is unevenly distributed across populations. Stronger surveillance systems, particularly in low-income and middle-income countries, are required. Additionally, we need more coordinated and inclusive policies to reduce the burden through early treatment and prevention, tailored to sex and age differences across locations. Responding to the mental health needs of our global population, especially those most vulnerable, is an obligation, not a choice. Gates Foundation, Queensland Health, and University of Queensland.
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.
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.
Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as non-alcoholic fatty liver disease, is one of the most prevalent liver diseases globally, contributing to both economic and health-related challenges. We aimed to evaluate the global, regional, and national burden of MASLD from 1990 to 2023, quantify the contribution of identified modifiable risk factors, and project future prevalence up to the year 2050. Estimates of MASLD prevalence and disability-adjusted life-years (DALYs) were produced by age, sex, region, Socio-demographic Index (SDI), and Healthcare Access and Quality (HAQ) index across 204 countries and territories from 1990 to 2023 as part of the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023. The MASLD burden attributable to three risk factors (smoking, high BMI, and high fasting plasma glucose) was assessed as part of the GBD comparative risk assessment. As a secondary analysis, we used these estimates to forecast MASLD prevalence up to 2050 using fasting plasma glucose and mean BMI as predictors. Furthermore, to examine the relative contributions of population ageing, population growth, and changes in MASLD prevalence rate to the forecasted changes in case counts from 2023 to 2050, we conducted a decomposition analysis. In 2023, approximately 1·3 billion (95% uncertainty interval [UI] 1·2 to 1·4) individuals were estimated to be living with MASLD (ie, 16·1% of the global population), with an age-standardised prevalence rate of 14 429·3 (95% UI 13 268·3 to 15 990·6) per 100 000 population, representing a percentage increase of 142·7% (95% UI 139·2 to 146·7) in crude numbers from 1990 (0·5 billion [0·5 to 0·6]) and of 28·6% (27·8 to 29·5) in the rate (11 217·2 [10 276·8 to 12 467·0] per 100 000 in 1990). An estimated 3·6 million (2·8 to 4·5) total DALYs were attributable to MASLD worldwide in 2023, corresponding to an age-standardised DALY rate of 39·6 (31·2 to 49·9) per 100 000 population. Despite a 116·3% (93·3 to 139·4) increase in crude DALYs (from 1·7 million [1·3 to 2·1] in 1990), its age-standardised estimate remained consistent (1·8% [-8·6 to 12·8]) from 1990 (38·9 [30·1 to 49·8] per 100 000) to 2023. There was substantial variation in age-standardised estimates across regions. North Africa and the Middle East had the highest prevalence rate (29 246·1 [26 848·3 to 32 048·7] per 100 000) and Andean Latin America showed the highest DALY rate (152·3 [114·1 to 194·7] per 100 000). By contrast, the high-income Asia Pacific region had the lowest prevalence rate (8653·5 [7923·7 to 9592·8] per 100 000) and east Asia had the lowest DALY rate (16·3 [13·5 to 19·9] per 100 000) among all GBD regions. North Africa and the Middle East showed disproportionately higher prevalence rates relative to other regions with similar SDIs. Lower SDIs and HAQs were associated with higher age-standardised DALY rates. The age-standardised prevalence rate was consistently higher in males (15 616·4 [14 349·2 to 17 263·3] per 100 000 people in 2023) than in females (13 245·2 [12 132·0 to 14 692·6] per 100 000 people), and peaked at age 80-84 years in both sexes. The number of MASLD prevalent cases was the highest in younger adults, peaking at age 35-39 years for males and age 55-59 years for females. Among the risk factors for MASLD, high fasting plasma glucose presented the largest contribution to the age-standardised DALY rate of total MASLD in 2023 (2·2 [95% UI 1·6 to 3·1] per 100 000 people), followed by high BMI (1·4 [0·6 to 2·4] per 100 000 people) and smoking (1·0 [0·3 to 1·8] per 100 000 people). Our forecasting model estimates that 1·8 billion (95% UI 1·6 to 2·0) individuals are likely to have MASLD by 2050, representing a 42·0% increase from 2023. The age-standardised prevalence rate is expected to increase to 15 774·9 (95% UI 14 613·9 to 17 336·2) per 100 000 people in 2050, representing an average annual percentage change of 0·3% (95% UI 0·3-0·3). According to our decomposition analysis, this change will be primarily due to population growth, particularly in sub-Saharan Africa and North Africa and Middle East, and less by population ageing or epidemiological change. With a global prevalence of 16·1% and approximately 1·3 billion people already living with MASLD in 2023, the condition has and will continue to have substantial health and economic impacts worldwide. An inverse association between the HAQ Index and age-standardised DALY rates suggests that countries with lower health-care access and quality might be less well positioned to manage the growing MASLD burden, underscoring the need for strengthened health-system capacity in these settings. Gates Foundation.
Dipeptidyl peptidase-1 (DPP1) inhibitors prevent the activation of neutrophil serine proteases and reduce exacerbations in people with bronchiectasis. We previously identified a novel effect of DPP1 inhibitors in reducing the neutrophil pseudoenzyme azurocidin-1 (AZU1). The aim of this study was to investigate the role of AZU1 in the pathophysiology of bronchiectasis. Sputum AZU1 concentrations were analysed in multiple cohorts. These consisted of two observational cohorts of patients with bronchiectasis (EMBARC BRIDGE cohort 1 and cohort 2) and a cohort of patients with chronic obstructive pulmonary disease (COPD; TARDIS COPD cohort) to correlate AZU1 with disease severity and exacerbations. A rhinovirus challenge study was used to investigate AZU1 concentrations during experimental exacerbation in COPD, people who smoke, and controls. A post-hoc analysis of the phase 2 WILLOW trial of brensocatib versus placebo was used to assess the effect of DPP1 inhibition on airway AZU1. Higher AZU1 sputum concentration was associated with increased bronchiectasis disease severity index (p<0·0001), decreased percentage predicted forced expiratory volume in 1 second (r=-0·4662, p<0·001), and increased exacerbation frequency (p<0·0019; EMBARC cohort 1, n=197). AZU1 was associated with radiological severity (Reiff score), symptoms (quality of life bronchiectasis respiratory symptom score), and bacterial infection (sputum microbiology and 16S microbiome alpha diversity; highest levels of AZU1 were found in airway samples with Pseudomonas aeruginosa; p<0·0001; EMBARC cohort 2, n=144). Bronchiectasis patients with bacterial and viral exacerbations had increased concentrations of AZU1 (p=0·0003; n=96). These findings were extended to COPD, in which AZU1 was related to COPD severity (COPD cohort, n=101), and in patients with COPD challenged with rhinovirus A16, AZU1 was increased at day 9 post-challenge (p<0·001; n=9). In-vitro AZU1 impaired ciliary function and epithelial integrity, suggesting a mechanism by which AZU1 drives disease pathogenesis. In a post-hoc analysis of the WILLOW trial, AZU1 was the most downregulated protein with brensocatib treatment (brensocatib 10 mg, n=71; brensocatib 25 mg, n=73; and placebo, n=71). Over 24 weeks, AZU1 was significantly reduced by DPP1 inhibition (p<0·0001). AZU1 was identified as a novel marker of disease severity in bronchiectasis, associated with bacterial infection and exacerbation, and targeted by DPP1 inhibition. EMBARC3 and Insmed.
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.
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. 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. 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%). 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. The Norwegian Research Council, the Nordic Cancer Union, the Norwegian Cancer Society, and the Health Fund of South-East Norway.
Chronic obstructive pulmonary disease (COPD) often coexists with sarcopenia, contributing to poorer exercise tolerance, quality of life, and prognosis. Although interest in this topic has increased, a comprehensive bibliometric overview is still lacking. English-language articles and reviews on COPD complicated with sarcopenia published between 2005 and 2025 were retrieved from the Web of Science Core Collection and Scopus. After screening and deduplication, bibliometric and visualisation analyses were conducted using bibliometrix/biblioshiny, VOSviewer, and CiteSpace to evaluate publication trends, major contributors, collaboration networks, co-citation patterns, and keyword evolution. A total of 922 publications from 421 journals were included. Output increased markedly over time, especially after 2018, peaking in 2025. The United States and China were the main contributors and major collaboration hubs, while several European countries showed strong international collaboration and high citation impact. Core journals included International Journal of Chronic Obstructive Pulmonary Disease, Journal of Cachexia, Sarcopenia and Muscle, and Clinical Nutrition. Co-citation analysis showed that the knowledge base was mainly supported by studies on COPD systemic effects and body composition, together with consensus documents on sarcopenia definition and grading. Research hotspots evolved from early work on weight loss, malnutrition, and muscle wasting to functional assessment and clinical outcomes, and more recently to interventions such as nutrition support, resistance training, and pulmonary rehabilitation, alongside emerging mechanistic themes including inflammation, oxidative stress, and metabolic abnormalities. Research on COPD complicated with sarcopenia has shifted from descriptive phenotypes to standardised assessment, functional outcomes, and clinical management. Future studies should strengthen multicentre longitudinal designs and multidisciplinary collaboration to better integrate mechanisms with clinical assessment and intervention.
Background and Objectives: Early identification of patients at risk for severe forms of acute cholangitis (AC) is crucial for guiding prompt therapeutic interventions. In addition to traditional biomarkers such as C-reactive protein (CRP), newer indices like the neutrophil-to-lymphocyte ratio (NLR) are cost-effective and easy-to-use diagnostic tools. In the context of limited evidence from Eastern European populations, this study aimed to compare the performance of NLR and CRP in identifying organ dysfunction-based severe presentation of acute cholangitis according to a modified TG18-derived classification. Materials and Methods: We conducted a retrospective study including patients admitted to Colentina Clinical Hospital between January 2021 and September 2025. Demographic, clinical, and laboratory data were collected from medical records, with a focus on admission inflammatory biomarkers: NLR and CRP. Symptom onset-to-presentation time was not recorded. Patients were stratified by disease severity according to a modified organ dysfunction-based severity classification, and comparative statistical analysis, including Receiver Operating Characteristic (ROC) curve analysis, was performed to assess the diagnostic performance and optimal cut-off values of both biomarkers for severe clinical presentation. Results: A total of 364 patients were included, with a median age of 68 years (IQR: 60-78), and a slight female predominance (55.5%). Of these, 231 were classified as non-severe and 133 as severe. Both CRP and NLR were significantly higher in severe cases (p = 0.042 and p = 0.018, respectively. Despite statistical significance, CRP showed limited discriminatory ability, whereas NLR showed only a marginal numerical advantage. ROC analysis showed poor discriminatory ability for both CRP (AUC = 0.564, 95% CI 0.503-0.624, p = 0.042) and NLR (AUC = 0.574, 95% CI 0.513-0.635, p = 0.018) in predicting severe AC incidence. The difference between AUCs was minimal (ΔAUC = 0.010, 95% CI -0.062 to 0.082, p = 0.78, DeLong test). Conclusions: Both CRP and NLR showed limited discriminatory performance in identifying organ dysfunction-based severe presentation of acute cholangitis. The small, non-significant difference between the two markers does not support a meaningful comparative advantage, and neither biomarker appears suitable for reliable early risk stratification on its own.
Clinical guidelines recommend regular colonoscopy surveillance for individuals at elevated risk for colorectal cancer (CRC). While colonoscopy surveillance is proven to reduce the incidence of CRC, colonoscopy is an invasive procedure that can impact patient-reported outcomes (PROs). Assessment of PROs is recommended as a key indicator of the quality of health service delivery. However, there is no standard set of PROs and PRO measures (PROMs) to be applied in individuals undergoing regular surveillance colonoscopy. The aim of this scoping review was to identify PROs and PROMs applied for this population. The review followed the Joanna Briggs Institute guidelines. Five databases were searched: Medline (OVID), Scopus, Web of Science, CINAHL, and PsycINFO (OVID). Data extracted included the PROs assessed, PROMs used, indications for surveillance colonoscopy, and assessment timepoints. 8684 studies were screened, and 91 were included. Eighteen PROs and 12 PROMs were identified. Abdominal discomfort (60%), abdominal pain (60%) and nausea (56%) were the most frequently collected PROs. PROs were predominantly assessed after bowel preparation/before colonoscopy (55%) and 1-2 days after colonoscopy (48%). Hospital Anxiety and Depression Scale (33.3%), Short Form-36 (33%), the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire 30-item (27%), and EQ-5D-5L (20%) were the most frequently used PROMs. There is variability in PROs and PROMs applied. This highlights the need for consensus on a standardised set of PROs to be assessed and PROMs to facilitate consistent and reliable data collection to better inform implementation and improve healthcare quality. The assessment of patient-reported outcomes is recommended as a key indicator of the quality of healthcare service delivery. Individuals at elevated risk for colorectal cancer need frequent colonoscopies and regular encounters with the health care system. Symptoms such as abdominal pain and vomiting are commonly reported in association with bowel preparation for colonoscopy, as well as complications following the procedure. It is therefore important to assess the patient-reported outcomes associated with colonoscopy in this population. However, there is a paucity of evidence on the standardised set of patient-reported outcomes to be assessed and patient-reported outcome measures to be applied. Our study identified the most frequently assessed patient-reported outcomes and the most frequently used measures. Notably, there was considerable variability in the patient-reported outcomes assessed and measures used, the timing of their assessment in relation to the colonoscopy procedure, as well as across different indications for surveillance colonoscopy. This shows the need to standardise patient-reported outcomes and measures to be applied in this population and at what timepoints. This will facilitate consistent and reliable data collection to better inform implementation and improve healthcare quality.
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.
Primary biliary cholangitis (PBC) is a liver disease frequently associated with extrahepatic manifestations. Although a relationship with kidney dysfunction has been reported, data about PBC and chronic kidney disease (CKD) are limited. We assessed the prevalence and incidence of CKD and identify associated risk factors in patients with PBC. This was a multicenter retrospective study involving 1058 consecutive PBC patients. The presence of metabolic comorbidities, including diabetes, hypertension, and dyslipidemia was collected. CKD was defined as eGFR < 60 mL/min/1.73 m2. Baseline CKD was found in 10% of patients. The number of metabolic factors was associated with progressively lower eGFR levels and higher rates of CKD. Hypertension[OR 2.77 (95%CI 1.60-4.82)], diabetes[OR 2.17(95%CI 1.13-4.18)], ALT[OR 0.92(95%CI 0.88-0.96)], albumin[OR 0.24(95%CI 0.13-0.43)], and platelets[OR 0.996(95%CI 0.992-0.999)] were associated with baseline CKD. CKD was associated with higher mortality (32.1% vs. 7.3%). Seven percent of patients developed CKD. Baseline FIB-4 was associated with CKD incidence: < 1.45: 3% (13/428), 1.45-3.25: 10.2% (31/303), > 3.25: 13.4% (11/82). Baseline eGFR values [OR 0.93(95%CI 0.90-0.96)], cirrhosis [OR 2.31(95%CI 1.09-4.88)], hypertension [OR 2.36 (95%CI 1.14-4.88)], and albumin [OR 0.31(95%CI 0.14-0.72)] were associated with CKD occurrence. Baseline eGFR values [OR 0.90 (95%CI 0.88-0.93)], hypertension at baseline [OR 2.01(95%CI 1.06-3.81)] and progression to cirrhosis [OR 4.50(95%CI 1.96-10.30)] were related to CKD incidence in non-cirrhotic patients. In the absence of comorbidities, maintaining treatment response after follow-up showed 0.9% of de novo CKD (vs. 8%). One of every ten PBC patients showed CKD, mainly related to metabolic factors (hypertension and diabetes), and advanced liver disease (albumin and platelets), increasing the risk of mortality. These conditions were also related to the CKD occurrence, even in non-cirrhotic patients.
Early detection is critical in pancreatic ductal adenocarcinoma (PDAC)-one of the most lethal malignancies due to its typically late diagnosis. In this study, we aimed to validate an epidemiological risk score (ERS) designed to identify individuals at increased risk of developing PDAC prior to the use of imaging or other diagnostic procedures. The ERS was constructed through a meta-analysis of 24 well-established epidemiological risk factors. We applied this score to a prospective cohort of 178 high-risk individuals with a family history of PDAC within the IMAGene project (ClinicalTrials.gov registration code: NCT06334458). To evaluate the predictive value of the ERS, all participants underwent whole-body or abdominal magnetic resonance imaging (MRI) and the findings were classified according to the Oncologically Relevant Findings Reporting and Data System criteria to identify and categorize lesions based on their malignant potential. External validation was conducted by using a subset of the UK Biobank (UKB) cohort (≈300 000 individuals), among whom 1648 were diagnosed with PDAC. Higher ERS values were associated with the presence of potentially malignant lesions on MRI. Both pancreatic and extra-pancreatic malignant lesions were more frequent among individuals with higher ERS scores (P = .01 and P = .02 respectively) compared with controls. External validation in PDAC cases within the UKB cohort confirmed these associations. Our findings support the integration of the ERS as a feasible, low-cost tool for PDAC risk stratification, with the potential to facilitate earlier detection and improve clinical outcomes.
Liver transplantation remains the definitive therapy for end-stage liver disease, yet Early Allograft Dysfunction (EAD) continues to challenge post-transplant outcomes. Several models have been developed to predict graft dysfunction and survival, including Olthoff's static definition, and three kinetic prediction scores: the Model for Early Allograft Function (MEAF), the Liver Graft Assessment Following Transplantation score (L-GrAFT), and the more recent Early Allograft Failure Simplified Estimation (EASE). While these scores have been validated in Western populations, data from Eastern Europe are limited. This retrospective study aimed to externally validate and compare these recipient-centred prediction models for EAD, Early Allograft Failure (EAF), and patient/graft survival in the Romanian national transplant program.Between January 2019 and May 2025, 281 adult recipients of donation-after-brain-death grafts at Fundeni Clinical Institute met inclusion criteria. EAD (Olthoff's definition) occurred in 79 patients (28.1%), while EAF (re-transplantation or death by POD 90) occurred in 27 patients (9.6%). The median recipient age was 52 years, with viral hepatitis representing the predominant aetiology. At 12 months, overall survival reached 86%. By Olthoff's criteria, survival was lower in EAD vs. non-EAD, though differences were not statistically significant. Risk stratification using L-GrAFT10 and EASE identified significant survival differences across patient groups, whereas MEAF stratification failed to reach significance. Among the models, EASE demonstrated the strongest predictive accuracy for both patient and graft survival at 3 and 6 months, outperforming Olthoff's classification. L-GrAFT10 showed the strongest association with mortality across strata, while MEAF provided robust prediction of EAD comparable to L-GrAFT10, with the advantage of relative computational simplicity.Findings confirm that established scores perform reliably within this Eastern European cohort, suggesting that regional differences in disease epidemiology do not diminish their predictive value. MEAF offered practical utility for early postoperative assessment of EAD, while EASE appeared to be the most accurate model for survival stratification. Broader multicentre studies - such as the ongoing global IMPROVEMENT study - remain necessary to optimize kinetic prediction models and guide clinical decision-making in liver transplantation.
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.
Esophageal adenocarcinoma (EAC) represents one of the most increasing malignancies in Western countries. The disease is multifactorial, involving modifiable risk factors and genetic susceptibility variants. These variants can be aggregated to a polygenic risk score (PRS) that reflects individual genetic risk. Investigation of the effects of lifestyle factors, PRS, and co-medication on EAC age at onset (AAO) is critical for shaping prevention strategies. A detailed questionnaire was used to assess pre-diagnostic exposure to lifestyle factors and clinical information from a large German EAC cohort. Linear regression analysis was performed to identify factors associated with EAC AAO in 1742 EAC patients. PRS was available for 1190 patients. Subgroup analyses were conducted to estimate the effects of the analyzed factors on AAO according to age group (early vs. late onset), sex, and prior diagnosis of Barrett's esophagus (BE). Earlier AAO was significantly associated with gastroesophageal reflux (GER), smoking and a higher PRS, whereas later AAO was associated with physical activity and higher consumption of fish and fruits. Among co-medication, combined use of proton pump inhibitors (PPIs) and acetylsalicylic acid (ASA) showed the most significant effect on AAO, whereas the use of PPIs and ASA alone showed weaker effects. This study represents the largest questionnaire-based analysis to date investigating factors influencing EAC development. Our findings show that the combined use of PPIs and ASA, both cost-effective medications, is associated with delayed EAC onset. In addition, lifestyle and genetics contribute to EAC AAO.
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.
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.
Monoclonal gammopathy of undetermined significance (MGUS) is a necessary precursor condition to multiple myeloma (MM). Given the role of autophagy in modulating MM risk, we investigated whether genetic variation in autophagy-related genes influences susceptibility to MGUS. We analyzed the association of 34,042 common autophagy-related single nucleotide polymorphisms (SNPs) with MGUS across six independent cohorts, five from Europe and one from North America, comprising 2317 MGUS cases and 282,358 controls. We also assessed their impact on immune parameters, including absolute counts of 91 blood-derived immune cell subsets and 103 circulating immunological proteins. Meta-analysis revealed a genome-wide significant association between the ULK4rs6599175C allele and increased MGUS risk (p = 3.35 × 10-8). Carriers of this allele showed reduced counts of memory B cell subsets (IgM+CD38+CD27+ and IgD+IgM+CD27+; p = .0038 and p = .0056, respectively) and natural effector B cells (CD24+CD38+IgD+IgM+ cells; p = .0060). Although these associations were not statistically significant after multiple testing correction, they suggest a role of ULK4 in early B-cell differentiation. Additionally, the CDKN2Ars2811710 variant showed a suggestive association with MGUS risk (p = 2.17 × 10-4), affecting transcription factor binding involved in B-cell proliferation and differentiation, although it lacked association with immune markers. In conclusion, we confirm a genome-wide significant association of the ULK4 locus and MGUS risk, supporting its role in early B-cell differentiation, and identify CDKN2A as a candidate susceptibility locus warranting further investigation.