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Probabilistic proton treatment planning:a novel approach for optimizing underdosage and overdosage probabilities of target and organ structures
No full textObjective:Uncertainties in treatment planning are typically managed using either margin-based or robust optimization. Margin-based methods expand the clinical target volume (CTV) towards a planning target volume, which is generally unsuited for proton therapy. Robust optimization considers worst-case scenarios, but its quality depends on the chosenuncertainty (scenario) set: excluding extremes reduces robustness, while including too many make plans overly conservative. Probabilistic optimization overcomes these limitations by modeling a continuous scenario distribution, enabling the use of statistical measures.Approach:We propose a novel approach to probabilistic optimization that steers plans towards individualized probability levels, to control CTV and organs-at-risks (OARs) under- and overdosage. Voxel-wise dose percentiles (d) are estimated by expected value (E) and standard deviation (SD) asE±δ⋅SD, whereδis iteratively tuned to match the target percentile of the underlying probability distribution (given setup and range uncertainties). The approach involves an inner optimization ofE±δ⋅SDfor fixedδ, and an outer optimization loop that updatesδ. Polynomial chaos expansion provides accurate and efficient dose estimates during optimization. We validated the method on a spherical CTV (prescribed 60 Gy) abutted by an OAR in different directions and a horseshoe-shaped CTV surrounding a cylindrical spine, under Gaussian-distributed setup (3 mm) and range (3%) uncertainties.Main results:For spherical cases with similar CTV coverage,P(D2%>30Gy)dropped by 10%-15%; for matched OAR dose,P(D98%>57Gy)increased by 67.5%-71%. In spinal plans,P(D98%>57Gy)increased by 10%-15% whileP(D2%>30Gy)dropped by 24%-28% in the same plan. Probabilistic and robust optimization times were comparable for spherical (hours) but longer for spinal cases (7.5-11.5 h vs 9-20 min).Significance. Compared to discrete scenario-based optimization, the probabilistic approach offered better OAR sparing or target coverage, depending on individualized priorities.</p
Breaking Barriers:Characterization of the Intradermal Lipopolysaccharide Challenge as an In Vivo Model for Controlled Induction of Vascular Leakage in Healthy Volunteers
No full textVascular leakage and its associated phenomena vasodilation and endothelial activation are pathophysiological features of various diseases. Multiple drug candidates targeting these phenomena are in development, necessitating translational models to demonstrate proof-of-pharmacology and proof-of-mechanism in early-phase clinical trials. This single-center experimental study evaluated the intradermal lipopolysaccharide (id LPS) challenge model as a tool to induce and characterize vascular leakage in healthy participants. Eight participants (male:female = 4:4) received id LPS in the volar forearms, followed by serial pharmacodynamic assessments, including imaging and suction blister induction up to 9 hours after injection. Id LPS administration resulted in significant increases in skin perfusion (P < 0.0001), erythema (P = 0.0013), and skin volume (P = 0.0008), indicating initial stages of inflammation and fluid extravasation. Blister fluid analysis revealed elevated extravascular concentrations of albumin (P = 0.0011), total protein (P < 0.0001), and neutrophils (P = 0.0342), supporting the presence of vascular leakage. Moreover, the expression of endothelial activation markers VCAM-1 (P = 0.0015), ICAM-1 (P = 0.0004), ITGB1 (P = 0.01), and E-selectin (P = 0.0218) increased significantly. Disruption of endothelial cell–cell integrity was supported by increased expression of VE-cadherin (P = 0.0002) in blister fluid. These findings support the applicability of the id LPS model for the induction of vascular leakage in humans. This model holds potential as a translational tool for evaluating the pharmacodynamic responses of vascular leakage-targeting drugs in early clinical development.</p
The expanding H5N1 avian influenza panzootic causes high mortality of skuas in Antarctica
No full textHigh pathogenicity avian influenza virus H5N1 subtype (H5N1 HPAIV), clade 2.3.4.4b, is expanding its host and geographical range, and invaded Antarctica in 2023. Although mortality in Antarctic wildlife from H5N1 HPAIV has been suspected, mainly based on virological analysis of swabs collected from dead animals, it has not been unequivocally diagnosed. Here we show that H5N1 HPAIV caused high mortality in a breeding colony of skuas at one of ten sites in Antarctica we visited in March 2024. By combined virological, bacteriological and pathological analyses, we found that H5N1 HPAIV caused multi-organ necrosis and rapid death in skuas, but not in other species examined. Taken together with recent data, skuas in Antarctica are at risk of continued mortality from H5N1 HPAIV infection, threatening their already small populations. Conversely, because of their wide distribution and ecological relevance, skuas may play a substantial role in the spread of the virus across Antarctica. Transdisciplinary surveillance is needed in coming years to monitor the impact of this poultry-origin disease on Antarctica’s unique wildlife.</p
Policy innovation in voluntary hospital private health insurance::Combining risk adjustment and risk sharing in Australia
No full textBackgroundAustralia’s voluntary hospital Private Health Insurance (PHI) uses community-rated premiums to enhance fairness and accessibility. However, community rating results in predictable profits on young, healthy people and predictable losses on the elderly and chronically ill, creating incentives for insurers to engage in risk selection. To address this, a risk equalisation scheme is applied.ObjectiveThis paper evaluates the effectiveness of Australia’s current risk equalisation scheme in achieving its goals and explores policy innovations integrating risk adjustment and risk sharing.MethodsWe simulate the current risk sharing-only scheme and compare it to alternative models combining risk adjustment and risk sharing. Each model is evaluated using indicators that capture incentives for risk selection, incentives for cost control and overall payment system fit. Additional analyses examine how these alternatives affect claims cost across product tiers.ResultsThe current scheme leaves substantial incentives for risk selection and contains weak incentives for insurers to control spending. Simulations of alternative payment systems show that modifications can simultaneously reduce incentives for risk selection and improve incentives for cost control, while maintaining fit. Changes in the payment system increase insurers’ net cost for basic, bronze, and silver plans, while decreasing costs for gold plans.ConclusionCombining risk adjustment with risk sharing shows promising potential for consumers in mitigating selection and improving incentives for cost control, while maintaining fit. This paper provides a direction for reforming the risk equalisation scheme to reduce selection incentives and enhance cost control
Impressionism:The History of a Label, 1874-1974
No full textImpressionism is everywhere. Works by artists associated with the movement areused to decorate waiting rooms in doctor’s offices, in the designs of coasters, biscuit boxes and other paraphernalia, for museum marketing on posters spread throughout cities and on social media, to sell cruises on the Seine, or in movies like the 1995 romantic comedy Clueless, in which a friend’s love rival is described by the movie’s heroine Cher as a “full-on Monet” for, just like his paintings, the rival is OK from far away, while “up close, it’s a big old mess.” Impressionism’s dissemination is not only limited to its art and artists, though; the label ‘Impressionism’ is everywhere too: in titles of exhibitions,the names of auction house departments, chapters in art history books, or in the lyrics of a Taylor Swift song. It is a market category; it is a much-loved art movement, an umbrella term for artists working in a similar style around the same period, a brand name, a label used to guide museumgoers’ expectations when attending exhibitions, or a way to position artists (art) historically. Because of this omnipresence, Impressionism appears to be part of the status quo; of the cultural and aesthetic framework that shapes our daily lives, and it is known to sell
Development and assessment of hydrogel-embedded metalloporphyrin sensors for monitoring of tissue Oxygenation
No full textBackground: Continuous, objective monitoring of tissue oxygenation is crucial for early detection of ischemia and for guiding interventions in reconstructive and transplant surgery. Existing monitoring approaches are often intermittent, operator-dependent, or vulnerable to optical confounders, limiting timely recognition of vascular compromise and equitable performance across patient populations. This dissertation investigates an implantable optical biosensing platform based on hydrogel-embedded metalloporphyrins to enable real-time monitoring of tissue oxygen tension (TOT). Methods and results: Injectable sensors were engineered using a PEGDA hydrogel matrix with metalloporphyrin-based phosphorescent dyes and evaluated using fluorescence/phosphorescence lifetime approaches to provide quantitative oxygen readouts. The platform was assessed across benchtop calibration, preclinical, and ex vivo models, including flap ischemia monitoring in rodent models, quantification of perfusion changes during topical vasodilator interventions, intrahepatic oxygen monitoring during normothermic machine perfusion of liver grafts, and characterization of oxygen dynamics during ischemia–reperfusion (including post-ischemic reactive hyperoxia). Conclusions:Hydrogel-embedded metalloporphyrin sensors support minimally invasive, continuous assessment of local oxygenation with potential to detect early ischemic changes, track therapeutic modulation of perfusion, and inform organ viability assessment. The work also addresses key translational considerations by evaluating the influence of skin pigmentation and implantation depth on optical sensing performance, supporting the development of more robust and equitable monitoring tools for clinical use.<br/
Shock effects of institutional quality, green technologies, and natural resources on Algeria's energy diversification
No full textAlgeria's hydrocarbon-dependent economy faces significant challenges in diversifying its energy mix to achieve sustainability and reduce vulnerability to global energy market fluctuations. Despite abundant natural resources, the country's heavy reliance on fossil fuels has hindered progress toward energy diversification, as measured by the energy diversification index. This study investigates the asymmetric impacts of institutional quality, green technologies, and natural resources on Algeria's energy diversification from 1995/Q1 to 2022/Q4, addressing a critical literature gap. Using the Fourier nonlinear autoregressive distributed lag model, the study explores long-term equilibrium relationships and asymmetric dynamics between these variables and energy diversification. The analysis reveals that positive shocks in institutional quality lead to substantial increases in energy diversification, underscoring strong governance's crucial role in promoting energy transitions. Conversely, negative institutional shocks significantly reduce energy diversification, highlighting the detrimental effects of declining governance quality. Similarly, positive green technology shocks enhance energy diversification, while negative shocks diminish it. Natural resources exhibit dual effects: positive shocks result in modest energy diversification increases, suggesting resource revenues can support renewable projects; however, negative shocks lead to decreases, emphasizing fiscal volatility's destabilizing impact on energy diversification. These findings confirm asymmetric relationships, as positive and negative shocks significantly influence Algeria's energy diversification differently. Policy implications underscore the need for continuous governance reforms, enhanced anti-corruption measures, and transparent regulatory frameworks to attract renewable energy investments. Strategic reallocation of hydrocarbon revenues—through mechanisms similar to Norway's sovereign wealth fund model—could mitigate fiscal risks and support green transitions, providing actionable insights for transforming Algeria's energy landscape.</p
Outcome bias in managerial decisions
No full textDecisions informed by past events can be distorted when outcomes partially determined by chance are misinterpreted as being purely skill-based. This can lead to outcome bias, where decisions are evaluated based on results rather than on the quality of the performance that produced them. Outcome bias is prevalent across various domains, including managerial decision-making. This paper investigates outcome bias in professional football, a highly competitive industry. The analysis focuses on managers who were replaced mid-season between 2017/18 and 2024/25 in the top divisions of the five major European football leagues. The main finding is that clubs tend to change managers in response to recent match results rather than to underlying performance indicators. This behavior reflects an economically inefficient decision-making process driven by outcome bias.</p
European Union values in teaching and learning in higher education:a bibliometric analysis
No full textThis study explores how the fundamental values of the European Union (EU), namely human rights, freedom, human dignity, the rule of law, democracy, and equality, are addressed in higher education through a bibliometric analysis. Drawing on 321 documents indexed in the Web of Science Core Collection, the study analyses publication trends, assesses the performance of authors, sources, and documents, and examines collaborative and conceptual structures within the field. Conceptually, the study situates EU values pedagogy within the broader literature on values education and citizenship education in higher education. The findings reveal a growing body of research, highlight thematic imbalances, such as the relative underrepresentation of human dignity and the rule of law, and point to limited international collaboration. Through the mapping of this fragmented and multidisciplinary field, the study provides a structured overview of research on democratic education and EU values pedagogy, offering guidance for future scholarly work.</p
On the role of personality traits in shaping responses to physician payment systems
No full textWe study the interplay of extrinsic and intrinsic motivations regarding the quality of care physicians provide. In particular, we analyze the role of personality traits in explaining the heterogeneity in responses to common physician payment systems. We utilize data from several behavioral experiments (659 subjects) on physician payment systems and from post-experimental surveys on personality traits. The experiments use equivalent health framings and decision situations with either fee-for-service (FFS) or capitation (CAP) as baseline payments. Blended payment systems—performance pay and mixed systems—are introduced at a within-subject level to complement the baseline payments. We find that personality traits contribute to explaining some heterogeneity in behavioral responses to payment incentives. Under baseline systems, more agreeable individuals provide higher quality of care. Blended payment systems enhance the aggregate treatment quality. Nevertheless, we observe a moderation effect in CAP-based blended systems: by Conscientiousness in mixed schemes, and by Conscientiousness and Agreeableness under performance pay. Quality increases are smaller for individuals higher in these traits. The moderation can be mainly explained by a ceiling effect, though we also observe a quality reduction/crowding-out effect. Our findings emphasize the importance of the interplay between financial incentives, physician provision behavior, and personality traits and inform the discussion on the design of tailored physician payment systems.</p