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Abstract Background In amyotrophic lateral sclerosis (ALS), neurofilament light chain (NfL) was introduced as a prognostic biomarker. More recently, NfL values can be shared on the patient’s ALS app. Also, the ALS functional rating scale (ALSFRS-R) is an established patient-reported assessment of disease progression. The scale can be obtained during clinic visits or remotely. However, few systematic data are available on the patients’ perception of prognostic information about NfL and ALSFRS-R and the remote sharing of these data. Methods In a multicenter study, 149 ALS patients were assessed for their perception of shared information about NfL and ALSFRS-R using an investigator-designed survey and established questionnaires. The recommendation of NfL and ALSFRS-R to fellow patients was assessed using the Net Promoter Score (NPS). Burden by shared information was investigated in two distinct settings: (1) clinic information when receiving results on NfL and/or ALSFRS-R during clinic visits and (2) remote information about NfL values and self-rating of the ALSFRS-R via the ALS app. General anxiety was measured by the Fear of Progression Questionnaire – Short Form (FoP-Q-SF). Results Information about NfL and ALSFRS-R, respectively (n = 149), were regarded as relevant for patients themselves (75.2% and 77.2%) and for research (98% and 96%). The NPS showed a high recommendation rate for NfL (+ 21) and ALSFRS-R (+ 26). Only a minority of patients perceived shared information about NfL as burdensome, with a lower burden in the clinic setting (n = 1, 4.2%) than in the remote setting (n = 8, 12%; p = 0.015). Remote digital assessment of the ALSFRS-R was well received, with a reported burden in 9.8% (n = 9) of the participants. The FoP-Q-SF revealed fear of progression in 40% of the respondents (n = 60). Conclusions This study underscored the relevance of information about NfL and ALSFRS-R from the patient’s perspective. Furthermore, patients proved to appreciate the relevance of this data for ALS research. Sharing information about NfL or ALSFRS-R was rarely perceived as burdensome even in a remote setting using the ALS app. These findings pave the way for further development of the patient-centered approach to sharing prognostic information in ALS.

High-quality annotations are a critical success factor for machine learning (ML) applications. To achieve this, we have traditionally relied on human annotators, navigating the challenges of limited budgets and the varying task-specific expertise, costs, and availability. Since the emergence of large language models (LLMs), their popularity for generating automated annotations has grown, extending possibilities and complexity of designing an efficient annotation strategy. Increasingly, computer vision capabilities have been integrated into general-purpose LLMs like ChatGPT. This raises the question of how effectively LLMs can be used in satellite image annotation tasks and how they compare to traditional annotator types. This study presents a comprehensive investigation and comparison of various human and automated annotators for image classification. We evaluate the feasibility and economic competitiveness of using the ChatGPT4-V model for a complex land usage annotation task and compare it with alternative human annotators. A set of satellite images is annotated by a domain expert and 15 additional human and automated annotators, differing in expertise and costs. Our analyzes examine the annotation quality loss between the expert and other annotators. This comparison is conducted through, first, descriptive analyzes, second, fitting linear probability models, and third, comparing F1-scores. Ultimately, we simulate annotation strategies where samples are split according to an automatically assigned certainty score. Routing low-certainty images to human annotators can cut total annotation costs by over 50% with minimal impact on label quality. We discuss implications regarding the economic competitiveness of annotation strategies, prompt engineering, and the task-specificity of expertise.

Abstract Desmin intermediate filaments play a crucial role in stress transmission and mechano-protection. The loss of its integrity triggers myofibril breakdown and muscle atrophy for which desmin phosphorylation (pDes) is a priming factor. We investigated whether eccentric accentuated resistance exercise (RE) influences the regulation of pDes, effecting its susceptibility to cleavage. Ten healthy persons performed 14 RE-sessions (2 per week). Muscle biopsies were collected in both untrained and trained conditions at rest (pre 1, pre 14) and one hour after RE (post 1, post 14). Western blotting and immunohistochemistry were utilized to assess desmin content, phosphorylation at several sites and susceptibility to cleavage. In untrained condition (pre 1, post 1), RE induced dephosphorylation of serin 31 and 60. Trained muscle exhibited more pronounced dephosphorylation at Serin 31 post-RE. Dephosphorylation was accompanied by reduced susceptibility of desmin to cleavage. Additionally, training increased total desmin content, upregulated baseline serine 31 phosphorylation and attenuated pDes at serine 60 and threonine 17. Our findings suggest that acute and repeated RE changes the phosphorylation pattern of desmin and its susceptibility to cleavage, highlighting pDes as an adaptive mechanism in skeletal muscle, contributing to the proteostatic regulation in response to recurring stress.

Plums are one of the most widely grown fruits in the Czech Republic. The demand for plums is increasing not only for the purpose of processing them into marmalades, preserves or for distilling, but also for the fruit itself as a dessert fruit. Therefore, it is crucial that breeding stations are producing genotypes suitable for consumption and processing. Evaluation of the growth parameters, fruit quality and fruit production of most of the varieties available on the market in the local climatic conditions of the region is important. If varieties are not properly selected, large economic losses are caused. The varieties selected for this study were ‘Bluefree’, ‘Cacanska lepotica’, ‘Haganta’, ‘Jojo’, ‘Jubileum’, ‘Presenta’, ‘President’, ‘Simona’, ‘Tophit’, ‘Kulinaria’. Trees were evaluated in the natural conditions of the orchard for 5 years. The monitored parameters were flower onset, fruit onset, flowering and harvesting time, fruit size, overall fruit quality and sugar content. The varieties ‘Bluefree’, ‘Haganta’, ‘Kulinaria’ and ‘President’ had the largest fruit size and high sugar contents and therefore were the most suitable for direct consumption. The varieties with the highest sugar content were ‘Haganta’, ‘President’ and ‘Presenta’, making them the most suitable for the processing market.

Abstract Background Monocytes comprise subsets of classical, intermediate and non-classical monocytes with distinct anti- or pro-tumor effects in breast cancer (BC). They are modulated by estrogen, and can contribute to BC control by endocrine therapy in preclinical models. Methods To elucidate whether changes in monocyte subsets are associated with treatment and response, we investigated peripheral blood samples of 73 postmenopausal women with estrogen receptor (ER) positive BC, who received aromatase inhibitor therapy with or without the mucin-1 vaccine tecemotide in the ABCSG34 trial. Blood was retrieved at baseline, midterm and end of therapy, and was analyzed for the distribution and ER expression of monocyte subsets by flow cytometry. Results When 40 healthy, age-matched women were compared with BC patients before treatment start, ER levels of monocytes did not differ, yet patients presented with a higher frequency of classical and fewer non-classical monocytes. Endocrine therapy triggered a significant increase in ER levels in all monocyte subsets, without affecting subset distribution. Vaccination had no overall impact on subset frequency and ER expression. Yet, a shift from intermediate to classical monocytes during therapy correlated with changes in plasma cytokines and chemokines and was significantly associated with low residual cancer burden in vaccinated patients. Without tecemotide, baseline ER levels in classical monocytes were significantly higher in women with good response to endocrine therapy. Conclusions This study identified classical monocytes to be associated with ER positive BC and with patient response to neoadjuvant endocrine treatment and cancer vaccination.

This paper deals with a new clinker-free hydraulic binder (3C), the synthesis of which was inspired by FBC ash with hydraulic properties based on the principle of lime-sulfate activation of metakaolin. The influence of the composition on the fundamental mechanical and chemical properties of the 3C binder was investigated (phase composition changes, compressive strength, porosity, setting time, flow table test and hydration heat) at the same water to binder ratio. The results showed that the 3C binder containing 61 wt.% metakaolin, 19 wt.% anhydrite II and 18 wt.% lime had the best mechanical properties. This binder achieved higher 7 and 28 day compressive strengths than reference Portland cement. The 3C binder appears to be very promising for the construction industry in the future and may become a new ecological substitute for high-emission Portland cement.

In time-pressured decisions, humans exploit contextual knowledge to reduce uncertainty about the unfolding situation and to improve behavioral control. However, in complex real-world settings, it remains unclear whether the explicit provision of contextual information is beneficial or not. We thus examined the information gain of explicitly provided information as a function of expertise, information uncertainty and acquisition phase. To this end, we measured the positioning of female handball players (N = 36 experts + 36 near-experts) in a virtual-reality defensive task as a function of their teammates' defensive-strength patterns, which was either explicitly instructed or had to be self-generated. Furthermore, the certainty of provided information was experimentally varied (67% vs. 83% consistent information). All eight groups-expertise (2) x acquisition condition (2) x information certainty (2)-improved performance in terms of the positional difference in their defense movements, meaning that they either moved more sideways to support their neighboring teammate or remained more often in their position when no support was required. However, an explicit-knowledge test showed no differences regarding pattern detection between the acquisition conditions, implying that the performance enhancement of the self-generated groups was not due to explicit-knowledge accumulation. Most notably, experts generally benefitted from explicit instructions whereas for near-experts, an information gain could only be revealed for comparably certain information. This interaction implies that future research on explicit provision vs. self-generation of contextual knowledge should pursue a more differential approach, thereby also considering gender and age as well as personality factors.

ABSTRACT Objective While statins have demonstrated a variety of antineoplastic effects in preclinical studies, several retrospective clinical studies and observational studies have not shown a consistent chemopreventive benefit against prostate cancer (PCa). Therefore, in this population‐based cohort study, we examined the association of statin intake on prostate specific antigen (PSA) values and risk of development of PCa. Method N = 4,314 men from the Swiss section of the European Randomized Study of Screening for Prostate Cancer (ERSPC) were evaluated. N = 761 men were statin users [Stat+]. The median follow‐up was 9.6 years. A transrectal prostate biopsy was performed in men with a PSA‐level ≥ 3 ng/mL. Mortality and incidence data was obtained through registry linkages. PCa incidence, total serum PSA level, free‐to‐total PSA level, and overall survival were compared between [Stat+] and [Stat−] patients. Results Total PSA values were significantly lower in [Stat+] patients at baseline (1.5 vs. 1.8 ng/mL, p

Abstract Background Pre-existing comorbidities increase the likelihood of post-stroke dysphagia. This study investigates comorbidity prevalence in patients with dysphagia after ischemic stroke. Methods The data of patients with acute ischemic stroke from two large representative cohorts (STROKE-CARD trial 2014–2019 and STROKE-CARD registry 2020–2022 – both study center Innsbruck, Austria) were analyzed for the presence of dysphagia at hospital admission (clinical swallowing examination). Comorbidities were assessed using the Charlson Comorbidity Index (CCI). Results Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital admission. Patients with dysphagia were older (77.8 ± 11.9 vs. 73.6 ± 14.3 years, p

Abstract Ion-beam radiotherapy is an advanced cancer treatment modality offering steep dose gradients and a high biological effectiveness. These gradients make the therapy vulnerable to patient-setup and anatomical changes between treatment fractions, which may go unnoticed. Charged fragments from nuclear interactions of the ion beam with the patient tissue may carry information about the treatment quality. Currently, the fragments escape the patient undetected. Inter-fractional in-vivo treatment monitoring based on these charged nuclear fragments could make ion-beam therapy safer and more efficient. We developed an ion-beam monitoring system based on 28 hybrid silicon pixel detectors (Timepix3) to measure the distribution of fragment origins in three dimensions. The system design choices as well as the ion-beam monitoring performance measurements are presented in this manuscript. A spatial resolution of $${{4}\,\hbox {mm}}$$ 4 mm along the beam axis was achieved for the measurement of individual fragment origins. Beam-range shifts of $${1.5}\,\hbox {mm}$$ 1.5 mm were identified in a clinically realistic treatment scenario with an anthropomorphic head phantom. The monitoring system is currently being used in a prospective clinical trial at the Heidelberg Ion Beam Therapy Centre for head-and-neck as well as central nervous system cancer patients.

The International Court of Justice advisory opinion addresses several complex legal questions. The Court examined whether these policies violate international law, particularly erga omnes obligations. Israel's actions were found to violate international law through the annexation of large parts of Palestinian territories. The Court explored the relationship between occupation and annexation, clarifying that while occupation is lawful if temporary and necessary, Israel's extended presence goes beyond this and amounts to annexation. The advisory opinion further addressed claims of racial segregation or apartheid, concluding that Israeli policies toward Palestinians demonstrate systematic discrimination and a policy of separation. This potentially may meet the legal definition of apartheid. The Court emphasized that all states and the UN have a duty not to recognise annexation and other violations for jus cogens. This opinion reaffirms the rights of the Palestinian people to self-determination and criticises the prolonged occupation for undermining those rights.

IntroductionDiabetes mellitus (DM) is a chronic metabolic disorder that increases fragility fracture risk. Conventional DXA-based areal bone mineral density (aBMD) assessments often underestimate this risk. Cortical Backscatter (CortBS) ultrasound, a radiation-free technique, non-invasively analyzes cortical bone’s viscoelastic and microstructural properties. This study aimed to evaluate CortBS’s discriminative performance in DM patients compared to DXA and characterize changes in cortical bone microstructure in Type 1 and Type 2 DM (T1DM, T2DM) patients.MethodsThis in-vivo study included 89 DM patients (T1DM = 39, T2DM = 48) and 76 age- and sex-matched controls. DXA measured aBMD, while CortBS measurements were taken at the anteromedial tibia using a medical ultrasound scanner with custom software. Multivariate analysis of variance assessed the impact of DM type on CortBS and DXA measurement results. Partial least squares discriminant analyses with cross-validation were used to compare the discrimination performance for vertebral, non-vertebral, and any fragility fractures, adjusting for gender, age, and anthropometric parameters (weight, height, BMI).ResultsFractures occurred in 8/23 T1DM, 17/18 T2DM, and 16/55 controls. DXA parameters were reduced in fracture patients, with significant diabetes impact. T2DM was associated with altered CortBS parameters, reduced scatterer density, and larger pores. CortBS outperformed DXA in discriminating fracture risk (0.61 ≤ AUC(DXA) ≤ 0.63, 0.68 ≤ AUC(CortBS) ≤ 0.69).ConclusionsBoth T1DM and T2DM showed altered bone metabolism, with T2DM linked to impaired tissue formation. CortBS provides insights into pathophysiological changes in diabetic bone and provided superior fracture risk assessment in DM patients compared to DXA.

IntroductionMonitoring internal load is crucial for athletes but often requires invasive methods for muscle-related parameters, limiting practicality. Infrared thermography (IRT) related parameters might overcome this limitation. This systematic review aimed to examine the available literature on the response of IRT related parameters to (non-)sport specific exercise and reveal relationships with internal load parameters in athletic populations.MethodsFour scientific databases were systematically searched (February 2024) with keywords related to IRT, load, and sports disciplines. Risk of bias was evaluated using QUADAS-2. Main inclusion criteria for studies were i) reporting of IRT related parameters and other internal load parameters prior/post (non-)sport specific exercise ii) inclusion of least Tier 2 athletes ≥ 18 years. After identifying n = 10,538 studies, 13 articles (n = 231 participants) were included.ResultsFollowing (non-)sport specific exercise in athletic populations, the majority of relevant studies showed a decrease in IRT related parameters within 15 min, while studies showed an increase in IRT related parameters following 30 min, 24 h, 48 h, and 72 h after exercise cessation. Relationships between alterations in IRT related parameters and other internal load parameters are inconsistent across the literature.ConclusionWhile the majority of studies show an increase in IRT related parameters following (non-)sport specific exercise, relationships with other internal load parameters and underlying physiological mechanisms evoking IRT related alterations are not conclusively revealed in athletic populations. Future research needs to assess the relationship of IRT related parameters especially with inflammatory parameters in athletic populations following (non-)sport specific exercise. Practitioners might assess IRT related parameters in conjunction with other load parameters.

BackgroundOsteoarthritis is one of the most common degenerative diseases of the musculoskeletal system and can ultimately lead to the need for surgery, such as total knee or hip arthroplasty. Functional movement deficits can be a prognostic factor for osteoarthritis in the lower extremities. Thus, training physiological movement patterns may help in the treatment of such functional deficits. Motivation to exercise frequently is of utmost importance and can be promoted by using digital real-time feedback. ObjectiveThis qualitative study aims to gather user recommendations for prototype feedback visualizations in a real-time exercise-feedback system called homeSETT for the treatment of functional deficits. The system provides real-time feedback to participants while performing exercises that focus on functional deficits, such as lateral trunk lean, pelvic drop, and valgus thrust. The findings of this study should help to optimize the prototype feedback visualizations. Thus, the main research questions were how patients, physiotherapists, and physicians evaluate the presented, current state of prototype feedback visualizations for selected functional exercises, and what improvements and variations would be recommended. MethodsTesting of the prototype feedback visualizations took place at a movement laboratory using a 3D optoelectronic movement analysis system. Data on usability factors were acquired using the thinking aloud method during and semistructured interviews after prototype testing. Transcribed audio recordings of semistructured interviews as well as scribing logs of the thinking aloud method were examined using qualitative content analysis. ResultsData were analyzed from 9 participants, comprising 2 (22%) patients, 2 (22%) physicians, and 5 (56%) physiotherapists. The mean age of the participants was 45 (SD 9) years and the mean work experience among the participating physiotherapists and physicians was 22 (SD 5) years. Each participant tested 11 different exercise-feedback combinations. Overall, results indicated that participants enjoyed the prototype feedback visualizations and believed that they could be used in therapeutic settings. Participants appreciated the simplicity, clarity, and self-explanatory nature of the feedback visualizations. While most participants quickly familiarized themselves, some struggled to recognize the feedback goals and connect the visualizations to their movements. Recommendations for improvement included optimizing color schemes, sensitivity, and difficulty adjustments. Adding instructional information and game design elements, such as repetition counting and reward systems, was deemed useful. The main study limitations were the small sample size and the use of feedback on performance as the sole feedback modality. ConclusionsThe prototype feedback visualizations were positively perceived by the participants and were considered applicable in therapy settings. Insights were gathered on improving the color scheme, sensitivity, and recognizability of the feedback visualizations. The implementation of additional gamification and instructional elements was emphasized. Future work will optimize the prototype feedback visualizations based on study results and evaluate the homeSETT system’s efficacy in eligible patient populations.

In modular educational systems, students are allowed to choose a part of their curriculum themselves. The rationale behind letting students choose their courses themselves is to enhance self-responsibility, improve student motivation, and allow for focus on specific areas of interest. A central instrument for bringing these systems to fruition is the timetable. However, scheduling the timetable in such systems can be an extremely challenging and time-consuming task. In this study, we present a framework for classifying modular educational systems in Europe that reflects different degrees of freedom regarding student choices and explore the consequences from the perspective of scheduling a timetable that satisfies all requirements from the organizational and pedagogical perspectives. For this purpose, we conducted interviews in Austria, Germany, Finland, Switzerland, the Netherlands, and Luxembourg, and applied the framework to these educational systems, finding that among them the Finnish system shows the highest degree of modularity. After analyzing the consequences of modularity from the scheduling perspective, we assess the necessity for automated scheduling methods, which are central to realizing the potential and many benefits of modular education. The framework developed in this paper can be used by educational systems to assess their degree of modularity and consider the right approach to timetabling based on it.

Abstract Sepsis, marked by organ dysfunction, necessitates reliable biomarkers. Ribonuclease inhibitor 1 (RNH1), a ribonuclease (RNase) inhibitor, emerged as a potential biomarker for acute kidney injury and mortality in thoracoabdominal aortic aneurysm patients. Our study investigates RNH1 dynamics in sepsis, its links to mortality and organ dysfunction, and the interplay with RNase 1 and RNase 5. Furthermore, we explore RNH1 as a therapeutic target in sepsis-related processes like inflammation, non-canonical inflammasome activation, and iron homeostasis. We showed that RNH1 levels are significantly higher in deceased patients compared to sepsis survivors and correlate with creatine kinase, aspartate and alanine transaminase, bilirubin, serum creatinine and RNase 5, but not RNase 1. RNH1 mitigated LPS-induced TNFα and RNase 5 secretion, and relative mRNA expression of ferroptosis-associated genes HMOX1, FTH1 and HAMP in PBMCs. Monocytes were identified as the predominant type of LPS-positive PBMCs. Exogenous RNH1 attenuated LPS-induced CASP5 expression, while increasing IL-1β secretion in PBMCs and THP-1 macrophages. As RNH1 has contradictory effects on inflammation and non-canonical inflammasome activation, its use as a therapeutic agent is limited. However, RNH1 levels may play a central role in iron homeostasis during sepsis, supporting our clinical observations. Hence, RNH1 shows promise as biomarkers for renal and hepatic dysfunction and hepatocyte injury, and may be useful in predicting the outcome of septic patients.

The study investigates how structured workout sessions influence the productivity of students in completing a thesis as the final assignment in the bachelor's degree. Eigh-semester students from the Physical Education study program participated, with one group engaging in a 30-minute workout over eight sessions and a control group of 15 students not participating in these sessions. Using observation and monitoring tools, the study assessed the impact of these workouts on thesis preparation. Regression analysis showed a determination coefficient (R’) of 0.729, indicating that 72.9% of the productivity variance was due to the workout sessions. Additionally, a 32% increase in assignment progress was observed in the experimental group. These results demonstrate a strong correlation between regular workouts and increased productivity in completing final assignments, highlighting the benefits of incorporating physical activity into academic routines.

Abstract The systemic inflammatory response following acute ischaemic stroke remains incompletely understood. We characterised the circulating inflammatory profile in 173 acute ischaemic stroke patients by measuring 65 cytokines and chemokines in plasma. Participants were grouped based on their inflammatory response, determined by high-sensitivity C-reactive protein levels in the acute phase. We compared stroke patients’ profiles with 42 people experiencing spontaneous cervical artery dissection without stroke. Furthermore, variations in cytokine levels among stroke aetiologies were analysed. Follow-up samples were collected in a subgroup of ischaemic stroke patients at three and twelve months. Ischaemic stroke patients had elevated plasma levels of HGF and SDF-1α, and lower IL-4 levels, compared to spontaneous cervical artery dissection patients without stroke. Aetiology-subgroup analysis revealed reduced levels of nine cytokines/chemokines (HGF, SDF-1α, IL-2R, CD30, TNF-RII, IL-16, MIF, APRIL, SCF), and elevated levels of IL-4 and MIP-1β, in spontaneous cervical artery dissection (with or without ischaemic stroke as levels were comparable between both groups) compared to other aetiologies. The majority of cytokine/chemokine levels remained stable across the study period. Our research indicates that stroke due to large artery atherosclerosis, cardioembolism, and small vessel occlusion triggers a stronger inflammatory response than spontaneous cervical artery dissection.

Abstract Background Point-of-care ultrasound (POCUS) is a critical diagnostic tool in various medical settings, yet its instruction in medical education is inconsistent. The Rapid Ultrasound for Shock and Hypotension (RUSH) protocol is a comprehensive diagnostic tool, but its complexity poses challenges for teaching and learning. This study evaluates the effectiveness of a single-day training in RUSH for medical students by assessing their performance in clinical scenarios. Methods In this prospective single-center observational proof-of-concept study, 16 medical students from Saarland University Medical Center underwent a single-day training in RUSH, followed by evaluations in clinical settings and on a high-fidelity simulator. Performance was assessed using a standardized scoring tool and time to complete the RUSH exam. Knowledge gain was measured with pre- and post-training written exams, and diagnostic performance was evaluated with an objective structured clinical examination (OSCE). Results Students demonstrated high performance in RUSH exam views across patients (median performance: 85–87%) and improved scanning times, although not statistically significant. They performed better on simulators than on live patients. Written exam scores significantly improved post-training, suggesting a gain in theoretical knowledge. However, more than a third of students could not complete the RUSH exam within five minutes on live patients. Conclusions Single-day RUSH training improved medical students’ theoretical knowledge and simulator performance but translating these skills to clinical settings proved challenging. The findings suggest that while short-term training can be beneficial, it may not suffice for clinical proficiency. This study underscores the need for structured and possibly longitudinal training programs to ensure skill retention and clinical applicability.

With the global digitalization of services, passenger Intelligent Transportation Systems (ITSs) have emerged as transformative components, yet the practical implementation of state-of-the-art measures to ensure information security and privacy presents substantial challenges. In this article, we propose a framework for information security and privacy management. The framework is validated through two empirical studies. First, the framework is used to extract data during the literature review defining state-of-the-art aspects and measures. Second, a survey-based analysis of running passenger ITSs in selected regions of the European Union provides insights into real-life ITS implementations, enabling a thorough comparison with the proposed state-of-the-art measures. The study also showed that the proposed framework depicts some dependencies between measures, and, thus, using its matrix structure for the state of information security and privacy management in the organization helps to cross-check the usage of policies or methodologies by the organization departments. Our findings resulted in recommendations for organizations developing ITSs to enhance their information security and privacy management systems and bridge the gap between research proposals and practical implementation.

This research provides a method for a reliable fatigue life estimation at high testing frequencies. The investigations are based on the lifetime prediction method StressLifeHCF considering test frequencies of 80 and 260 Hz for normalized SAE 1045 (C45E, 1.1191) steel. Therefore, load increase tests and constant amplitude tests were carried out using a resonant testing rig. To ensure a mechanism-oriented lifetime prediction, the material response to dynamic loading is monitored via temperature and electrical resistance measurements. Due to the higher energy input per time unit, when the test frequency is increased, the heat dissipation also increases. For this reason, a precise differentiation between frequency- and temperature-related effects for adequate fatigue assessment is challenging. To evaluate the temperature’s influence on electrical resistance, an electrical resistance-temperature hysteresis is measured, and the frequency influence is analyzed by considering cyclic deformation curves. In addition to an extension of the fatigue life due to an increased test frequency, the lifetime prediction method was validated for high frequencies. The generated S-N curves show a reliable agreement with the data points from conventional constant amplitude tests. In this context, the temperature correction of the electrical resistance proved to be an important input variable for a reliable lifetime prediction.

Background Living with a family member who has a long-term health condition (HC) is associated with poorer health and well-being outcomes, but the number and socio-demographics of people and families impacted by a family member who has an HC is unknown. Methods Using the Integrated Data Infrastructure (IDI), a collection of linked administrative datasets for the full New Zealand (NZ) population, we identified n= 1,043,172 families using 2013 NZ Census data, and used health data over the previous 5-years to ascertain whether people in these families (n=3,137,517) had cancer, chronic obstructive pulmonary disease, coronary health disease, diabetes, dementia, gout, stroke, traumatic brain injury (TBI) or a mental health/behavioural condition (MHBC). Results Over 60% of families included at least one person with a HC. The most common HCs were MHBCs (39.4% of families), diabetes (16.0%), and TBI (13.9%). A high proportion of multi-generation families (73.9%) included a member with a HC. Two-thirds (67.7%) of Pacific Peoples either had a HC themselves or were living with a family member who had a HC, compared with 62.3% of Europeans and 62.5% of Māori (the indigenous peoples of NZ). At the highest level of socioeconomic deprivation, 57.6% of children lived with a family member who had a HC. Conclusions Three in five NZ families were living with a HC, with differences in the proportion affected according to family composition, socio-economic status and an individuals’ ethnicity. This suggests that there are a substantial number of people at risk of the associated poor outcomes.

In minimally invasive surgery, grippers are essential for tissue manipulation. However, in commercial tendon‐driven systems, challenges remain, including tendon fatigue and bulkiness. Promising alternatives are magnetically actuated systems, offering contactless steering but limited forces. To overcome this, a miniaturized, locally actuated magnetic gripper with variable stiffness is presented. The gripper employs thin planar coils (75 μm) and a radially magnetized plunger, enabling local actuation and enhanced orientation control. The variable stiffness compliant mechanism made from shape‐memory polymer facilitates different gripping strategies. In its rigid state, pulsed pulling forces of 340 mN and continuous forces of 90 mN are achieved, exceeding the gripper weight by factors of 70 and 18, respectively. The soft state, with a fast response time of 20 ms, enables soft gripping of various targets, including moving ones and rat tissue samples. Demonstrating the applicability, contactless steering and target retrieval within a stomach phantom is showcased. This study introduces promising improvements to magnetically actuated grippers for surgical procedures, addressing key challenges in current designs.

IntroductionPosterior circulation stroke can lead to ataxia, manifesting in a loss of coordination and balance. Patients experience difficulty in activities of daily living and an increased risk of falling, both profoundly affecting quality of life. In individuals with neurodegenerative diseases, coordination exercises have been shown to lead to a reduction in ataxic symptoms. There is, however, limited evidence on the effect of physical therapy, specifically coordination exercises in patients with stroke-related ataxia. We therefore present a study protocol for a prospective trial.MethodsThe purpose of this trial is to investigate the effects of coordination exercises compared to standard physiotherapy on balance and walking in ataxic stroke patients. Therefore, a prospective, single-blinded randomized controlled trial is currently ongoing at the Clinical Department of Neurology, Medical University of Innsbruck, Austria, in collaboration with two local rehabilitation facilities in Austria, Hochzirl Hospital and the Clinic for Rehabilitation Münster. Balance is the primary outcome of the study as assessed using the Berg Balance Scale. Secondary outcomes are concerned with walking, risk and number of falls, independence in daily life, and quality of life, rated using appropriate scales and scores. Patients are allocated applying a 1:1 ratio and a stratified block randomization. In both groups recruited individuals undergo five 45-min treatment sessions per week, totaling 20 sessions of coordination exercises (IG) or standard physiotherapy (CG) over the course of 4 weeks. Data is collected at the baseline (T0), after the 4-week supervised practice (T1), and after another 8 weeks of independent home-based training (T2).DiscussionThis is the first randomized controlled trial investigating the effects of coordination exercises on balance and walking in people with stroke-related ataxia. As stroke guidelines emphasize the limited evidence of treatment for ataxic symptoms, this study aims to contribute further knowledge regarding tailored interventions for these patients.Clinical Trial RegistrationGerman Clinical Trials Registry (drks.de). Identifier: DRKS00020825.

BackgroundOsteoarthritis of the hip joint is an increasing functional and health-related problem. The most common surgical treatment is hip replacement to reduce pain and improve function. Rehabilitation after total hip arthroplasty (THA) is not regulated in Austria and mostly depends on the patient’s own initiative and possibilities. Functional deficits, such as valgus thrust of the leg, functional Trendelenburg gait, or Duchenne limp, are characteristic symptoms before and, due to the performance learning effect prior to surgery, also after the operation. Addressing these deficits is possible through neuromuscular-focused exercise therapy. The efficacy of such therapy relies significantly on the quality of performance, the frequency of exercise, and the duration of engagement. Enhancing sustainability is achievable through increased motivation and real-time feedback (RTF) on exercise execution facilitated by digital feedback systems. ObjectiveThis study will be performed to quantify the medium-term effectiveness of digital home exercise feedback systems on functional performance following THA. MethodsA clinical trial with a cluster-randomized, 2-arm, parallel-group design with an 8-week intervention phase and subsequent follow-ups at 3 and 6 months postsurgery will be conducted. Feedback during exercising will be provided through a blended-care program, combining a supervised group exercise program with a self-developed digital feedback system for home exercise. In total, 70 patients will be recruited for baseline. The primary outcome parameters will be the frontal knee range of motion, pelvic obliquity, and lateral trunk lean. Secondary outcomes will be the sum scores of patient-reported outcomes and relevant kinematic, kinetic, and spatiotemporal parameters. ResultsThe trial started in January 2024, and the first results are anticipated to be published by June 2025. RTF-supported home exercise is expected to improve exercise execution quality and therapeutic adherence compared to using paper instructions for excise guidance. ConclusionsThe anticipated findings of this study aim to offer new insights into the effect of a blended-care program incorporating digital RTF on exercise therapy after unilateral THA, in addition to knowledge on the functional status 3 and 6 months postsurgery, for further improvement in the development of rehabilitation guidelines following THA. Trial RegistrationClinicalTrials.gov: NCT06161194; https://clinicaltrials.gov/study/NCT06161194 International Registered Report Identifier (IRRID)PRR1-10.2196/59755

Abstract Hydraulic fluid power systems are essential for a range of engineering applications such as transportation, heavy industry, and robotics. The scale of the industry is such that hydraulic pumps are estimated to account for 15% of all the energy consumption in the European Union and yet the average efficiency of fluid power systems is only 22%. The digitalization of hydraulic systems offers significant advantages in terms of energy efficiency, performance, reduced maintenance, and automation. However, this requires advances in the integration of smart sensing technologies to provide real‐time feedback on the operation and health of hydraulic components. This review details developing trends in hydraulic fluid power research and provides an overview of progress related to the digitalization of these systems and their integration within an Industry 4.0 framework. The fundamentals of relevant sensor technologies and innovative approaches for integrating sensors into hydraulics systems are discussed. Methods to deliver power to the sensors and associated electronics through harvested pressure ripples are also reviewed. An outlook with respect to future directions in this field is given, including an assessment of the potential for exploiting advanced manufacturing technologies, in particular additive manufacturing, to facilitate successful sensor integration into hydraulic fluid power systems.

Abstract Many biological processes rely on endogenous electric fields (EFs), including tissue regeneration, cell development, wound healing, and cancer metastasis. Mimicking these biological EFs by applying external direct current stimulation (DCS) is therefore the key to many new therapeutic strategies. During DCS, the charge transfer from electrode to tissue relies on a combination of reversible and irreversible electrochemical processes, which may generate toxic or bio‐altering substances, including metal ions and reactive oxygen species (ROS). Poly(3,4‐ethylenedioxythiophene) (PEDOT) based electrodes are emerging as suitable candidates for DCS to improve biocompatibility compared to metals. This work addresses whether PEDOT electrodes can be tailored to favor reversible biocompatible charge transfer. To this end, different PEDOT formulations and their respective back electrodes are studied using cyclic voltammetry, chronopotentiometry, and direct measurements of H2O2 and O2. This combination of electrochemical methods sheds light on the time dynamics of reversible and irreversible charge transfer and the relationship between capacitance and ROS generation. The results presented here show that although all electrode materials investigated generate ROS, the onset of ROS can be delayed by increasing the electrode's capacitance via PEDOT coating, which has implications for future bioelectronic devices that allow longer reversibly driven pulse durations during DCS.

The ecology of forest ecosystems depends on the composition of trees. Capturing fine-grained information on individual trees at broad scales provides a unique perspective on forest ecosystems, forest restoration, and responses to disturbance. Individual tree data at wide extents promises to increase the scale of forest analysis, biogeographic research, and ecosystem monitoring without losing details on individual species composition and abundance. Computer vision using deep neural networks can convert raw sensor data into predictions of individual canopy tree species through labeled data collected by field researchers. Using over 40,000 individual tree stems as training data, we create landscape-level species predictions for over 100 million individual trees across 24 sites in the National Ecological Observatory Network (NEON). Using hierarchical multi-temporal models fine-tuned for each geographic area, we produce open-source data available as 1 km2 shapefiles with individual tree species prediction, as well as crown location, crown area, and height of 81 canopy tree species. Site-specific models had an average performance of 79% accuracy covering an average of 6 species per site, ranging from 3 to 15 species per site. All predictions are openly archived and have been uploaded to Google Earth Engine to benefit the ecology community and overlay with other remote sensing assets. We outline the potential utility and limitations of these data in ecology and computer vision research, as well as strategies for improving predictions using targeted data sampling.

Ziel der Studie ist eine genaue Untersuchung der populationsnormalisierten Behandlungskosten von Orphan Drugs. Zu diesem Zweck wurde bereits im Jahr 2022 eine Studie zur Betrachtung der Therapiekosten von Orphan Drugs für die Jahre 2005 bis 2021 durchgeführt. Die Berechnungen wurden nun im Rahmen eines Studienupdates validiert, wobei die identische Grundgesamtheit herangezogen wurde. Das Update ermöglichte eine Inflationsbereinigung basierend auf dem Preisindex des Jahres 2022 sowie lückenlose Behandlungskosten nach AMNOG-Bewertung und Preisverhandlung für alle Orphan Drugs. Die Analyse zeigt, dass das AMNOG als Preisregulierungsinstrument auch bei Orphan Drugs seine Funktion erfüllt. Seit AMNOG-Einführung sind die inflationsbereinigten normalisierten Behandlungskosten für Orphan Drugs sowohl im Hinblick auf den Einführungspreis (minus 25%) als auch auf den Erstattungsbetrag (minus 6%) gesunken.

Abstract Trillions of microorganisms, collectively known as the microbiome, inhabit our bodies with the gut microbiome being of particular interest in biomedical research. Bacteriophages, the dominant virome constituents, can utilize suppressor tRNAs to switch to alternative genetic codes (e.g., the UAG stop-codon is reassigned to glutamine) while infecting hosts with the standard bacterial code. However, what triggers this switch and how the bacteriophage manipulates its host is poorly understood. Here, we report the discovery of a subgroup of minimal hepatitis delta virus (HDV)-like ribozymes – theta ribozymes – potentially involved in the code switch leading to the expression of recoded lysis and structural phage genes. We demonstrate their HDV-like self-scission behavior in vitro and find them in an unreported context often located with their cleavage site adjacent to tRNAs, indicating a role in viral tRNA maturation and/or regulation. Every fifth associated tRNA is a suppressor tRNA, further strengthening our hypothesis. The vast abundance of tRNA-associated theta ribozymes – we provide 1753 unique examples – highlights the importance of small ribozymes as an alternative to large enzymes that usually process tRNA 3’-ends. Our discovery expands the short list of biological functions of small HDV-like ribozymes and introduces a previously unknown player likely involved in the code switch of certain recoded gut bacteriophages.

Currently, with the threat of quantum computer attacks, the idea of combining several same-type primitives has reemerged. This is also the case for cryptographic keys where a hybrid quantum key exchange combination allows for preserving the security guarantees of pre-quantum schemes and achieving quantum resistance of post-quantum schemes. In this article, we present a concrete 3-key combiner system implemented on a Field Programmable Gate Arrays (FPGA) platform. Our system involves a pre-quantum Key EXchange scheme (KEX), a post-quantum key encapsulation mechanism, and a Quantum Key Distribution (QKD) algorithm. The proposed 3-key combiner is proven to be secure in the quantum standard model and it is INDistinguishable under a Chosen-Ciphertext Attack (IND-CCA). Our combiner can run in small FPGA platforms due to its relatively low resources usage. In particular, the key combiner without QKD is able to output up to 1 624 keys per second and the key combiner with QKD is able to output up to 9.2 keys per second.

We show that matter-wave diffraction off a single standing laser wave can be used as an accurate measurement scheme for photophysical molecular parameters. These include state-dependent optical polarizabilities and photon-absorption cross sections, the relaxation rates for fluorescence, internal conversion, and intersystem crossing, as well as ionization or cleavage probabilities. We discuss how the different photophysical processes manifest as features of the interference pattern, and we determine the accuracy of molecular parameters estimated from a realistic measurement with finite particle numbers. The analysis is based on an analytic calculation in Wigner representation, which accounts for the laser-induced coherent and incoherent dynamics, for the finite longitudinal and transverse coherence in the matter-wave beam, the gravitational and Coriolis acceleration, and an imperfect standing laser wave.

Ewing Sarcoma Breakpoint Region 1 and POZ/BTB And AT Hook Containing Zinc Finger 1 (EWSR1::PATZ1) gene fusion central nervous system (CNS) tumors are increasingly recognized as a potential distinct entity, with only limited reported cases. The imaging characteristics of these tumors have not been well established. In this study, we provide a detailed radiological description of a case in a 24‑year‑old man and conduct a literature review to identify common imaging features. A total of seven cases, including our own, were evaluated. Histopathological diagnoses included two ependymomas, an infantile glioblastoma, an astroblastoma, a ganglioglioma, and two gliomas not otherwise specified. Common imaging patterns included avid contrast enhancement, intratumoral cysts, intraventricular location or extension leading to hydrocephalus, and sharp delineation. Additional frequently observed features included calcifications and hemorrhagic foci. In conclusion, although the histopathological appearance of EWSR1::PATZ1 gene fusion CNS tumors is diverse, there are consistent imaging features. Recognition of these features can be valuable in the diagnostic process, as radiologists can be the first to suggest the diagnosis.

Triclosan and Triclocarban, preservatives widely used in cosmetics and other consumer products, underwent evaluation using a battery of new-approach methodologies in vitro (NAMs). Specifically, the Microplate Ames Test (MPF™ Test, Xenometrix, Allschwil, Switzerland) was employed to assess mutagenicity, the Comet assay in vitro on the HaCat cell line and the Mammalian Chromosome Aberration Test were utilized to evaluate genotoxicity, and the XenoScreen® YES/YAS assay was applied to investigate endocrine disruption. The chemicals did not exhibit any positive responses for mutagenicity. However, the mammalian chromosome aberration test identified both chemicals as being positive for genotoxicity at 10 µg/mL. In the Comet assay, the percentage of DNA in the tail significantly increased in a concentration-dependent manner (at 5 and 10 µg/mL for Triclosan, at 2.5, 5, and 10 µg/mL for Triclocarban). The positive response depended on the increasing concentration and the duration of exposure. Triclosan, but not Triclocarban in any of the endocrine assays performed, indicated a potential for endocrine activity in the anti-estrogenic and anti-androgenic assays. The positive in vitro results detected were obtained for concentrations relevant to final products. The alarming findings obtained with the use of new-approach methodologies (NAMs) justify the current precautionary regulatory approach, limiting the use of these preservatives.

Abstract Obesity is an enormous health problem, and many patients do not respond to any of the available therapies. Deep brain stimulation (DBS) is currently investigated as a potential treatment for morbid obesity. In this study, we tested the hypothesis that high-frequency DBS targeting the nucleus accumbens (NAc) shell region reduces food intake and weight gain in mice fed a high-fat diet. We implanted male C57BL/6J mice with bilateral electrodes and a head-mounted microstimulator enabling continuous stimulation for up to 5 weeks. In successfully operated animals (n = 9 per group, high-frequency vs. sham stimulation), we investigated immediate and long-term stimulation effects on metabolic and behavioral phenotypes. Here we show that stimulation acutely induced a transient reduction in energy expenditure and locomotor activity but did not significantly affect spontaneous food intake, social interaction, anxiety or exploratory behaviors. In contrast, continuous stimulation over 5 weeks led to a decrease in food intake and thigmotaxis (the tendency to stay near walls in an open lit arena). However, chronic stimulation did not substantially change weight gain in mice fed a high-fat diet. Our results do not support the use of continuous high-frequency NAc shell DBS as a treatment for obesity. However, DBS can alter obesity-related parameters with differing short and long-term effects. Therefore, future research should employ time and context-sensitive experimental designs to assess the potential of DBS for clinical translation in this area.

Abstract The wealth of text data generated by social media has enabled new kinds of analysis of emotions with language models. These models are often trained on small and costly datasets of text annotations produced by readers who guess the emotions expressed by others in social media posts. This affects the quality of emotion identification methods due to training data size limitations and noise in the production of labels used in model development. We present LEIA, a model for emotion identification in text that has been trained on a dataset of more than 6 million posts with self-annotated emotion labels for happiness, affection, sadness, anger, and fear. LEIA is based on a word masking method that enhances the learning of emotion words during model pre-training. LEIA achieves macro-F1 values of approximately 73 on three in-domain test datasets, outperforming other supervised and unsupervised methods in a strong benchmark that shows that LEIA generalizes across posts, users, and time periods. We further perform an out-of-domain evaluation on five different datasets of social media and other sources, showing LEIA’s robust performance across media, data collection methods, and annotation schemes. Our results show that LEIA generalizes its classification of anger, happiness, and sadness beyond the domain it was trained on. LEIA can be applied in future research to provide better identification of emotions in text from the perspective of the writer.

Abstract Measuring forest biodiversity using terrestrial surveys is expensive and can only capture common species abundance in large heterogeneous landscapes. In contrast, combining airborne imagery with computer vision can generate individual tree data at the scales of hundreds of thousands of trees. To train computer vision models, ground‐based species labels are combined with airborne reflectance data. Due to the difficulty of finding rare species in a large landscape, many classification models only include the most abundant species, leading to biased predictions at broad scales. For example, if only common species are used to train the model, this assumes that these samples are representative across the entire landscape. Extending classification models to include rare species requires targeted data collection and algorithmic improvements to overcome large data imbalances between dominant and rare taxa. We use a targeted sampling workflow to the Ordway Swisher Biological Station within the US National Ecological Observatory Network (NEON), where traditional forestry plots had identified six canopy tree species with more than 10 individuals at the site. Combining iterative model development with rare species sampling, we extend a training dataset to include 14 species. Using a multi‐temporal hierarchical model, we demonstrate the ability to include species predicted at

Der deutsche Gesetzgeber hat mit dem Arzneimittelmarkt-neuordnungsgesetz (AMNOG) im Jahr 2011 das Prinzip der nutzenbasierten Preisbildung gesetzlich verankert. So orientiert sich die Preisverhandlung seitdem neben den Jahrestherapiekosten vergleichbarer Arzneimittel und Abgabepreisen in anderen EU-Ländern maßgeblich am Zusatznutzen eines Arzneimittels. Ziel des Gesetzes war es, den Preis für neue Arzneimittel mit Patentschutz bzw. neuem Unterlagenschutz im Anschluss an eine Zusatznutzenbewertung zu verhandeln. Die Nutzenbewertung erfolgt gegenüber der zweckmäßigen Vergleichstherapie (zVT). Dieser ermittelte Zusatznutzen bildet mit den zuvor benannten Kriterien die Grundlage für die Erstattungspreisverhandlung, welche auf Basis des Beschlusses des Gemeinsamen Bundesausschusses (G-BA) zwischen dem pharmazeutischen Unternehmer und dem Spitzenverband Bund der Krankenkassen (GKV-SV) geführt wird. Der hieraus resultierende Preisabschlag auf den Einführungspreis ist die Grundlage für die Berechnung der AMNOG-Einsparungen nach § 130b SGB V. Diese berechnen sich durch die Umsatzdifferenz des betrachteten realen Umsatzes (Preis entspr. Erstattungsbetragsverhandlung x Menge) und eines „fiktiven“ Umsatzes (Preis ohne Erstattungsbetragsverhandlung x Menge), welcher ohne die AMNOG-Preisverhandlungen erstattet worden wäre.

Summary: Impaired spatial navigation is early marker of Alzheimer’s disease (AD). We examined ability of self- and informant-reported navigation questionnaires to discriminate between clinically and biomarker-defined participants, and associations of questionnaires with navigation performance, regional brain atrophy, AD biomarkers, and biomarker status. 262 participants (cognitively normal, with subjective cognitive decline, amnestic mild cognitive impairment [aMCI], and mild dementia) and their informants completed three navigation questionnaires. Navigation performance, magnetic resonance imaging volume/thickness of AD-related brain regions, and AD biomarkers were measured. Informant-reported questionnaires distinguished between cognitively normal and impaired participants, and amyloid-β positive and negative aMCI. Lower scores were associated with worse navigation performance, greater atrophy in AD-related brain regions, and amyloid-β status. Self-reported questionnaire scores did not distinguish between the groups and were weakly associated with navigation performance. Other associations were not significant. Informant-reported navigation questionnaires may be a screening tool for early AD reflecting atrophy of AD-related brain regions and AD pathology.

Background Data on impact of COVID‐19 vaccination and outcomes of patients with COVID‐19 and acute ischemic stroke undergoing mechanical thrombectomy are scarce. Addressing this subject, we report our multicenter experience. Methods and Results This was a retrospective analysis of patients with COVID‐19 and known vaccination status treated with mechanical thrombectomy for acute ischemic stroke at 20 tertiary care centers between January 2020 and January 2023. Baseline demographics, angiographic outcome, and clinical outcome evaluated by the modified Rankin Scale score at discharge were noted. A multivariate analysis was conducted to test whether these variables were associated with an unfavorable outcome, defined as modified Rankin Scale score >3. A total of 137 patients with acute ischemic stroke (48 vaccinated and 89 unvaccinated) with acute or subsided COVID‐19 infection who underwent mechanical thrombectomy attributable to vessel occlusion were included in the study. Angiographic outcomes between vaccinated and unvaccinated patients were similar (modified Thrombolysis in Cerebral Infarction ≥2b: 85.4% in vaccinated patients versus 86.5% in unvaccinated patients; P=0.859). The rate of functional independence (modified Rankin Scale score, ≤2) was 23.3% in the vaccinated group and 20.9% in the unvaccinated group (P=0.763). The mortality rate was 30% in both groups. In the multivariable analysis, vaccination status was not a significant predictor for an unfavorable outcome (P=0.957). However, acute COVID‐19 infection remained significant (odds ratio, 1.197 [95% CI, 1.007–1.417]; P=0.041). Conclusions Our study demonstrated no impact of COVID‐19 vaccination on angiographic or clinical outcome of COVID‐19–positive patients with acute ischemic stroke undergoing mechanical thrombectomy, whereas worsening attributable to COVID‐19 was confirmed.

IntroductionThis study aimed to emphasize the importance of cranial nerve (CN) palsies in spontaneous cervical artery dissection (sCeAD).MethodsA search term-based literature review was conducted on “cervical artery dissection” and “cranial nerve palsy.” English and German articles published until October 2023 were considered.ResultsCranial nerve (CN) palsy in sCeAD is evident in approximately 10% of cases. In the literature, isolated palsies of CN II, III, VII, IX, X, and XII have been reported, while CN XI palsy only occurs in combination with other lower cranial nerve palsies. Dissection type and mural hematoma localization are specific to affected CN as CN palsies of II or III are solely evident in those with steno-occlusive vessel pathologies located at more proximal segments of ICA, while those with CN palsies of IX, X, XI, and XII occur in expansive sCeAD at more distal segments. This dichotomization emphasizes the hypothesis of a different pathomechanism in CN palsy associated with sCeAD, one being hypoperfusion or microembolism (CN II, III, and VII) and the other being a local mass effect on surrounding tissue (CN IX, X, XI, and XII). Clinically, the distinction between peripheral palsies and those caused by brainstem infarction is difficult. This differentiation is key, as, according to the reviewed cases, peripheral cranial nerve palsies in sCeAD patients mostly resolve completely over time, while those due to brainstem stroke do not, making cerebrovascular imaging appraisal essential.DiscussionIt is important to consider dissections as a potential cause of peripheral CN palsies and to be aware of the appropriate diagnostic pathways. This awareness can help clinicians make an early diagnosis, offering the opportunity for primary stroke prevention.

RNA, widely recognized as an information-carrier molecule, is capable of catalyzing essential biological processes through ribozymes. Despite their ubiquity, specific functions in a biological context and phenotypes based on the ribozymes' activity are often unknown. Here, we present the discovery of a subgroup of minimal HDV-like ribozymes, which reside 3' to viral tRNAs and appear to cleave the 3'-trailers of viral premature tRNA transcripts. This proposed tRNA-processing function is unprecedented for any ribozymes, thus, we designate this subgroup as theta ribozymes. Most theta ribozymes were identified in Caudoviricetes bacteriophages, the main constituent (>90%) of the mammalian gut virome. Intriguingly, our findings further suggest the involvement of theta ribozymes in the transition of certain bacteriophages between distinct genetic codes, thus possibly contributing to the phage lysis trigger. Our discovery expands the limited repertoire of biological functions attributed to HDV-like ribozymes and provides insights into the fascinating world of RNA catalysis.

Background The individual HLA-I genotype is associated with cancer, autoimmune diseases and infections. This study elucidates the role of germline homozygosity or allelic imbalance of HLA-I loci in esophago-gastric adenocarcinoma (EGA) and determines the resulting repertoires of potentially immunogenic peptides.Methods HLA genotypes and sequences of either (1) 10 relevant tumor-associated antigens (TAAs) or (2) patient-specific mutation-associated neoantigens (MANAs) were used to predict good-affinity binders using an in silico approach for MHC-binding (www.iedb.org). Imbalanced or lost expression of HLA-I-A/B/C alleles was analyzed by transcriptome sequencing. FluoroSpot assays and TCR sequencing were used to determine peptide-specific T-cell responses.Results We show that germline homozygosity of HLA-I genes is significantly enriched in EGA patients (n=80) compared with an HLA-matched reference cohort (n=7605). Whereas the overall mutational burden is similar, the repertoire of potentially immunogenic peptides derived from TAAs and MANAs was lower in homozygous patients. Promiscuity of peptides binding to different HLA-I molecules was low for most TAAs and MANAs and in silico modeling of the homozygous to a heterozygous HLA genotype revealed normalized peptide repertoires. Transcriptome sequencing showed imbalanced expression of HLA-I alleles in 75% of heterozygous patients. Out of these, 33% showed complete loss of heterozygosity, whereas 66% had altered expression of only one or two HLA-I molecules. In a FluoroSpot assay, we determined that peptide-specific T-cell responses against NY-ESO-1 are derived from multiple peptides, which often exclusively bind only one HLA-I allele.Conclusion The high frequency of germline homozygosity in EGA patients suggests reduced cancer immunosurveillance leading to an increased cancer risk. Therapeutic targeting of allelic imbalance of HLA-I molecules should be considered in EGA.

Abstract Futibatinib is a covalently binding FGFR1–4 inhibitor that received US Food and Drug Administration approval for the treatment of patients with previously treated, advanced intrahepatic cholangiocarcinoma harboring FGFR2 gene fusions/rearrangements. This phase I trial evaluated the pharmacokinetics (PKs), safety, and tolerability of futibatinib in subjects with impaired hepatic function and matched healthy volunteers. Twenty‐two subjects with hepatic impairment (8 mild [Child‐Pugh 5–6], 8 moderate [7–9], and 6 severe [10–15]) and 16 matched healthy control subjects received a single oral dose of futibatinib 20 mg. Futibatinib PKs were compared between subjects with mild/moderate/severe hepatic impairment and each corresponding control cohort and the overall control cohort. Relationships between futibatinib PKs and Child‐Pugh scores and liver function tests were examined via scatter/regression plots. Compared with matched controls, the area under the plasma concentration–time curve from time zero to infinity increased by 21%/20%/18% and the maximum plasma concentration (Cmax) increased by 43%/15%/10% in subjects with mild/moderate/severe hepatic impairment, respectively. Changes were not considered clinically relevant: geometric mean ratios were within 80%–125%, except for Cmax in subjects with mild hepatic impairment (143%). No obvious trends were observed among futibatinib PK parameters versus Child‐Pugh scores, bilirubin, albumin, international normalized ratio, and aspartate aminotransferase (all p > 0.05). Futibatinib was well‐tolerated, with only four grade 1 treatment‐emergent adverse events (mild hepatic impairment = 2 and control = 2). The results demonstrate that futibatinib dose adjustments due to mild/moderate/severe hepatic impairment are not necessary in patients receiving futibatinib 20 mg daily.