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Abstract In the present study road safety impact analysis for certain advanced driver assistance systems (ADAS) was conducted. Based on a literature review, expert interviews and current adaptations in legislation, the most promising nine ADAS were selected. The impact was analysed based on statistical crash data from Austria. Factors such as infrastructure and weather conditions, market penetration, expected functionality of sensors, user acceptance and risk homeostasis were considered. A software tool was developed to calculate the crash reduction potential of the selected ADAS for the scenarios 2025, 2030 and 2040. The results show that the ADAS related to warning/braking have the greatest future reduction potential and could lead to a reduction of up to 8,700 crashes and 70 fatalities in Austria in 2040. In addition, the Intelligent Speed Assistance system would lead to an overall crash reduction of 8% compared to current crash numbers in Austria in 2040. The Turning Assistant for heavy goods vehicles shows the lowest reduction in crashes and casualties, but due to the highest severity per crash (93 fatalities per 1,000 crashes), it nevertheless provides an important contribution to the reduction of fatalities in road traffic. However, to benefit from the ADAS safety potential, it is highly relevant that these systems are used in a correct manner. In the future, it will be necessary to provide users with more information on the correct use, benefits and limitations of the respective ADAS and to integrate the use of these systems into driver education procedures and tests.

Abstract The mammalian neocortex comprises an enormous diversity regarding cell types, morphology, and connectivity. In this work, we discover a post-transcriptional mechanism of gene expression regulation, protein translation, as a determinant of cortical neuron identity. We find specific upregulation of protein synthesis in the progenitors of later-born neurons and show that translation rates and concomitantly protein half-lives are inherent features of cortical neuron subtypes. In a small molecule screening, we identify Ire1α as a regulator of Satb2 expression and neuronal polarity. In the developing brain, Ire1α regulates global translation rates, coordinates ribosome traffic, and the expression of eIF4A1. Furthermore, we demonstrate that the Satb2 mRNA translation requires eIF4A1 helicase activity towards its 5’-untranslated region. Altogether, we show that cortical neuron diversity is generated by mechanisms operating beyond gene transcription, with Ire1α-safeguarded proteostasis serving as an essential regulator of brain development.

Abstract The chemokine CXCL12 promotes glioblastoma (GBM) recurrence after radiotherapy (RT) by facilitating vasculogenesis. Here we report outcomes of the dose-escalation part of GLORIA (NCT04121455), a phase I/II trial combining RT and the CXCL12-neutralizing aptamer olaptesed pegol (NOX-A12; 200/400/600 mg per week) in patients with incompletely resected, newly-diagnosed GBM lacking MGMT methylation. The primary endpoint was safety, secondary endpoints included maximum tolerable dose (MTD), recommended phase II dose (RP2D), NOX-A12 plasma levels, topography of recurrence, tumor vascularization, neurologic assessment in neuro-oncology (NANO), quality of life (QOL), median progression-free survival (PFS), 6-months PFS and overall survival (OS). Treatment was safe with no dose-limiting toxicities or treatment-related deaths. The MTD has not been reached and, thus, 600 mg per week of NOX-A12 was established as RP2D for the ongoing expansion part of the trial. With increasing NOX-A12 dose levels, a corresponding increase of NOX-A12 plasma levels was observed. Of ten patients enrolled, nine showed radiographic responses, four reached partial remission. All but one patient (90%) showed at best response reduced perfusion values in terms of relative cerebral blood volume (rCBV). The median PFS was 174 (range 58-260) days, 6-month PFS was 40.0% and the median OS 389 (144-562) days. In a post-hoc exploratory analysis of tumor tissue, higher frequency of CXCL12+ endothelial and glioma cells was significantly associated with longer PFS under NOX-A12. Our data imply safety of NOX-A12 and its efficacy signal warrants further investigation.

Abstract We use the numerical conformal bootstrap to study boundary quantum electrodynamics, the theory of a four dimensional photon in a half space coupled to charged conformal matter on the boundary. This system is believed to be a boundary conformal field theory with an exactly marginal coupling corresponding to the strength of the interaction between the photon and the matter degrees of freedom. In part one of this project, we present three results. We show how the Maxwell equations put severe constraints on boundary three-point functions involving two currents and a symmetric traceless tensor. We use semi-definite programming to show that any three dimensional conformal field theory with a global U(1) symmetry must have a spin two gap less than about 1.05. Finally, combining a numerical bound on an OPE coefficient and some Ward identities involving the current and the displacement operator, we bound the displacement operator two-point function above. This upper bound also constrains a boundary contribution to the anomaly in the trace of the stress tensor for these types of theories.

Abstract The human pathogen Neisseria gonorrhoeae ascends into the upper female reproductive tract to cause damaging inflammation within the Fallopian tubes and pelvic inflammatory disease (PID), increasing the risk of infertility and ectopic pregnancy. The loss of ciliated cells from the epithelium is thought to be both a consequence of inflammation and a cause of adverse sequelae. However, the links between infection, inflammation, and ciliated cell extrusion remain unresolved. With the use of ex vivo cultures of human Fallopian tube paired with RNA sequencing we defined the tissue response to gonococcal challenge, identifying cytokine, chemokine, cell adhesion, and apoptosis related transcripts not previously recognized as potentiators of gonococcal PID. Unexpectedly, IL-17C was one of the most highly induced genes. Yet, this cytokine has no previous association with gonococcal infection nor pelvic inflammatory disease and thus it was selected for further characterization. We show that human Fallopian tubes express the IL-17C receptor on the epithelial surface and that treatment with purified IL-17C induces pro-inflammatory cytokine secretion in addition to sloughing of the epithelium and generalized tissue damage. These results demonstrate a previously unrecognized but critical role of IL-17C in the damaging inflammation induced by gonococci in a human explant model of PID.

Therapeutic management of patients with leptomeningeal carcinomatosis (LC) may require treatment of concomitant hydrocephalus (HC) in addition to intrathecal chemotherapy (ITC). Ventriculoperitoneal shunts (VPS) equipped with a valve for manual deactivation of shunt function and a concomitant reservoir for application of ITC pose an elegant solution to both problems. The present study evaluates indication, feasibility, and safety of such a modified shunt/reservoir design (mS/R). All patients with LC aged ≥ 18 years who had undergone mS/R implantation between 2013 and 2020 at the authors’ institution were further analyzed. ITC was indicated following the recommendation of the neuro-oncological tumor board and performed according to a standardized protocol. Sixteen patients with LC underwent mS/R implantation for subsequent ITC and concomitant treatment of HC. Regarding HC-related clinical symptoms, 69% of patients preoperatively exhibited lethargy, 38% cognitive impairment, and 38% (additional) visual disturbances. Postoperatively, 86% of patients achieved subjective improvement of HC-related symptoms. Overall, postoperative complications occurred in three patients (19%). No patient encountered cancer treatment-related complications. The present study describes a combination procedure consisting of a standard VPS-system and a standard reservoir for patients suffering from LC and HC. No cancer treatment-related complications occurred, indicating straightforward handling and thus safety.

Abstract Selective binding of TCR-like antibodies that target a single tumour-specific peptide antigen presented by human leukocyte antigens (HLA) is the absolute prerequisite for their therapeutic suitability and patient safety. To date, selectivity assessment has been limited to peptide library screening and predictive modeling. We developed an experimental platform to de novo identify interactomes of TCR-like antibodies directly in human tissues using mass spectrometry. As proof of concept, we confirm the target epitope of a MAGE-A4-specific TCR-like antibody. We further determine cross-reactive peptide sequences for ESK1, a TCR-like antibody with known off-target activity, in human liver tissue. We confirm off-target-induced T cell activation and ESK1-mediated liver spheroid killing. Off-target sequences feature an amino acid motif that allows a structural groove-coordination mimicking that of the target peptide, therefore allowing the interaction with the engager molecule. We conclude that our strategy offers an accurate, scalable route for evaluating the non-clinical safety profile of TCR-like antibody therapeutics prior to first-in-human clinical application.

Abstract Background Alcohol misuse is common and causes substantial harm. Internet-delivered cognitive behaviour therapy (ICBT) is effective in reducing alcohol misuse; however, the literature investigating how treatment outcomes are impacted by patients’ preferences for therapist- versus self-guided ICBT for alcohol misuse is sparse. Methods In this preference trial, 74 eligible patients (who reported ≥ 14 drinks in the previous week and obtained scores suggesting hazardous or harmful drinking) chose between enrolling in either therapist- or self-guided ICBT for alcohol misuse. We investigated whether those who chose therapist- versus self-guided ICBT differed in their (a) drinking outcomes—as measured by Timeline Follow-Back (TLFB) and heavy drinking days (HDD) at post-treatment and 3-month follow-up—and (b) post-treatment ICBT engagement and satisfaction. Results The majority (81.1%) of eligible patients chose therapist-guided ICBT. These patients reported higher psychotropic medication use, drinking difficulties, and anxiety symptoms. For both the therapist- and self-guided patients, a modified intention-to-treat analysis revealed large within-group treatment effects for TLFB (β = − 2.64, SE 0.66; p

BACKGROUND: Recent trends in Switzerland indicate a concerning rise in simultaneous polysubstance use among adolescents, a practice marked by the concurrent or sequential consumption of multiple psychoactive substances, notably alcohol and cannabis, alongside prescription medications (e.g. benzodiazepines) and illicit drugs, resulting in dozens of fatal outcomes. However, data on simultaneous polysubstance use and evidence-based approaches to effective prevention is lacking. AIMS OF THE STUDY: The study aimed to explore and gain insights into use patterns, use settings, use motives, harm-reduction strategies, concerns associated with substance use, and support and counselling services from the point of view of adolescents practicing simultaneous polysubstance use in Switzerland. METHODS: An exploratory study was conducted via an online survey (n = 116) and two focus group discussions with affected Swiss adolescents aged 14 to 20. A mixed-methods approach was applied to gain insights and better understand the phenomenon of simultaneous polysubstance use among Swiss adolescents. Quantitative survey data obtained between November 2021 and March 2023 by means of convenience sampling – organised by distributing flyers (in three national languages) among several project partners, on the internet, over social media and by word of mouth – was analysed descriptively, whereas qualitative survey data and focus group data were thematically explored. A concurrent nested design was employed, utilising quantitative findings as a core foundation for addressing research questions, while qualitative findings were instrumental in validating and providing contextual depth to the results. RESULTS: Our findings reveal a preference of the sample for combining alcohol with cannabis and/or other substances (e.g. benzodiazepines or hard drugs) in social settings, driven by diverse motives, including enhancement of experiences and partly maladaptive coping mechanisms leading to self-medication. Despite some awareness of the potential harms, there is a significant reliance on peer-shared strategies for harm reduction, highlighting a gap in formal support and counselling services, some of which are perceived by adolescents as lacking empathy and relevance. CONCLUSIONS: This study underscores the urgency of developing targeted, youth-centred interventions that resonate with the lived realities of adolescents, aiming not only to reduce substance use but also to address the broader psychosocial factors contributing to simultaneous polysubstance use. By shedding light on the complex dynamics of adolescent polysubstance use, our research contributes to the ongoing dialogue on effective prevention strategies, advocating for a holistic approach encompassing education, policy reform and community support to tackle this multifaceted public health challenge.

ABSTRACT The composition of respiratory fluids influences the stability of viruses in exhaled aerosol particles and droplets, though the role of respiratory organics in modulating virus stability remains poorly understood. This study investigates the effect of organic compounds on the stability of influenza A virus (IAV) in deposited droplets. We compare the infectivity loss of IAV at different relative humidities (RHs) over the course of 1 h in 1-µL droplets consisting of phosphate-buffered saline (without organics), synthetic lung fluid, or nasal mucus (both containing organics). We show that IAV stability increases with increasing organic:salt ratios. Among the various organic species, proteins are identified as the most protective component, with smaller proteins stabilizing IAV more efficiently at the same mass concentration. Organics act by both increasing the efflorescence RH and shortening the drying period until efflorescence at a given RH. This research advances our mechanistic understanding of how organics stabilize exhaled viruses and thus influence their inactivation in respiratory droplets.IMPORTANCEThis study investigates how the composition of respiratory fluids affects the stability of viruses in exhaled droplets. Understanding virus stability in droplets is important as it impacts how viruses spread and how we can combat them. We focus on influenza A virus (IAV) and investigate how different organic compounds found in lung fluid and nasal mucus protect the virus from inactivation. We demonstrate that the ratio of organics to salt in the fluid is an indicator of IAV stability. Among organics, small proteins are particularly effective at protecting IAV. Their effect is in part explained by the proteins’ influence on the crystallization of salts in the droplets, thereby shielding the viruses from prolonged exposure to harmful salt concentrations. Understanding these mechanisms helps us grasp how viruses sustain their infectivity over time in respiratory droplets, contributing to efforts in controlling infectious diseases.

IntroductionModern histocompatibility algorithms depend on the comparison and analysis of high-resolution HLA protein sequences and structures, especially when considering epitope-based algorithms, which aim to model the interactions involved in antibody or T cell binding. HLA genotype imputation can be performed in the cases where only low/intermediate-resolution HLA genotype is available or if specific loci are missing, and by providing an individuals’ race/ethnicity/ancestry information, imputation results can be more accurate. This study assesses the effect of imputing high-resolution genotypes on molecular mismatch scores under a variety of ancestry assumptions.MethodsWe compared molecular matching scores from “ground-truth” high-resolution genotypes against scores from genotypes which are imputed from low-resolution genotypes. Analysis was focused on a simulated patient-donor dataset and confirmed using two real-world datasets, and deviations were aggregated based on various ancestry assumptions.ResultsWe observed that using multiple imputation generally results in lower error in molecular matching scores compared to single imputation, and that using the correct ancestry assumptions can reduce error introduced during imputation.DiscussionWe conclude that for epitope analysis, imputation is a valuable and low-risk strategy, as long as care is taken regarding epitope analysis context, ancestry assumptions, and (multiple) imputation strategy.

Background In England, voluntary sector specialist (VSS) services are central to supporting victim-survivors of sexual violence (SV). However, empirical evidence is lacking about the scope, range and effectiveness of VSS provision for SV in England.Objectives To undertake national surveys to map SV VSS service provision and describe arrangements for funding and commissioning.Design Cross-sectional surveys.Setting VSS services for SV and commissioners from multiple organisations across England (January–June 2021).Methods Senior staff working in VSS services and commissioners from multiple organisations were surveyed electronically. Surveys explored SV service commissioning, funding and delivery, partnerships between organisations, perceived unmet need for services, and views about facilitators and challenges. Data were analysed descriptively to characterise VSS service provision for SV and commissioning across England.Results 54 responses were received from VSS providers and 34 from commissioners. Data demonstrated a complex and evolving funding and commissioning landscape in which providers typically secured funding from multiple sources, impacting consistency and scope of service provision. It was common for multiple organisations to co-commission services, demonstrating trends towards larger contracts that may disadvantage smaller specialist providers. Numerous examples of partnership working between organisations were identified, although developing partnerships was noted as challenging, particularly between VSS organisations. There was clear evidence of unmet need for services, with some groups of victim-survivors such as those from black and minority ethnic groups, often underserved by specialist services. However, there was also evidence of innovative service development and commissioning approaches to meet the needs of victim-survivors who face challenges accessing services.Conclusions This study provides novel insights into SV service provision and commissioning in England, including unmet needs among victim-survivors.

Purpose: Superior sulcus tumors are frequently treated with neoadjuvant chemoradiation therapy (nCRT) followed by surgery via a trimodal approach. The INKA study evaluated the replacement of photon irradiation by carbon ion radiation therapy (C12-RT) in this regimen. Methods and Materials: The prospective INKA study included patients with locally advanced non-small cell superior sulcus tumors (

Abstract Population dynamics are driven by stochastic and density‐dependent processes acting on demographic rates. Individuals differ demographically, and to capture these differences, models of population dynamics are usually structured by age and stage, rarely by sex. An effect of sex on population dynamics is expected if the dynamics of males and females differ, requiring an unequal sex ratio at birth and/or sex‐specific survival probabilities. Goshawks (Accipiter gentilis) show large sexual size dimorphism and differential survival, but it is unknown whether males and females contribute differently to population dynamics. We studied a goshawk population in northern Germany over 47 years using brood monitoring data, collected feathers and nestling ringing data. We jointly analyzed the data using a two‐sex integrated population model and performed retrospective and prospective population analyses to understand whether the demographic drivers of population change differ between the sexes. The population showed large fluctuations, during which the number of breeding pairs doubled, but the long‐term trend of the population was slightly negative. Female survival exceeded male survival during the first year of life. Females started to reproduce at a younger age than males, productivity increased with female age, the sex ratio of nestlings was male biased and there was moderate male immigration. Despite these differences, temporal variation in sex ratio did not contribute to population dynamics and the contribution of temporal variation in survival was similar for both sexes. Variation in first‐year survival was the strongest driver in this population, regulated by a weak density‐dependent feedback acting through female first‐year survival. Overall, the contributions of the two sexes to population dynamics were similar in this monogamous species with strong sexual size dimorphism.

Road transport is a significant contributor to Green House Gas (GHG) emissions in the European Union (EU) and is responsible for approximately 25% of total GHG emissions in the EU13. The European Commission has proposed stricter CO2 emissions targets for heavy-duty vehicles that require manufacturers to achieve a reduction of 90% in average fleet emissions from new vehicles by 2040 compared to a 2019 baseline. To meet these ambitious targets, there is an urgent need to explore alternative pathways away from conventional fossil fuel-based powertrain systems like electrified powertrains and carbon–neutral fuels. One promising option is the plug-in hybrid electric powertrain concept, which combines the advantages of both power sources, enabling improved fuel efficiency and reduced CO2 emissions. However, the potential of such a plug-in hybrid powertrain needs to be evaluated for heavy-duty trucks.This study focuses on the development of control strategies for the Energy Management System (EMS) of the above powertrain concept. First, a control strategy for the non-predictive EMS’s start/stop functionality and optimization of the torque split between the combustion engine and electric machine is developed and calibrated for efficient engine operation depending on the battery state of charge. In addition, a predictive EMS’s control strategy is developed that uses horizon information of the driving route for optimal utilization of electrical energy within the prediction horizon, thereby further enhancing fuel consumption reduction. The predictive EMS uses Adaptive Equivalent Consumption Minimization Strategy (A-ECMS) with Pontryagin’s Minimization Principle (PMP) for online equivalence factor adaptation, providing local optimal solutions in real-time. The study concludes with the energy savings achieved through the implementation of these strategies using real-world driving cycles in the heavy-duty transport sector.

AIM OF THIS STUDY: General internal medicine is a crucial element in healthcare systems. Understanding how many people are and will be working in this field is important to maintain and improve quality for patients in healthcare systems. This can provide a basis for political decisions. METHODS: We conducted a cross-sectional study to analyse the current and future workforce of generalists (general practitioners and internists in hospitals) in Switzerland. The Swiss Society of General Internal Medicine (SSGIM) distributed a survey to all members. Respondents were asked about their current average workload in 2023 and planned workload in 2033. The responses were used to calculate full-time equivalent (FTE) for the current and future workforce of generalists and to extrapolate FTE for all active SSGIM members. To model the demand by 2033, we derived different scenarios. RESULTS: Of all 6,232 active SSGIM members, 2,030 (33%) participated: 46% female, 25% (largest age group) 56-65 years old, 19% still in postgraduate training. The average workload in 2023 was 78% for female and 87% for male generalists; the FTE extrapolated to all active SSGIM members in 2023 was 5,246. By 2033, 1,935 FTEs (36%) will retire, 502 FTEs (10%) will reduce their workload, 116 FTEs (2%) will increase their workload and 2,800 FTEs (53%) will remain in the workforce with the same workload as in 2023. To maintain the same workforce as in 2023, 2,321 new FTEs (44%) will be needed by 2033. To fill this gap of 232 FTE new generalists per year, we modelled different scenarios with assumptions of interest, workload, migration and dropouts. CONCLUSIONS: Within only one decade, 44% of the current workforce of generalists will disappear, mainly due to retirement and decreased workload. To fill this gap, various scenarios need to be incorporated. Politicians are called upon to create the political framework to create attractive training and working conditions for generalists to address the future demand for healthcare services.