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Abstract KRAS-dependent acinar-to-ductal metaplasia (ADM) is a fundamental step in the development of pancreatic ductal adenocarcinoma (PDAC), but the involvement of cell death pathways remains unclear. Here, we show that key regulators of programmed cell death (PCD) become upregulated during KRAS-driven ADM, thereby priming transdifferentiated cells to death. Using transgenic mice and primary cell and organoid cultures, we show that transforming growth factor (TGF)-β-activated kinase 1 (TAK1), a kinase regulating cell survival and inflammatory pathways, prevents the elimination of transdifferentiated cells through receptor-interacting protein kinase 1 (RIPK1)-mediated apoptosis and necroptosis, enabling PDAC development. Accordingly, pharmacological inhibition of TAK1 induces PCD in patient-derived PDAC organoids. Importantly, cell death induction via TAK1 inhibition does not appear to elicit an overt injury-associated inflammatory response. Collectively, these findings suggest that TAK1 supports cellular plasticity by suppressing spontaneous PCD activation during ADM, representing a promising pharmacological target for the prevention and treatment of PDAC.

Abstract Aims Nocturnal hypoxaemic burden, quantified as time spent with oxygen saturation below 90% (T90), is an established independent predictor of mortality in heart failure (HF) with reduced ejection fraction. The prognostic value of T90 in HF with preserved ejection fraction (HFpEF) is unknown. This study aims to determine the association of T90 with adverse outcomes in HFpEF. Methods and results One hundred twenty‐six patients prospectively included from our specialised HFpEF outpatient clinic underwent ambulatory home sleep monitoring to obtain oximetry data, including T90. We investigated the association between T90 and a composite endpoint of HF hospitalisations or all‐cause mortality. Nocturnal hypoxaemic burden in this HFpEF population was high, with a median T90 of 13.7 min. In only 10 patients (7.9%), oxygen saturation was at no time point below 90%. After median 34 months [IQR 18.4–52.0] of follow‐up, 32 patients (25%) reached the composite endpoint. T90 was significantly associated with the composite endpoint, also after adjusting for potential confounders (HR 1.004 (95% CI 1.001–1.007, P = 0.019) per 1 min T90 increase or HR 1.265 (95% CI 1.061–1.488) per 1 h T90 increase). Patients with HFpEF in the highest T90 tertile (T90 ≥ 31.4 min) had a significantly higher event rate compared to patients in the lowest two T90 tertiles, with 19 (45%) versus 13 (15%) events, respectively (P

Background: In Europe, the health situation is primarily influenced by non-communicable diseases. Comparable information on key indicators for the European region can highlight potential areas for improvement in prevention and care. Method: Based on EHIS 3, age-standardised prevalences of three disease groups and two indicators of self-assessed health among those affected were presented for Germany (n = 22,708) and the average of 29 European countries (n = 301,960). Results: The disease prevalence estimates in Germany were higher compared to the European average: diabetes 8.4 % vs. 7.4 %, cardiovascular diseases 6.8 % vs. 5.7 %, chronic respiratory diseases 11.4 % vs. 7.9 %. Likewise, the proportion with self-assessed very good or good general health among those affected was also higher in Germany (diabetes 35.8 % vs. 30.7 %, cardiovascular diseases 25.3 % vs. 18.9 %, chronic respiratory diseases 44.7 % vs. 41.9 %). For limitations in everyday activities, higher proportions were found in Germany for diabetes (65.6 % vs. 60.6 %) and chronic respiratory diseases (64.5 % vs. 57.6 %). Germany showed similar gender-, age- and education-specific differences for disease prevalence, but in part less pronounced differences for the indicators of self-assessed health than the European average. Conclusions: Further analysis of the differences for the indicators considered between Germany and the European average and the possible underlying factors, such as differences in prevention, diagnosis, disease severity and care, is required. The educational inequalities observed across Europe suggest considerable potential for promoting health equity.

The effects of Content and Language Integrated Learning (CLIL) on students' foreign language skill development have been overestimated by previous studies, as most studies needed to have considered selection and preparation effects appropriately. We used complete survey data from a 1996-2003 cohort to investigate English skill development of N = 332 German CLIL and N = 6,401 non-CLIL grammar school students from grade seven (M = 12.64, SD = 0.60) to grade eleven (M = 16.72, SD = 0.70). We found selection effects for prior achievement, sociodemographic variables, and cognitive abilities. After propensity score matching, data revealed significant preparation effects of additional English lessons for the CLIL students. When controlling selection and preparation effects, CLIL compensated for the assumed fading out-effect but did not contribute significant added value measured by a C-test. We commend to include selection and preparation effects when analyzing CLIL effects.

Multilingualism is often associated with advantages for acquiring additional languages. Theoretical approaches explain these advantages by assuming a Common Underlying Proficiency or a Metalinguistic Awareness. At the State Europe School in Berlin, students from different language backgrounds receive instruction in German and a partner language according to two-way immersion (TWI). It is unclear how this bilingual instruction affects the acquisition of a third language. We examined the English proficiency of N = 656 TWI sixth-grade students and N = 739 mainstream students via a C-test. Multiple regression analyses revealed that TWI students exhibited higher English proficiency than mainstream students despite having received less English instruction. The results showed additional effects of German- and partner-language reading skills. The findings support the assumption of TWI programs that the use of two languages of instruction fosters third language acquisition.

Animal studies have pointed at the liver as a hotspot for per- and polyfluoroalkyl substances (PFAS) accumulation and toxicity; however, these findings have not been replicated in human populations. We measured concentrations of seven PFAS in matched liver and plasma samples collected at the time of bariatric surgery from 64 adolescents in the Teen-Longitudinal Assessment of Bariatric Surgery (Teen-LABS) study. Liver:plasma concentration ratios were perfectly explained (r2 > 0.99) in a multilinear regression (MLR) model based on toxicokinetic (TK) descriptors consisting of binding to tissue constituents and membrane permeabilities. Of the seven matched plasma and liver PFAS concentrations compared in this study, the liver:plasma concentration ratio of perfluoroheptanoic acid (PFHpA) was considerably higher than the liver:plasma concentration ratio of other PFAS congeners. Comparing the MLR model with an equilibrium mass balance model (MBM) suggested that complex kinetic transport processes are driving the unexpectedly high liver:plasma concentration ratio of PFHpA. Intratissue MBM modeling pointed to membrane lipids as the tissue constituents that drive the liver accumulation of long-chain, hydrophobic PFAS, whereas albumin binding of hydrophobic PFAS dominated PFAS distribution in plasma. The liver:plasma concentration data set, empirical MLR model, and mechanistic MBM modeling allow the prediction of liver from plasma concentrations measured in human cohort studies. Our study demonstrates that combining biomonitoring data with mechanistic modeling can identify underlying mechanisms of internal distribution and specific target organ toxicity of PFAS in humans.

Background & Aims: Hepatocellular carcinoma (HCC) is the third-leading and fastest rising cause of cancer-related death worldwide. The discovery and preclinical development of compounds targeting HCC are hampered by the absence of authentic tractable systems recapitulating the heterogeneity of HCC tumors in patients and the tumor microenvironment (TME). Methods: We established a novel and simple patient-derived multicellular tumor spheroid model based on clinical HCC tumor tissues, processed using enzymatic and mechanical dissociation. After quality controls, 22 HCC tissues and 17 HCC sera were selected for tumor spheroid generation and perturbation studies. Cells were grown in 3D in optimized medium in the presence of patient serum. Characterization of the tumor spheroid cell populations was performed by flow cytometry, immunohistochemistry (IHC), and functional assays. As a proof of concept, we treated patient-derived spheroids with FDA-approved anti-HCC compounds. Results: The model was successfully established independently from cancer etiology and grade from 22 HCC tissues. The use of serum from patients with HCC was essential for tumor spheroid generation, TME function, and maintenance of cell viability. The tumor spheroids comprised the main cell compartments, including epithelial cancer cells, as well as all major cell populations of the TME [i.e. cancer-associated fibroblasts (CAFs), macrophages, T cells, and endothelial cells]. Tumor spheroids reflected HCC heterogeneity, including variability in cell type proportions and TME, and mimicked the original tumor features. Moreover, differential responses to FDA-approved anti-HCC drugs were observed between the donors, as observed in patients. Conclusions: This patient HCC serum-tumor spheroid model provides novel opportunities for drug discovery and development as well as mechanism-of-action studies including compounds targeting the TME. This model will likely contribute to improve the therapeutic outcomes for patients with HCC. Impact and implications:: HCC is a leading and fast-rising cause of cancer-related death worldwide. Despite approval of novel therapies, the outcome of advanced HCC remains unsatisfactory. By developing a novel patient-derived tumor spheroid model recapitulating tumor heterogeneity and microenvironment, we provide new opportunities for HCC drug development and analysis of mechanism of action in authentic patient tissues. The application of the patient-derived tumor spheroids combined with other HCC models will likely contribute to drug development and to improve the outcome of patients with HCC.

Objective Impaired hepatic expression of protein tyrosine phosphatase delta (PTPRD) is associated with increased STAT3 transcriptional activity and reduced survival from hepatocellular carcinoma in patients with chronic hepatitis C virus infection. However, the PTPRD-expressing hepatic cell types, signalling pathways responsive to PTPRD and their role in non-viral liver disease are largely unknown.Methods We studied PTPRD expression in single-cell and bulk liver transcriptomic data from mice and humans, and established a Ptprd-deficient mouse model for metabolic dysfunction-associated steatohepatitis (MASH). Identified pathways were validated by perturbation studies in human hepatocytes and PTPRD substrates by pull-down assays. The clinical relevance was further explored in a cohort with metabolic disease by ranking patients according to PTPRD expression and analysing its association with metabolic disease markers.Results The analysis of individuals ranked according to PTPRD expression and Ptprd-deficient mice, showed that PTPRD levels were associated with hepatic glucose/lipid signalling and peroxisome function. Hepatic PTPRD expression is impaired in aetiologies of chronic liver diseases that are associated with metabolic disease. We further validated PTPRD as a STAT3 phosphatase in the liver, acting as a regulator of peroxisomal fatty acid metabolism. During MASH, low PTPRD led to increased liver steatosis in Ptprd+/− mice and a pronounced unfolded protein response, which impacts insulin signalling. Accordingly, silencing of PTPRD blunted insulin-induced AKT phosphorylation. Patients with obesity and low hepatic PTPRD expression exhibit increased levels of metabolic risk factors.Conclusion Our data revealed an important regulatory role of the hepatic PTPRD-STAT3 axis in maintaining glucose/lipid homeostasis, which is recapitulated in clinical manifestations of metabolic liver disease.

IntroductionAnxiety and depression are major causes of disability in Arab countries, yet resources for mental health services are insufficient. Mobile devices may improve mental health care delivery (mental m-Health), but the Arab region's mental m-Health app landscape remains under-documented. This study aims to systematically assess the features, quality, and digital safety of mental m-Health apps available in the Arab marketplace. We also contrast a set of recommended Australian apps to benchmark current strategies and evidence-based practices and suggest areas for improvement in Arabic apps.MethodsFifteen Arab country-specific iOS Apple Stores and an Android Google Play Store were searched. Apps that met the inclusion criteria were downloaded and evaluated using the Mobile App Rating Scale (MARS) and the Mobile App Development and Assessment Guide (MAG).ResultsTwenty-two apps met the inclusion criteria. The majority of apps showed no evidence of mental health experts being involved in the app design processes. Most apps offered real-time communication with specialists through video, text, or audio calls rather than evidence-based self-help techniques. Standardized quality assessment showed low scores for design features related to engagement, information, safety, security, privacy, usability, transparency, and technical support. In comparison to apps available in Australia, Arabic apps did not include evidence-based interventions like CBT, self-help tools and crisis-specific resources, including a suicide support hotline and emergency numbers.DiscussionIn conclusion, dedicated frameworks and strategies are required to facilitate the effective development, validation, and uptake of Arabic mental mHealth apps. Involving end users and healthcare professionals in the design process may help improve app quality, dependability, and efficacy.

Aging is associated with changes in circulating levels of various molecules, some of which remain undefined. We find that concentrations of circulating taurine decline with aging in mice, monkeys, and humans. A reversal of this decline through taurine supplementation increased the health span (the period of healthy living) and life span in mice and health span in monkeys. Mechanistically, taurine reduced cellular senescence, protected against telomerase deficiency, suppressed mitochondrial dysfunction, decreased DNA damage, and attenuated inflammaging. In humans, lower taurine concentrations correlated with several age-related diseases and taurine concentrations increased after acute endurance exercise. Thus, taurine deficiency may be a driver of aging because its reversal increases health span in worms, rodents, and primates and life span in worms and rodents. Clinical trials in humans seem warranted to test whether taurine deficiency might drive aging in humans.

Abstract Background Proliferating cancer cells shift their metabolism towards glycolysis, even in the presence of oxygen, to especially generate glycolytic intermediates as substrates for anabolic reactions. We hypothesize that a similar metabolic remodelling occurs during skeletal muscle hypertrophy. Methods We used mass spectrometry in hypertrophying C2C12 myotubes in vitro and plantaris mouse muscle in vivo and assessed metabolomic changes and the incorporation of the [U‐13C6]glucose tracer. We performed enzyme inhibition of the key serine synthesis pathway enzyme phosphoglycerate dehydrogenase (Phgdh) for further mechanistic analysis and conducted a systematic review to align any changes in metabolomics during muscle growth with published findings. Finally, the UK Biobank was used to link the findings to population level. Results The metabolomics analysis in myotubes revealed insulin‐like growth factor‐1 (IGF‐1)‐induced altered metabolite concentrations in anabolic pathways such as pentose phosphate (ribose‐5‐phosphate/ribulose‐5‐phosphate: +40%; P = 0.01) and serine synthesis pathway (serine: −36.8%; P = 0.009). Like the hypertrophy stimulation with IGF‐1 in myotubes in vitro, the concentration of the dipeptide l‐carnosine was decreased by 26.6% (P = 0.001) during skeletal muscle growth in vivo. However, phosphorylated sugar (glucose‐6‐phosphate, fructose‐6‐phosphate or glucose‐1‐phosphate) decreased by 32.2% (P = 0.004) in the overloaded muscle in vivo while increasing in the IGF‐1‐stimulated myotubes in vitro. The systematic review revealed that 10 metabolites linked to muscle hypertrophy were directly associated with glycolysis and its interconnected anabolic pathways. We demonstrated that labelled carbon from [U‐13C6]glucose is increasingly incorporated by ~13% (P = 0.001) into the non‐essential amino acids in hypertrophying myotubes, which is accompanied by an increased depletion of media serine (P = 0.006). The inhibition of Phgdh suppressed muscle protein synthesis in growing myotubes by 58.1% (P

Background: The nationwide study German Health Update (GEDA) 2021/2022-Diabetes was conducted to assess the current healthcare and health situation of adults with diabetes in Germany. Methods: GEDA 2021/2022-Diabetes comprises a sample of adults with diagnosed diabetes from the general population. The analysis focuses on adults aged 45 years and over with type 2 diabetes (N = 1,448) and provides selected indicators on diabetes care as well as mental, social and general health. Results: 87.5 % of participants aged 45 years and over with type 2 diabetes are treated with blood glucose-lowering medication. 36.5 % receive insulin alone or in combination with other antidiabetics; 0.7 % use an insulin pump. Almost 96 % had an HbA1c measurement in the last year and about two thirds each report annual foot and eye examinations, participation in a diabetes self-management education programme and self-monitoring of their feet and of blood glucose (12.0 % with continuous glucose monitoring). On average, the quality of diabetes care is perceived as moderate. 23.8 % rate their mental health as excellent/very good. More than a tenth each have anxiety or depressive symptoms and feelings of loneliness. Half rate their general health as very good/good. Conclusions: There is a potential for improvement in the quality of diabetes care and the mental and physical health of adults with type 2 diabetes.

Background: Migration-related factors, such as language barriers, can be relevant to the risk, healthcare and complications of type 2 diabetes in people with a history of migration. Diabetes-related data from people with selected citizenships were analysed on the basis of the nationwide survey German Health Update: Fokus (GEDA Fokus). Methods: The diabetes risk of persons without diabetes (n = 4,698, 18 – 79 years), key figures on healthcare and secondary diseases of persons with type 2 diabetes (n = 326, 45 – 79 years) and on concomitant diseases (n = 326 with type 2 diabetes compared to n = 2,018 without diabetes, 45 – 79 years) were stratified according to sociodemographic and migration-related characteristics. Results: Better German language proficiency is associated with a lower risk of diabetes. Diabetes-related organ complications are observed more frequently in persons who report experiences of discrimination in the health or care sector. Both persons with and without diabetes are more likely to have depressive symptoms when they reported experiences of discrimination. A stronger sense of belonging to the society in Germany is associated with reporting depressive symptoms less often in people without diabetes, but not in people with type 2 diabetes. Conclusions: The differences according to migration-related characteristics indicate a need for improvement in the prevention and care of type 2 diabetes. Migration-sensitive indicators should be integrated into the surveillance of diabetes.

Agricultural land use and management fundamentally impacts the condition of natural resources like waterbodies, soils, and biodiversity. Modelling the anthropogenic effects on those resources over time requires detailed knowledge of the temporal and spatial distribution of crops. However, currently available crop type maps for Europe either lack the required spatial resolution or the temporal and spatial coverage. We develop and apply a probabilistic, spatially explicit crop type mapping approach that is suitable for ex-post and ex-ante modelling. The approach allows to quantify epistemic and aleatoric uncertainty related to estimated crop shares by providing an ensemble of maps. We implement the method for the EU-28 for the years 2010 – 2020, distinguishing between 28 different crop types at 1 km resolution. Based on a model of the data generating process that conceptually links field-, grid cell- and region-level crop acreages, our approach considers soil, climate, and topography information, as well as administrative data. The validation with ground-truthing data for France indicates that the generated crop type maps are plausible. The provided uncertainty intervals capture differences in uncertainty across space and time and correctly identify grid cells and crops where estimations are less precise. The generated maps constitute a unique data product of high practical value, e.g., for agri-environmental modelling applications. We see additional potential in using the approach to disaggregate the regional or national predictions of socio-economic ex-ante prediction models.

Background & Aims: Chronic HBV infection is the leading cause of liver disease and of hepatocellular carcinoma. The improvement of antiviral therapy remains an unmet medical need. Capsid assembly modulators (CAMs) target the HBV core antigen (HBc) and inhibit HBV replication. Although CAM-A compounds are well-known inducers of aberrant viral capsid aggregates, their mechanisms of action in HBV-hepatocyte interactions are poorly understood. Recently, we demonstrated that CAM-A molecules lead to a sustained reduction of HBsAg in the serum of HBV replicating mice and induce HBc aggregation in the nucleus of HBc-expressing cells leading to cell death. Methods: The mechanism of action by which CAM-A compounds induce cell death was investigated using an HBV infection model, HBc-overexpressing HepG2-NTCP cells, primary human hepatocytes, and HBV replicating HepAD38 cells. Results: We first confirmed the decrease in HBsAg levels associated with CAM-A treatment and the induction of cell toxicity in HBV-infected differentiated HepaRG cells. Next, we showed that CAM-A-mediated nuclear aggregation of HBc was associated with cell death through the activation of apoptosis. Transcriptomic analysis was used to investigate the mechanism of action driving this phenotype. CAM-A-induced HBc nuclear aggregation led to the upregulation of ANXA1 expression, a documented driver of apoptosis. Finally, silencing of ANXA1 expression delayed cell death and apoptosis in CAM-A-treated cells, confirming its direct involvement in CAM-A-induced cell death. Conclusions: Our results unravel a previously undiscovered mechanism of action involving CAM-As and open the door to new therapeutic strategies involving CAM to achieve a functional cure in patients with chronic infections. Impact and implications:: Chronic HBV infection is a global health threat. To date, no treatment achieves viral clearance in chronically infected patients. In this study, we characterized a new mechanism of action of an antiviral molecule targeting the assembly of the viral capsid (CAM). The study demonstrated that a CAM subtype, CAM-A-induced formation of aberrant structures from HBV core protein aggregates in the nucleus leading to cell death by ANXA1-driven apoptosis. Thus, CAM-A treatment may lead to the specific elimination of HBV-infected cells by apoptosis, paving the way to novel therapeutic strategies for viral cure.

Background: Per-and polyfluoroalkyl substances (PFAS) contamination may disrupt sleep through disrupted metabolic and immune functions. The study aims to investigate the association and potential mechanism between PFAS and sleep. Methods: We included 136 young adults recruited between 2014-2018 and 76 were re-assessed between 2020-2022. Additional 8 participants only had complete data between 2020-2022. Plasma PFAS (PFOS, PFOA, PFHxS, PFHpS, PFPeS, PFNA, PFDA) were measured at both visits using liquid-chromatography high-resolution mass spectrometry. Plasma proteins were measured by Olink® Explore 384 Cardiometabolic and Inflammation Panel I. Sleep duration was self-reported at both visits along with follow-up sleep disturbance and sleep-related impairment using validated instruments. We utilized multiple linear regression to explore the association between individual PFAS (in tertile) and these sleep outcomes. PFAS associated with sleep outcomes were subjected to computational toxicology analysis using the Comparative Toxicogenomics Database and Toxicology in the 21st Century database to identify potential genetic links between them. Mediation analysis using proteomic data was then performed to confirm the findings from computational toxicology analysis. Results: At baseline, one tertile increase in PFDA was associated with 0.39 (95 % CI: 0.05, 0.73) hours of shorter nightly sleep duration, and, at follow-up, PFHxS and PFOA were associated with 0.39 (95 % CI: 0.05, 0.72) and 0.32 (95 % CI: 0.01, 0.63) hours shorter sleep duration, respectively. One tertile increase in PFOS exposure was associated with a 2.99-point increase in sleep disturbance scores (95 % CI: 0.67, 5.31) and a 3.35-point increase in sleep-related impairment scores (95 % CI: 0.51, 6.20). Computational toxicology and mediation analyses identified potential mediating roles for several proteins in the PFAS-sleep associations, including 11-beta-dehydrogenase isozyme 1 (HSD11B1), cathepsin B (CTSB) and several immune system-related proteins. Conclusion: Future large scale epidemiological and mechanistic studies should confirm our findings and test effect measure modification of the associations by age.

Isocitrate dehydrogenase (IDH) mutant gliomas are the most common adult, malignant primary brain tumors diagnosed in patients younger than 50, constituting an important cause of morbidity and mortality. In recent years, there has been significant progress in understanding the molecular pathogenesis and biology of these tumors, sparking multiple efforts to improve their diagnosis and treatment. In this consensus review from the Society for Neuro-Oncology (SNO), the current diagnosis and management of IDH-mutant gliomas will be discussed. In addition, novel therapies, such as targeted molecular therapies and immunotherapies, will be reviewed. Current challenges and future directions for research will be discussed.

Vocational education and training (VET) is a common form of upper secondary school tracking in countries around the world. There are ongoing debates regarding the effects of this differentiation on academic and labor market outcomes; however, evidence on civic outcomes is lacking. Using a unique cohort study in Germany (N = 2461) and a doubly robust weighting approach with a rich set of baseline covariates to address selection bias, we estimated the effects of VET (relative to academic upper secondary school) on political interest, internal political efficacy, and intent to vote across 15 years of late adolescence and early adulthood. We estimated negative effects of VET on these civic outcomes, particularly as participants grew older. Implications for future research and VET policy are discussed.

This article examines the extent to which normative beliefs on acculturation constitute (a) individual resources and risk factors for adolescents facing developmental tasks and (b) institutional norms that define developmental milieus in secondary schools. To what extent do egalitarianism, multiculturalism, assimilationism, and segregationism help or hinder academic and psychosocial adjustment in mid-adolescence? We examined how both individually endorsed beliefs and socially shared beliefs at the 10th-grade cohort level relate to students' academic performance, educational and occupational aspirations, motivational and emotional attachment to school, self-esteem, and life satisfaction. Data came from a random sample of 15- to 17-year-olds in Berlin, Germany, assessed at the end of Grades 9 and 10 (N = 1,992). Multivariate analyses identified egalitarianism and multiculturalism as the most prevalent acculturation beliefs, forming a combined belief pattern that pairs recognition of equality with respect for diversity. At the individual level, this belief pattern was positively related to academic and psychosocial adjustment. Assimilationism beliefs were associated with higher motivational and emotional attachment to school in both minority and majority students. Segregationism beliefs were associated with higher self-esteem in all adolescents regardless of background, but with lower levels of academic performance in immigrant youth. At the grade cohort level, a single bipolar factor (egalitarianism/multiculturalism vs. assimilationism/segregationism) described the institutional diversity culture. An environment characterized by egalitarianism/multiculturalism beliefs was positively associated with motivational and emotional attachment to school but not related to academic adjustment or psychological well-being.