Search

International cooperation depends on conditional commitments between states. We examine the politics of conditional commitments in climate change using three experiments in ten major carbon-emitting countries. We specifically investigate whether public pledges of conditional action made by national governments increase public support for ambitious climate action in other countries. We find that only unconditional pledges increase public support for policy ambition in foreign countries. Additionally, countries seeking financial and technical transfers only gain foreign support for transfers when they combine conditional pledges with ambitious unconditional pledges. We also observe that the public in most countries only favors making part of their country’s climate pledge conditional on other countries’ actions when their home country makes an unconditional commitment at or above the average level necessary to prevent dangerous warming. Overall, public preferences are unconditionally aligned with addressing the climate problem. Conditional commitments are more aligned with increasing domestic support for climate policy than unlocking more ambitious settlements between countries.

Summary: Macrophages play crucial roles in organ-specific functions and homeostasis. In the adrenal gland, macrophages closely associate with sinusoidal capillaries in the aldosterone-producing zona glomerulosa. We demonstrate that macrophages preserve capillary specialization and modulate aldosterone secretion. Using macrophage-specific deletion of VEGF-A, single-cell transcriptomics, and functional phenotyping, we found that the loss of VEGF-A depletes PLVAP+ fenestrated endothelial cells in the zona glomerulosa, leading to increased basement membrane collagen IV deposition and subendothelial fibrosis. This results in increased aldosterone secretion, called “haptosecretagogue” signaling. Human aldosterone-producing adenomas also show capillary rarefaction and basement membrane thickening. Mice with myeloid cell-specific VEGF-A deletion exhibit elevated serum aldosterone, hypokalemia, and hypertension, mimicking primary aldosteronism. These findings underscore macrophage-to-endothelial cell signaling as essential for endothelial cell specialization, adrenal gland function, and blood pressure regulation, with broader implications for other endocrine organs.

Abstract Objectives Artificial intelligence (AI) has tremendous potential to help radiologists in daily clinical routine. However, a seamless, standardized, and time-efficient way of integrating AI into the radiology workflow is often lacking. This constrains the full potential of this technology. To address this, we developed a new reporting pipeline that enables automated pre-population of structured reports with results provided by AI tools. Methods Findings from a commercially available AI tool for chest X-ray pathology detection were sent to an IHE-MRRT-compliant structured reporting (SR) platform as DICOM SR elements and used to automatically pre-populate a chest X-ray SR template. Pre-populated AI results could be validated, altered, or deleted by radiologists accessing the SR template. We assessed the performance of this newly developed AI to SR pipeline by comparing reporting times and subjective report quality to reports created as free-text and conventional structured reports. Results Chest X-ray reports with the new pipeline could be created in significantly less time than free-text reports and conventional structured reports (mean reporting times: 66.8 s vs. 85.6 s and 85.8 s, respectively; both p

Flexible learning addresses students' needs for more flexibility and autonomy in shaping their learning process, and is often realised through online technologies in a blended learning design. While higher education institutions are increasingly considering replacing classroom time and offering more blended learning, current research is limited regarding its effectiveness and modifying design factors. This study analysed a flexible study programme with 133 courses in a blended learning design in different disciplines over more than 4 years with a mixed-methods approach. In the analysed flexible study programme, classroom instruction time was reduced by 51% and replaced with an online learning environment in a blended learning format (N students = 278). Student achievement was compared to the conventional study format (N students = 1068). The estimated summary effect size for the 133 blended learning courses analysed was close to, but not significantly different from, zero (d = - 0.0562, p = 0.3684). Although overall effectiveness was equivalent to the conventional study format, considerable variance in the effect sizes between the courses was observed. Based on the relative effect sizes of the courses and data from detailed analyses and surveys, heterogeneity can be explained by differences in the implementation quality of the educational design factors. Our results indicate that when implementing flexible study programmes in a blended learning design, particular attention should be paid to the following educational design principles: adequate course structure and guidance for students, activating learning tasks, stimulating interaction and social presence of teachers, and timely feedback on learning process and outcomes.

Throughout the last decades, engaging with cultural landscapes has been a scientific, social, ethical, political, and economic imperative that calls for novel theoretical approaches, effective strategies and, above all, participatory action. Facing this multifarious challenge, academic disciplines have to redefine their traditional methods and aims, and demonstrate an openness towards new and risky paths of scientific pursuits. The present paper arose from interdisciplinary cooperation between the humanities and social sciences with the main objective to explore the potential of cultural landscapes as resources for social innovation in rural regions, addressing issues such as out-migration of original inhabitants, unemployment, and an overaging population. Based on an overview of landscape semantics and theoretical approaches, the paper first analyzes (cultural) landscape and social innovation as applied concepts. In a second step, both disciplinary angles mingle into a joint approach. Moving from methodologies to challenges, the authors discuss the Social Grid Model, which allows for an integrated analysis of social networks, institutions, and cognitive frames. They also delve into the Structured Democratic Dialogue as a tool for the revitalization of ‘active’ and ‘inactive’ cultural landscapes by reinforcing the role of local communities. Finally, the authors investigate how such novel ideas for the promotion of tangible and intangible heritage in rural habitats can be employed by example of two intervention regions in Greece (Koumasa) and the People’s Republic of China (Honghe Hani Rice Terraces), and as part of an orchestrated collective action.

Abstract Endothelial cells (EC) are key players in vascular function, homeostasis and inflammation. EC show substantial heterogeneity due to inter-individual variability (e.g. sex-differences) and intra-individual differences as they originate from different organs or vessels. This variability may lead to different responsiveness to external stimuli. Here we compared the responsiveness of female human primary EC from the aorta (HAoEC) and coronary arteries (HCAEC) to Epidermal Growth Factor Receptor (EGFR) activation. EGFR is an important signal integration hub for vascular active substances with physiological and pathophysiological relevance. Our transcriptomic analysis suggested that EGFR activation differentially affects the inflammatory profiles of HAoEC and HCAEC, particularly by inducing a HCAEC-driven leukocyte attraction but a downregulation of adhesion molecule and chemoattractant expression in HAoEC. Experimental assessments of selected inflammation markers were performed to validate these predictions and the results confirmed a dual role of EGFR in these cells: its activation initiated an anti-inflammatory response in HAoEC but a pro-inflammatory one in HCAEC. Our study highlights that, although they are both arterial EC, female HAoEC and HCAEC are distinguishable with regard to the role of EGFR and its involvement in inflammation regulation, what may be relevant for vascular maintenance but also the pathogenesis of endothelial dysfunction.

Abstract Background Concurrent malignant brain tumors in patients with multiple sclerosis (MS) constitute a rare but paradigmatic phenomenon for studying neuroimmunological mechanisms from both molecular and clinical perspectives. Methods A multicenter cohort of 26 patients diagnosed with both primary brain tumors and multiple sclerosis was studied for disease localization, tumor treatment-related MS activity, and molecular characteristics specific for diffuse glioma in MS patients. Results MS neither predisposes nor protects from the development of gliomas. Patients with glioblastoma WHO grade 4 without isocitratdehydrogenase (IDH) mutations have a longstanding history of MS, whereas patients diagnosed with IDH-mutant astrocytoma WHO grade 2 receive multiple sclerosis diagnosis mostly at the same time or later. Concurrent MS is associated with a lesser extent of tumor resection and a worse prognosis in IDH-mutant glioma patients (PFS 32 vs. 64 months, p = 0.0206). When assessing tumor-intrinsic differences no distinct subgroup-defining methylation pattern is identified in gliomas of MS patients compared to other glioma samples. However, differential methylation of immune-related genetic loci including human leukocyte antigen locus on 6p21 and interleukin locus on 5q31 is found in MS patients vs. matched non-MS patients. In line, inflammatory disease activity increases in 42% of multiple sclerosis patients after brain tumor radiotherapy suggesting a susceptibility of multiple sclerosis brain tissue to pro-inflammatory stimuli such as ionizing radiation. Conclusions Concurrent low-grade gliomas should be considered in multiple sclerosis patients with slowly progressive, expansive T2/FLAIR lesions. Our findings of typically reduced extent of resection in MS patients and increased MS activity after radiation may inform future treatment decisions.

Abstract Purpose Kidney volume is important in the management of renal diseases. Unfortunately, the currently available, semi-automated kidney volume determination is time-consuming and prone to errors. Recent advances in its automation are promising but mostly require contrast-enhanced computed tomography (CT) scans. This study aimed at establishing an automated estimation of kidney volume in non-contrast, low-dose CT scans of patients with suspected urolithiasis. Methods The kidney segmentation process was automated with 2D Convolutional Neural Network (CNN) models trained on manually segmented 2D transverse images extracted from low-dose, unenhanced CT scans of 210 patients. The models’ segmentation accuracy was assessed using Dice Similarity Coefficient (DSC), for the overlap with manually-generated masks on a set of images not used in the training. Next, the models were applied to 22 previously unseen cases to segment kidney regions. The volume of each kidney was calculated from the product of voxel number and their volume in each segmented mask. Kidney volume results were then validated against results semi-automatically obtained by radiologists. Results The CNN-enabled kidney volume estimation took a mean of 32 s for both kidneys in a CT scan with an average of 1026 slices. The DSC was 0.91 and 0.86 and for left and right kidneys, respectively. Inter-rater variability had consistencies of ICC = 0.89 (right), 0.92 (left), and absolute agreements of ICC = 0.89 (right), 0.93 (left) between the CNN-enabled and semi-automated volume estimations. Conclusion In our work, we demonstrated that CNN-enabled kidney volume estimation is feasible and highly reproducible in low-dose, non-enhanced CT scans. Automatic segmentation can thereby quantitatively enhance radiological reports.

Abstract Background Women with pathogenic BRCA1 or BRCA2 variants are at high risk for breast and ovarian cancer. Preventive options include risk-reducing breast and ovarian surgeries and intensified breast surveillance. However, individual decision-making is often associated with decisional conflicts. Two evidence-based decision aids have recently been developed for these women (healthy or with unilateral breast cancer) for the German context to support them in their decision-making process. This study evaluated their effectiveness. Methods In a randomized controlled study, women (aged 18–70 years) with pathogenic BRCA1 or BRCA2 variants were randomly assigned 1:1 to the intervention (IG, n = 230) or control (CG, n = 220) group. All participants received usual care. After baseline survey (t0), IG participants additionally received the DAs. Follow-up surveys were at three (t1) and six (t2) months. Primary outcome was decisional conflict at t1. Secondary analyses included decision status, decision regret, knowledge on risks and preventive options, self-reported psychological symptoms, acceptability of DAs, and preparation for decision-making. Results Of 450 women recruited, 417 completed t0, 398 completed t1 and 386 completed t2. Compared to CG, IG participants had lower decisional conflict scores at t1 (p = 0.049) and t2 (p = 0.006) and higher scores for knowledge (p = 0.004), acceptability (p = 0.000), and preparation for decision-making (p

Abstract Introduction Diffuse midline gliomas (DMG) are universally lethal central nervous system tumors that carry almost unanimously the clonal driver mutation histone-3 K27M (H3K27M). The single amino acid substitution of lysine to methionine harbors a neoantigen that is presented in tumor tissue. The long peptide vaccine H3K27M-vac targeting this major histocompatibility complex class II (MHC class II)-restricted neoantigen induces mutation-specific immune responses that suppress the growth of H3K27M+ flank tumors in an MHC-humanized rodent model. Methods INTERCEPT H3 is a non-controlled open label, single arm, multicenter national phase 1 trial to assess safety, tolerability and immunogenicity of H3K27M-vac in combination with standard radiotherapy and the immune checkpoint inhibitor atezolizumab (ATE). 15 adult patients with newly diagnosed K27M-mutant histone-3.1 (H3.1K27M) or histone-3.3 (H3.3K27M) DMG will be enrolled in this trial. The 27mer peptide vaccine H3K27M-vac will be administered concomitantly to standard radiotherapy (RT) followed by combinatorial treatment with the programmed death‐ligand 1 (PD-L1) targeting antibody ATE. The first three vaccines will be administered bi-weekly (q2w) followed by a dose at the beginning of recovery after RT and six-weekly administrations of doses 5 to 11 thereafter. In a safety lead-in, the first three patients (pts. 1–3) will be enrolled sequentially. Perspective H3K27M-vac is a neoepitope targeting long peptide vaccine derived from the clonal driver mutation H3K27M in DMG. The INTERCEPT H3 trial aims at demonstrating (1) safety and (2) immunogenicity of repeated fixed dose vaccinations of H3K27M-vac administered with RT and ATE in adult patients with newly diagnosed H3K27M-mutant DMG. Trial registration NCT04808245.

Abstract Background Written medical examinations consist of multiple-choice questions and/or free-text answers. The latter require manual evaluation and rating, which is time-consuming and potentially error-prone. We tested whether natural language processing (NLP) can be used to automatically analyze free-text answers to support the review process. Methods The European Board of Radiology of the European Society of Radiology provided representative datasets comprising sample questions, answer keys, participant answers, and reviewer markings from European Diploma in Radiology examinations. Three free-text questions with the highest number of corresponding answers were selected: Questions 1 and 2 were “unstructured” and required a typical free-text answer whereas question 3 was “structured” and offered a selection of predefined wordings/phrases for participants to use in their free-text answer. The NLP engine was designed using word lists, rule-based synonyms, and decision tree learning based on the answer keys and its performance tested against the gold standard of reviewer markings. Results After implementing the NLP approach in Python, F1 scores were calculated as a measure of NLP performance: 0.26 (unstructured question 1, n = 96), 0.33 (unstructured question 2, n = 327), and 0.5 (more structured question, n = 111). The respective precision/recall values were 0.26/0.27, 0.4/0.32, and 0.62/0.55. Conclusion This study showed the successful design of an NLP-based approach for automatic evaluation of free-text answers in the EDiR examination. Thus, as a future field of application, NLP could work as a decision-support system for reviewers and support the design of examinations being adjusted to the requirements of an automated, NLP-based review process. Clinical relevance statement Natural language processing can be successfully used to automatically evaluate free-text answers, performing better with more structured question-answer formats. Furthermore, this study provides a baseline for further work applying, e.g., more elaborated NLP approaches/large language models. Key points • Free-text answers require manual evaluation, which is time-consuming and potentially error-prone. • We developed a simple NLP-based approach — requiring only minimal effort/modeling — to automatically analyze and mark free-text answers. • Our NLP engine has the potential to support the manual evaluation process. • NLP performance is better on a more structured question-answer format. Graphical Abstract

Background and objectiveObtaining informed consent in neonatal emergency research is challenging. The aim of this study was to assess parental perceptions of informed consent following participation in a clinical trial in neonatal emergency care.MethodsThis was a supplementary analysis of a randomised controlled trial comparing video and direct laryngoscopy for neonatal endotracheal intubation in the delivery room and neonatal intensive care unit. After obtaining informed consent for the clinical trial, parents were asked to answer a series of self-administered questions about their perceptions of clinical trial participation and the consent process. Informed consent had been given either before birth, after birth but before inclusion in the trial, or after inclusion in the trial.ResultsWe received responses from 33 mothers and 27 fathers (n = 60) of the 63 preterm and term infants who participated in the study. Fifty-three (89.8%, n = 59) parents agreed that infants should participate in clinical trials, and 51 (85%, n = 60) parents agreed that parents should be asked for informed consent. Fifty-three (89.8%, n = 59) parents felt that their infant's participation in this particular trial would be beneficial. Fifty-two (86.7%, n = 60) parents felt that the informed consent process was satisfactory. One parent (100%, n = 1) approached before birth, 23 parents (82.1%, n = 28) approached after birth but before enrolment and 26 (83.9%, n = 31) parents approached after enrolment were satisfied with the timing of the consent process. Eight (13.3%, n = 60) parents felt some pressure to provide informed consent. Of these, two (25%) were approached before enrolment and six (75%) were approached after enrolment.ConclusionParents valued their infant's participation in an emergency neonatal clinical trial and considered it important to be asked for consent. In this study, it seemed less important whether consent was obtained before or after the intervention. Future studies may need to investigate which form of consent is most acceptable to parents for the individual study in question.

Macroalgae are considered healthy food ingredients due to their content in numerous bioactive compounds, and the traditional use of whole macroalgae in Asian cuisine suggests a contribution to longevity. Although much information is available about the bioactivity of pure algal compounds, such as different polyphenols and polysaccharides, documentation of potential effects of whole macroalgae as part of Western diets is limited. Lifestyle- and age-related diseases, which have a high impact on population health, are closely connected to underlying chronic inflammation. Therefore, we have studied crude extracts of green (Ulva fenestrata) and brown (Saccharina latissima) macroalgae, as two of the most promising food macroalgae in the Nordic countries for their effect on inflammation in vitro. Human macrophage-like reporter THP-1 cells were treated with macroalgae extracts and stimulated with lipopolysaccharide (LPS) to induce inflammatory signalling. Effects of the macroalgae extracts were assessed on transcription factor activity of NF-κB and IRF as well as secretion and/or expression of the cytokines TNF-α and IFN-β and chemokines IL-8 and CXCL10. The crude macroalgae extracts were further separated into polyphenol-enriched and polysaccharide-enriched fractions, which were also tested for their effect on transcription factor activity. Interestingly, we observed a selective activation of NF-κB, when cells were treated with macroalgae extracts. On the other hand, pretreatment with macroalgae extracts selectively repressed IRF activation when inflammatory signaling was subsequently induced by LPS. This effect was consistent for both tested species as well as for polyphenol- and polysaccharide-enriched fractions, of which the latter had more pronounced effects. Overall, this is the first indication of how macroalgae could modulate inflammatory signaling by selective activation and subsequent repression of different pathways. Further in vitro and in vivo studies of this mechanism would be needed to understand how macroalgae consumption could influence the prevention of noncommunicable, lifestyle- and age-related diseases that are highly related to unbalanced inflammatory processes.