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Abstract: The B-cell lymphoma 2 inhibitor venetoclax (VEN) in combination with hypomethylating agents has been approved for first-line treatment of patients with acute myeloid leukemia (AML) ineligible for intensive treatment. VEN-containing treatment strategies may also be effective in relapsed/refractory (R/R) AML; however, comparative studies with conventional therapies for fit patients as a bridge-to-transplant strategy are limited. Using propensity score matching (PSM), we compared 37 patients with R/R AML, who received VEN-based salvage therapy as bridge to allogeneic hematopoietic stem cell transplantation (allo-HCT), with 90 patients from the German Study Alliance Leukemia AML registry, who were treated with non–VEN-containing salvage therapy according to their treating physician’s choice (TPC). The overall response rate among VEN patients was higher than the TPC control cohort (62% vs 42%; P = .049). Overall, 73% of VEN-treated patients vs 63% of TPC patients were bridged to allo-HCT (P = .41). After a median follow-up of 34.3 months for the VEN and 21.0 months for the TPC cohort, the median overall survival (OS) were 15.8 months (95% confidence interval [CI], 10.6 to not evaluable) and 10.5 months (95% CI, 6.8-19.6; P = .15), respectively. PSM revealed a trend toward improved OS for VEN patients (hazard ratio, 0.70; 95% CI, 0.41-1.22; P = .20). Median event-free survival was significantly longer in the VEN cohort (8.0 months) than the TPC cohort (3.7 months; P = .006). Our data suggest that VEN-based salvage therapy is a safe and effective bridge to allo-HCT for this difficult-to-treat AML patient population.

Abstract Precision oncology offers new cancer treatment options, yet sequencing methods vary in type and scope. In this study, we compared whole-exome/whole-genome (WES/WGS) and transcriptome sequencing (TS) with broad panel sequencing by resequencing the same tumor DNA and RNA as well as normal tissue DNA for germline assessment, from 20 patients with rare or advanced tumors, who were originally sequenced by WES/WGS ± TS within the DKFZ/NCT/DKTK MASTER program from 2015 to 2020. Molecular analyses resulted in a median number of 2.5 (gene panel) to 3.5 (WES/WGS ± TS) treatment recommendations per patient. Our results showed that approximately half of the therapy recommendations (TRs) of both sequencing programs were identical, while approximately one-third of the TRs in WES/WGS ± TS relied on biomarkers not covered by the panel. Eight of 10 molecularly informed therapy implementations were supported by the panel, the remaining two were based on biomarkers absent from the panel, highlighting the potential additional clinical benefit of WGS and TS.

Abstract In patients with amyotrophic lateral sclerosis (ALS), mechanical insufflation-exsufflation (MI-E) addresses cough deficiency to achieve major therapeutic goals: improving costal muscle and joint function, reducing atelectasis through insufflation, and clearing bronchial secretions via exsufflation. Despite its perceived benefits, there is limited systematic research on MI-E provision, symptom alleviation, or patient satisfaction. The research platform Ambulanzpartner coordinated this longitudinal observational study conducted in 12 German ALS centers from July 2018 to September 2023. Patients were enrolled based on ALS-related cough deficiency requiring MI-E therapy. The study recorded provision, reasons for withholding MI-E, clinical parameters, therapy frequency, subjective cough deficiency, and symptomatic relief. Satisfaction with MI-E therapy was determined by the likelihood of recommendation. Out of 694 ALS patients indicated for MI-E, 527 (75.9%) received the therapy. The primary reason for non-provision was that the patient had died before provision (n = 66 of 167; 39.5%). These patients were significantly more affected as represented by higher progression rates and lower cough peak flows (CPF) at the time of MI-E indication (p

Abstract Hemophagocytic lymphohistiocytosis (HLH) is an excessive immune activation with cytokine storm und multi-organ dysfunction. It can occur secondarily, especially due to viral infections like COVID-19. Rapid treatment is crucial for favourable outcomes, but diagnosing HLH is challenging. The most common diagnostic instrument is the H-Score. However, the prognostic value of the H-score has not yet been assessed in detail in the spotlight of secondary HLH in severe COVID-19. COVID-19 patients treated between February 2020 and April 2021 at the intensive care unit (ICU) of the Department of Infectious Diseases and Tropical Medicine, Clinic Favoriten, Vienna, Austria, were included in this study. Data were assessed retrospectively by document review, and the follow-up period was at least 90 days. A total of 208 critically ill COVID-19 patients with an age of 61.8 ± 13.6 years were enrolled in this study. We found an average H-Score in the entire study collective of 94 ± 51 points, and 8.7% had a score ≥ 169 testing positive for HLH. A positive score was associated with increased mortality rates at 28 (66.7 vs. 26.3%, p

Abstract Purpose The management of soft tissue sarcoma (STS) at reference centers with specialized multidisciplinary tumor boards (MTB) improves patient survival. The German Cancer Society (DKG) certifies sarcoma centers in German-speaking countries, promoting high standards of care. This study investigated the variability in treatment recommendations for localized STS across different German-speaking tertiary sarcoma centers. Methods In this cross-sectional case-based survey study, 5 anonymized patient cases with imaging data of localized STS were presented to MTBs of 21 German-speaking tertiary referral hospitals. Centers provided recommendations on treatment sequence and modalities, along with the consensus level within their MTB. Agreement percentages were calculated, and consensus levels were rated on a scale of 1 to 10. Results Five patient cases were discussed resulting in 105 recommendations. Agreement percentages for case 1 to 5 were 14.3%, 61.9%, 33.3%, 52.4% and 9.3%, with a median agreement percentage of 33.3%. Grouping pre- and postoperative therapies as "perioperative" and including recommendations with and without regional hyperthermia raised the median agreement to 47.6%. The mean consensus level within each center across all 5 cases was 9.5. Conclusion This first case-based analysis of inter-center agreement for STS management in German-speaking countries reveals low inter-center agreement but high intra-center consensus. Our study includes nearly all tertiary sarcoma centers in German-speaking countries, affirming its strong external validity. These findings suggest potential and clinically very relevant differences in treatment standards among sarcoma centers. Enhanced case-based exchanges and collaborative efforts are needed to reduce discrepancies and standardize the management of STS patients.

Abstract Lung fibrosis development utilizes alveolar macrophages, with mechanisms that are incompletely understood. Here, we fate map connective tissue during mouse lung fibrosis and observe disassembly and transfer of connective tissue macromolecules from pleuro-alveolar junctions (PAJs) into deep lung tissue, to activate fibroblasts and fibrosis. Disassembly and transfer of PAJ macromolecules into deep lung tissue occurs by alveolar macrophages, activating cysteine-type proteolysis on pleural mesothelium. The PAJ niche and the disassembly cascade is active in patient lung biopsies, persists in chronic fibrosis models, and wanes down in acute fibrosis models. Pleural-specific viral therapeutic carrying the cysteine protease inhibitor Cystatin A shuts down PAJ disassembly, reverses fibrosis and regenerates chronic fibrotic lungs. Targeting PAJ disassembly by targeting the pleura may provide a unique therapeutic avenue to treat lung fibrotic diseases.

Background and objective: Management of a long proximal ureteral stricture is challenging. Buccal mucosal graft (BMG) ureteroplasty is a reliable technique for ureteral reconstruction that avoids the morbidity of bowel interposition or autotransplantation. We compared open and robotic BMG ureteroplasty in a two-center study. Methods: We compared prospectively recorded data for 26 patients who underwent robotic or open BMG ureteroplasty at two academic institutions. Stricture location and length, previous reconstructive interventions, complications, and success rates were assessed and compared. A descriptive statistical analysis was performed. Key findings and limitations: We compared ten patients in the robotic group and 16 in the open group. Stricture location had similar distributions in the open versus robotic group (pelvic junction, 25% vs 20%; proximal ureter, 56.3% vs 60%; middle ureter, 18.7% vs 20%). Median stricture length was significantly longer in the robotic group (26 vs 17 mm; p = 0.01). The rate of previous reconstructive interventions was higher in the robotic group (80% vs 37.5%; p = 0.001). However, previous reconstructive interventions were more complex for the open surgery group. There were no intraoperative complications, and postoperative complication rates were similar in the open and robotic groups (18.7% vs 20%; p = 0.19). Median intraoperative blood loss was significantly lower in the robotic group (300 vs 175 ml; p = 0.03). The success rate was 93.7% in the open group and 90.0% in robotic group. Conclusions and clinical implications: We observed high success rates and low perioperative morbidity for both open and robotic BMG ureteroplasty. The robotic approach was associated with significantly lower intraoperative blood loss. Patient summary: Narrowing of the ureter, which is the tube draining urine from the kidney into the bladder, may need surgical treatment. For reconstruction of long segments, use of a tissue graft from the inside of the mouth is an effective surgical option. Robot-assisted surgery is as safe as open surgery and is associated with lower blood loss.

Thalamocortical sleep spindles, i.e., oscillatory bursts at ∼12–15 Hz of waxing and waning amplitude, are a hallmark feature of non-rapid eye movement (NREM) sleep and believed to play a key role in memory reactivation and consolidation. Generated in the thalamus and projecting to neocortex and hippocampus, they are phasically modulated by neocortical slow oscillations (80 Hz). This hierarchical cross-frequency nesting, where slower oscillations group faster ones into certain excitability phases, may enable phase-dependent plasticity in the neocortex, and spindles have thus been considered windows of plasticity in the sleeping brain. However, the assumed phasic excitability modulation had not yet been demonstrated for spindles. Utilizing a recently developed real-time spindle detection algorithm, we applied spindle phase-triggered transcranial magnetic stimulation (TMS) to the primary motor cortex (M1) hand area to characterize the corticospinal excitability profile of spindles via motor evoked potentials (MEP). MEPs showed net suppression during spindles, driven by a “pulse of inhibition” during its falling flank with no inhibition or facilitation during its peak, rising flank, or trough. This unidirectional (“asymmetric”) modulation occurred on top of the general sleep-related inhibition during spindle-free NREM sleep and did not extend into the refractory post-spindle periods. We conclude that spindles exert “asymmetric pulsed inhibition'' on corticospinal excitability. These findings and the developed real-time spindle targeting methods enable future studies to investigate the causal role of spindles in phase-dependent synaptic plasticity and systems memory consolidation during sleep by repetitively targeting relevant spindle phases.

Abstract Despite remarkable advances, radiation therapy (RT) remains inefficient for some bulky tumors, radioresistant tumors, and certain pediatric tumors. Minibeam radiation therapy (MBRT) has emerged as a promising approach, reducing normal tissue toxicity while enhancing immune responses. Preclinical studies using X-rays and proton MBRT have demonstrated enhanced therapeutic index for aggressive tumor models. Combining MBRT’s advantages of spatial dose fractionation with the physical and biological benefits of carbon ions could be a step further toward unleashing the full potential of MBRT. This study aims to perform the first in vivo study of local and systemic responses of a subcutaneous mouse osteosarcoma (metastatic) model to carbon MBRT (C-MBRT) versus conventional carbon ion therapy (CT). Irradiations were conducted at the GSI Helmholtz Centre in Germany using 180 MeV/u 12C ions beam. All irradiated animals received an average dose (20 Gy) and displayed a significant and similar tumor growth delay in addition to a decreased metastasis score compared to the non-irradiated group. In the C-MBRT group, 70% of the tumor volume received the valley dose, which is a very low dose of 1.5 Gy. The remaining 30% of the tumor received the peak dose of 105 Gy, resulting in an average dose of 20 Gy. These results suggest that C-MBRT triggered distinct mechanisms from CT and encourage further investigations to confirm the potential of C-MBRT for efficient treatment of radioresistant tumors.

Aims: The aim of the present study was to analyze the oncological and neurological outcome of patients undergoing interdisciplinary treatment for primary malignant bone and soft-tissue tumours of the spine within the last seven decades, and changes over time. Methods: We retrospectively analyzed our single-centre experience of prospectively collected data by querying our tumour registry (Medical University of Vienna). Therapeutic, pathological, and demographic variables were examined. Descriptive data are reported for the entire cohort. Kaplan-Meier analysis and multivariate Cox regression analysis were applied to evaluate survival rates and the influence of potential risk factors. Results: A total of 119 consecutive patients (mean age 38 years (SD 37; 1 to 83), mean follow-up 66 months (SD 26; 0 to 505) were investigated. Histological entities included Ewing’s sarcoma (EWS; 33), chondrosarcoma (CSA; 20), osteosarcoma (OSA; 22), and soft-tissue sarcoma (STS; 44). Surgery was performed in 88 patients (74%). Neurological parameters improved in 18 patients (20%) after surgery. Overall, 32 patients (36%) suffered from surgical complications requiring revision. The median survival was 42 months (IQR 10 to 204). The one-, five-, and ten-year survival rates were 73%, 47%, and 39%, respectively. Corresponding five-year survival rates for EWS, CSA, OSA, and STS were 63%, 61%, 40%, and 32%, respectively. The decade of diagnosis, histological entity, surgical intervention, resection margin, and the presence of metastases had significant influence on survival. (Neo-)adjuvant therapies alone had no significant influence on overall survival. Conclusion: Our study clearly demonstrates the positive impact of improved surgical techniques, as well as refined imaging methods and evolved adjuvant therapy options, on survival rate in all tumour entities. However, despite a multimodal treatment plan, the long-term mortality of these tumours remains high. Cite this article: Bone Jt Open 2025;6(2):109–118.

Abstract Identifying crystal defects is vital for unraveling the origins of many physical phenomena. Traditionally used order parameters are system-dependent and can be computationally expensive to calculate for long molecular dynamics simulations. Unsupervised algorithms offer an alternative independent of the studied system and can utilize precalculated atomistic potential descriptors from molecular dynamics simulations. We compare the performance of three such algorithms (PCA, UMAP, and PaCMAP) on silicon and water systems. Initially, we evaluate the algorithms for recognizing phases, including crystal polymorphs and the melt, followed by an extension of our analysis to identify interstitials, vacancies, and interfaces. While PCA is found unsuitable for effective classification, it has been shown to be a suitable initialization for UMAP and PaCMAP. Both UMAP and PaCMAP show promising results overall, with PaCMAP proving more robust in classification, except in cases of significant class imbalance, where UMAP performs better. Notably, both algorithms successfully identify nuclei in supercooled water, demonstrating their applicability to ice nucleation in water.

Abstract Purpose Fetal lower urinary tract obstruction (LUTO) is a rare congenital disease associated with high morbidity and mortality due to pulmonary hypoplasia and renal insufficiency. Fetal management includes early vesicoamniotic shunting (VAS), a technique that has evolved in recent years to preserve kidney function. Previous publications have focused on intrauterine shunt complications, such as dislocation and preterm premature rupture of membranes (PPROM). In our study we aimed to assess postnatal shunt related complications that became obvious after birth. Materials and Methods We describe our preliminary experience with 25 fetuses who underwent VAS with a Somatex® shunt as well as postnatal shunt removal at two experienced centers for fetal medicine. The intrauterine course, underlying pathology, postnatal outcome and details on shunt explantation and related complications were assessed. The data were retrospectively analysed in relation to the intrauterine course, underlying pathology, further malformations, and perioperative characteristics with a focus on the complication spectrum and type of intervention. Results Twenty-five fetuses underwent VAS at a median of 17 weeks. Two newborns were excluded because they died within the first 24 hours of life secondary to fulminant lung hypoplasia. In ten (43%) newborns, shunt removal was performed under local anaesthesia. In 13 (57%) neonates, the shunt was explanted surgically, and five (22%) of these operations were defined as complex. Conclusion Intrauterine VAS with a Somatex® shunt is feasible, and in the majority of cases, shunt explantation can be easily performed after birth. However, the umbrellas may cause intraabdominal tissue damage, peritoneal adhesions or skin defects, and early surgical management of VAS associated complications might be necessary.

Abstract Background The development of oral squamous cell carcinoma on the molecular level and the resulting prognosis for patients have remained poorly understood. While AngiomiR-31 was implicated in the progression and metastasis of OSCC. However, this connection has not yet been investigated in more detail and tested for its significance with regard to new therapies and the prognosis of patients. Methods Through a systemic analysis of putative target genes of AngiomiR-31 in OSCC, this study aimed to highlight possible prognostic markers and genes that might improve prognostic predictability in patients with oral squamous cell carcinoma, especially regarding AngiomiR-31 as an outstanding mediator of angiogenesis. The study is based on gene data from 83 OSCC samples. Potentially relevant genes were selected and sorted by TNM, grading and UICC in these 83 OSCC whole-genome microarray datasets. Data was analysed and tested for significance. Results Through our investigation 20 potential target genes, including tumor suppressor genes, oncogenes and genes not yet categorized, were found and their expression correlated significantly with the expression of AngiomiR-31. Conclusion These findings contribute to a more profound understanding of the molecular mechanisms underlying OSCC progression and may have implications for the development of novel therapeutic strategies targeting AngiomiR-31 in OSCC. Further validation of these genes is needed to validate their clinical relevance and potential as prognostic markers or therapeutic targets in OSCC.

Aims: To explore the relationship between plant communities and key environmental drivers in the Andes of northwest Patagonia, Argentina, and to evaluate the applicability of traditional phytosociological definitions to this region. Methods: We conducted 141 vegetation samples using a stratified systematic sampling design. This was done along two steep gradients of aridity and temperature, which are further modified by local factors that include successional changes due to fire and soil variation. We employed a series of multivariate approaches, including hierarchical clustering, Indicator Species Analysis (ISA), restricted Monte Carlo permutation tests, and both constrained and unconstrained ordinations, to identify (a) the main plant community types, (b) their representative species, and (c) the primary drivers of variation in species composition. Finally, we compared the obtained groups and species to associations described by earlier expert-based classifications. Results: From the set of analyses, we identified six different plant community types with 241 recorded species. We found significant differences across communities’ species composition and their environmental indicators. Among the considered environmental variables, elevation and annual precipitation had the strongest effect on species composition. Additionally, variation in composition was significantly related to forest structure, land use and soil characteristics. We further outlined the influence of locally biased classifications based on a predominance of sampling in areas western to the Andes in classification systems developed in the region. Conclusion: Our analysis allowed us to identify the most relevant environmental drivers and indicator species of the six classified plant communities based on numerical methods. The findings highlight the importance of considering full ecological gradients and communities’ responses for developing stable classification approaches. Taxonomic reference: Anton and Zuloaga (2023). Abbreviations: db-RDA = distance-based Redundancy Analysis; ISA = Indicator Species Analysis; NMDS = Non-metric Multi-Dimensional Scaling.

Abstract Background Improving quality of life (QoL) is important for the treatment of people with bipolar disorder (BD). Early-BipoLife is a German multicentre naturalistic, prospective-longitudinal observational cohort study investigating early recognition and intervention in people at increased risk of developing a BD. This analysis aims to investigate influencing factors and changes in QoL as a basis for the development of early intervention strategies in patients with at risk syndrome for BD. Method A cohort of 1086 participants (15–35 years) with at least one risk factor (EPIbipolar criteria) for BD was assessed over the course of 2 years. Changes in QoL (WHOQOL-BREF) were evaluated in a mixed model for repeated measures. Results Compared to an age-matched comparison group, people at risk for BD showed significant lower QoL in all domains at baseline. The overall QoL of the psychological well-being domain of the WHOQOL-BREF increased over the 2 year study course (p

Abstract Background We evaluated the acceleration of a three-dimensional isotropic flow-independent magnetic resonance angiography (MRA) (relaxation-enhanced angiography without contrast and triggering, REACT) of neck arteries using compressed SENSE (CS) combined with deep learning (adaptive intelligence, AI)-based reconstruction (CS-AI). Methods Thirty-four volunteers received 3-T REACT MRA, acquired threefold: (i) CS acceleration factor 7 (CS7), scan time 1:20 min:s; (ii) CS acceleration factor 10 (CS10), scan time 0:55 min:s; and (iii) CS-AI acceleration factor 10 (CS10-AI), scan time 0:55 min:s. Two radiologists rated the image quality of seven arterial segments and overall image noise. Additionally, a pairwise forced-choice comparison was conducted. Apparent signal-to-noise ratio (aSNR) and contrast-to-noise ratio (aCNR) were measured, and image sharpness was assessed using the edge-rise distance (ERD). Multiple t-tests and nonparametric tests with Bonferroni correction were performed for comparison to CS7 as the reference standard. Results Compared to CS7, CS10 showed lower image quality (p 0.999). Compared to CS7, aSNR and aCNR were lower in CS10 (p

Abstract This study investigates the determinants of perceived scenic beauty in Austrian municipalities using social media data. Employing a multimodal approach, we analyze geo-referenced metadata and visual content from Flickr, focusing on the number of “favorite” clicks as a proxy for landscape attractiveness. The analysis integrates spatial models to explore direct and spillover effects of environmental features and physical activities, such as skiing and cycling, on landscape aesthetics. Our findings reveal that both subjective factors (e.g., physical activities) and intrinsic environmental characteristics (e.g., water bodies and Natura 2000 areas) significantly influence scenic beauty. Notably, skiing activity exerts stronger direct and indirect effects during the winter season, while environmental factors are more dominant in shaping perceptions during summer. Despite seasonal variations, spatial dependence and hotspots underscore the role of location-specific tourism and ecological attributes. This research highlights the potential of leveraging geo-referenced social media data for large-scale assessments of landscape aesthetics while acknowledging inherent biases, such as those in activity datasets like Strava with a particular type of assessed individuals. By addressing these challenges, this study advances the understanding of how environmental and human factors interplay in the perception of scenic landscapes, offering insights for sustainable tourism and regional planning.

Abstract Perinatal obesity is associated with an increased risk of metabolic diseases and hepatic dysfunction in offspring. However, the underlying mechanisms of this metabolic programming remain incompletely understood. This study aimed to elucidate the influence of maternal obesity and early life exposure to high-fat diet on offspring liver phenotype, hepatokine profile, and key components of hepatic metabolism. To this end, we employed a murine high-fat diet-induced perinatal obesity model, investigating the offspring in early life and late adulthood. After exposure to perinatal obesity, the offspring showed a significantly increased body weight in early life with no histological signs of steatosis, but a dysregulated hepatokine profile. Proteomic profiling, followed by molecular analyses, revealed a decreased lipogenesis and increased fatty acid oxidation, suggesting a protective mechanism against the development of steatosis. These changes were accompanied by increased markers of lipid peroxidation and DNA damage, indicating increased oxidative stress. Concomitantly, the antioxidative enzymes catalase and superoxide dismutase 2 were significantly reduced and oxidative phosphorylation was impaired, implying an altered oxidative stress response. While changes in oxidative stress level were only detected in early life, the lipid metabolism was altered across life span. This metabolic programming could determine the resilience and susceptibility to chronic liver disease later in life.

Abstract Globally, forest ecosystems face increasing climate warming-driven stress. Crown dieback is commonly used as an indicator of declining tree vitality and is closely related to reduced stem radial growth rates. In a xeric northern Patagonian Nothofagus pumilio population, in which the majority of trees possess damaged crowns, we explored the relationship between percent crown damage and growth trends (basal area increment, BAI), interannual growth variability, and the climate sensitivity of growth. The majority of trees show stable BAI since about 1940 despite 5 to > 50% crown damage, which ranges from dieback of small branches to the presence of decades-old snagged branches. A minority of trees with more severe crown damage (> 50 to 95%) show continued growth decline during the last 80 years, but have not yet died. Crown damage was the best predictor of the BAI trend which turned negative at about 50% damage. Stronger damaged trees showed a higher growth sensitivity to summer heat and drought. Thus, the health of this population is apparently not threatened by crown damage up to 50%. Rather, trees might profit from the reduced foliage area, allowing them to stabilize their water relations and maintain stable but fairly slow growth in a drying climate.

Abstract Based on previous in vitro experiments with specimens of porcine mandibular premolars, the simulation of the periodontal ligament response to force in the initial phase of orthodontic tooth movement is described. The initial response of the periodontal ligament can be simulated with a poro-visco-hyperelastic model. For the ground substance a hyperelastic constitutive model for compressible material was used. To facilitate parameter identification a reduced order model and an optimal interpolation metamodel were used. Parameters for the constitutive model identified herein are in good agreement with published values. They indicate a high initial compressibility of the periodontal ligament, which may be attributed to the compressibility of the vascular system within the periodontal ligament. Dimensionless analysis suggests that poroelastic behaviour will gradually cease when viscoelastic relaxation progresses. This was observed as well in the simulation and confirmed by varying the poroelastic model parameters within physically justified limits. Alveolar bone permeability has a significant influence on the flow of pore fluid in the periodontium due to poroelasticity. It is argued that in vivo alveolar bone perforation may adapt locally to optimise for the predominant load situation. A strain rate hardening effect was observed, which is not covered by the simulation, and may be the subject of further investigations.

Abstract Reservoir computing (RC) is among the most promising approaches for AI-based prediction models of complex systems. It combines superior prediction performance with very low CPU-needs for training. Recent results demonstrated that quantum systems are also well-suited as reservoirs in RC. Due to the exponential growth of the Hilbert space dimension obtained by increasing the number of quantum elements small quantum systems are already sufficient for time series prediction. Here, we demonstrate that three-dimensional systems can already well be predicted by quantum reservoir computing with a quantum reservoir consisting of the minimal number of qubits necessary for this task, namely four. This is achieved by optimizing the encoding of the data, using spatial and temporal multiplexing and recently developed read-out-schemes that also involve higher exponents of the reservoir response. We outline, test and validate our approach using eight prototypical three-dimensional chaotic systems. Both, the short-term prediction and the reproduction of the long-term system behavior (the system’s “climate”) are feasible with the same setup of optimized hyperparameters. Our results may be a further step towards the realization of a dedicated small quantum computer for prediction tasks in the NISQ-era.

Abstract Background The Patient-Reported Outcomes Measurement Information System (PROMIS) Sleep Disturbance v1.0 item bank (27 items) measures sleep disturbances. Rather than the full item bank, an 8-item short form (PROMIS SD SF 8b) or computerized adaptive testing (CAT) can be used. This study compares the performance of the PROMIS SD SF 8b with two CAT algorithms in postmenopausal women. Methods This is a secondary analysis of data collected for the original psychometric testing of the PROMIS Sleep Disturbance item bank, in a sub-sample of women aged ≥55. A graded response model (GRM) was fitted for the item bank, then simulations evaluated the performance of CAT algorithms and the short form, in terms of root mean square error (RMSE) versus the latent trait estimate derived from the full bank. Two CAT algorithms were tested: CAT1 (stop once standard error

Abstract Background Smartphone screen time has risen sharply in recent years. Even though an association between smartphone use and mental health is well documented, it is still unclear whether this is simply a correlation or causality. The aim of this study is to investigate the effects of smartphone screen time reduction on mental health indicators. Methods This non-blinded, parallel randomized controlled trial (RCT) was performed to investigate the impact of a 3-week screen time reduction to ≤ 2 h/d in healthy students on stress (PSQ), well-being (WHO-5), depressive symptoms (PHQ-9), and sleep quality (ISI) at baseline (t0), post-intervention (t1), and at follow-up (t2 = 6 weeks after t1). For the intention to treat analysis, repeated measures ANOVAs and post-hoc tests (for time as well as group differences) were performed and effect sizes were presented as partial eta squared (η2 = time × group) and group-mean differences. Results In total, 111 out of 125 healthy students (70 females; mean age = 22.68 ± 2.6 years; mean screen time = 276 ± 115.1 min/day) were randomly assigned to intervention—(n = 58; 3 weeks of screen time reduction to ≤ 2 h/day) or control group (n = 53). Although no differences were observed at baseline (t0), significant post-intervention (t1) effects of small to medium size were observed on well-being (η2 = .053), depressive symptoms (η2 = .109), sleep quality (η2 = .048), and stress (η2 = .085). Significant group differences (p ≤ .05) were found post-intervention (t1) for depressive symptoms (Mean Difference (MD) = 2.11, Standard Error (SE) = 0.63, 95% Confidence Interval (CI) [0.87, 3.36]), sleep quality (MD = 2.59, SE = 0.97, 95% CI [0.66, 4.51]), well-being (MD = -1.54, SE = 0.68, 95% CI [.-2.89, -0.18]), and stress (MD = 6.91, SE = 3.48, 95% CI [0.01, 13.81]). Screen time increased rapidly after the intervention and at follow-up the values were once again approaching the initial level. Conclusions The study highlights mental health improvements through smartphone screen time reduction. Three weeks of screen time reduction showed small to medium effect sizes on depressive symptoms, stress, sleep quality, and well-being. The results suggest a causal relationship, rather than a merely correlative one, between daily smartphone screen time and mental health. Trial registration The study was preregistered on Open Science Framework (trial registration number: A9K76) on November 8, 2023.

Abstract Background The discovery of cellular tumor networks in glioblastoma, with routes of malignant communication extending far beyond the detectable tumor margins, has highlighted the potential of supramarginal resection strategies. Retrospective data suggest that these approaches may improve long-term disease control. However, their application is limited by the proximity of critical brain regions and vasculature, posing challenges for validation in randomized trials. Anterior temporal lobectomy (ATL) is a standardized surgical procedure commonly performed in patients with pharmacoresistant temporal lobe epilepsy. Translating the ATL approach from epilepsy surgery to the neuro-oncological field may provide a model for investigating supramarginal resection in glioblastomas located in the anterior temporal lobe. Methods The ATLAS/NOA-29 trial is a prospective, multicenter, multinational, phase III randomized controlled trial designed to compare ATL with standard gross-total resection (GTR) in patients with newly-diagnosed anterior temporal lobe glioblastoma. The primary endpoint is overall survival (OS), with superiority defined by significant improvements in OS and non-inferiority in the co-primary endpoint, quality of life (QoL; “global health” domain of the European organization for research and treatment of cancer (EORTC) QLQ-C30 questionnaire). Secondary endpoints include progression-free survival (PFS), seizure outcomes, neurocognitive performance, and the longitudinal assessment of six selected domains from the EORTC QLQ-C30 and BN20 questionnaires. Randomization will be performed intraoperatively upon receipt of the fresh frozen section result. A total of 178 patients will be randomized in a 1:1 ratio over a 3-year recruitment period and followed-up for a minimum of 3 years. The trial will be supervised by a Data Safety Monitoring Board, with an interim safety analysis planned after the recruitment of the 57th patient to assess potential differences in modified Rankin Scale (mRS) scores between the treatment arms 6 months after resection. Assuming a median improvement in OS from 17 to 27.5 months, the trial is powered at > 80% to detect OS differences with a two-sided log-rank test at a 5% significance level. Discussion The ATLAS/NOA-29 trial aims to determine whether ATL provides superior outcomes at equal patients’ Qol compared to GTR in anterior temporal lobe glioblastoma, potentially establishing ATL as the surgical approach of choice for isolated temporal glioblastoma and redefining the standard of care for this patient population. Trial registration German Clinical Trials Register (DRKS00035314), registered on October 18, 2024.

Abstract Background Virtual reality (VR) is increasingly used in healthcare education, offering immersive training experiences that are as effective as conventional methods, with benefits like cost-effectiveness, replicating complex scenarios, and reduced need for physical resources. However, the use of VR as an assessment tool is still emerging, particularly in nursing and medical education. The aim of this systematic review was to examine how immersive VR is used as an assessment tool for nursing and medical students. Methods Embase, PubMed, PsycINFO, Cochrane, CINAHL, and ERIC were searched for articles that assessed nursing and/or medical students using immersive/HMD VR. The data was extracted, and content analysis was performed. Results Twenty-six studies met the inclusion criteria, investigating VR assessments in various settings mostly emergencies. Assessments focused on core competencies Patient Care such as first triage, Interpersonal and Communication Skills (e.g., interprofessional communication), and Medical Knowledge (e.g., about coma), utilizing a range of assessment methods from knowledge to performance levels. VR was used either as an automated or supporting assessment tool. Practical considerations in VR implementation were also examined, such as hardware and software. Conclusion The use of VR in medical education assessment shows promise, particularly for emergency scenarios and performance-based tasks related to core competencies such as Patient Care, Interpersonal and Communication Skills, and Medical Knowledge. While this technology offers opportunities to automate assessments and reduce examiner workload, challenges related to software, costs, and feasibility must be addressed. Additionally, aligning learning objectives, teaching methods, and VR assessments through constructive alignment is essential to ensure effective implementation as both a teaching and evaluation tool.

Abstract Background and aims Liver cancer is the third leading cause of cancer related death due to treatment resistance and late onset of symptoms (Rumgay in J Hepatol 77: 1598–1606, 2022). The role of external beam radiotherapy (EBRT) in treatment of unresectable liver cancer needs to be defined. The use of particle therapy such as carbon ion radiation therapy (CIRT) with high linear energy transfer (LET) could increase efficacy of EBRT while limiting the toxic effects of radiation on non-cancerous liver tissue. Promising effects of CIRT have been described in several studies during the past decades, mostly in Japan. To date, no standardized treatment protocol has been established and European data on CIRT for liver cancer is lacking. This retrospective analysis aims to investigate efficacy and safety of hypofractionated CIRT compared to photon-based stereotactic body radiation (SBRT) in primary liver cancer. Method Thirty-six (n = 36) and twenty (n = 20) patients with primary malignant liver tumors were treated with hypofractionated CIRT (4 fractions) and photon-based SBRT, respectively, between 2011 and 2022 and were retrospectively evaluated for survival, local control, and toxicity. Results Two-year local control rate after CIRT was 92.3%. Compared to photon- based SBRT, CIRT scores with a significantly longer median distant progression free survival (3.1 versus 0.9 years). In a matched pair comparison of the two treatment regimens, the CIRT cohort demonstrated both longer 2-year overall survival (100% versus 59.6%) and longer 2-year distant PFS (75.7% versus 22.9%). No significant impairment of liver function was observed in either cohort. Conclusion In this retrospective analysis, patients who received CIRT presented excellent local tumor control and had better oncologic outcomes than patients who received photon-based SBRT. SBRT with carbon ions is a promising local ablative treatment option that needs further investigation in large prospective trials.

Abstract Background Several publications have raised concerns that female stroke patients may be at a disadvantage when accessing stroke treatment services. These publications have found significant regional differences in the provision of stroke treatment to male and female patients. In this study, we provide current nationwide data on stroke management differences between men and women in Germany. Methods This large retrospective cohort study used national datasets from the German Federal Statistical Office for 2017–2022. We examined differences between female and male stroke patients in terms of case volume, intravenous thrombolysis (IVT), mechanical thrombectomy (MTE), stroke unit (SU) treatment, intrahospital mortality, and prevalence of atrial fibrillation (AF). Results Data from more than 1.3 million hospitalised stroke patients were included. Forty-seven percent of the patients were female. Female patients were older and more frequently ≥ 80 years old (50.3% versus 29.4%). Rates of IVT (16.3% versus 16.3%) were similar for both sexes but higher in females when adjusted for age. MTE rates (8.2% versus 6.3%) were consistently higher in female patients across all age groups. Female patients had higher rates of intrahospital mortality (9.1% versus 6.2%), and admission to SUs (73.6% versus 76.0%) was less common. Treatment rates in intensive care units were similar (10.6% versus 10.5%). AF, a surrogate for embolic (and more severe) strokes, was more prevalent in females (32.6% versus 25.4%). Conclusions We found no evidence that female stroke patients in Germany face any disadvantage in accessing stroke treatment services. Acute stroke treatment rates were generally similar or higher when compared to males. Higher intrahospital mortality and lower SU rates were attributed to greater age, comorbidities, and stroke severity. However, the differences were not fully explained when adjusting for AF and age. Further research is needed on sex differences in stroke mechanisms and outcomes.

Abstract Before medical professionals are permitted to use a medical device, they first must be instructed in its use. However, it is well known that this method is hazardous for both the staff and the patients due to its inadequate quality. In order to address this problem, we investigated the potential of digital technologies for enhancing medical device training. For this, we designed and implemented several diverse training methods: (1) conventional training by a medical instructor, (2) video-based training, (3) mobile application training on a tablet, (4) virtual reality training, and (5) augmented reality training. Since each method provides identical training content to the user, we compared the resulting learning outcomes between the methods. The findings indicate that virtual and augmented reality training is superior to conventional training. These digital technologies offer the opportunity to reduce the burden on healthcare professionals and increase patient safety.

Abstract Low anterior resection (LAR) and abdominoperineal resection (APR) are the two main surgical procedures after preoperative chemoradiotherapy (CRT) for locally advanced rectal cancer. APR is associated with poorer prognosis; however existing data do not consider intensified CRT (5-Fluorouracil (5-FU)/Oxaliplatin + radiation) protocols. Clinicopathological data of patients treated with APR and LAR from the CAO/ARO/AIO-04 trial were analysed in terms of prognostic parameters and quality of life (QoL). Based on higher response rate after intensified CRT, subgroup analyses were performed. Data from n = 1173 patients were assessed. APR after preoperative CRT was associated with a significantly worse overall survival (p = 0.0056), disease-free survival (p

Abstract Background Harmonizing core outcome domains allows for pooling data, comparing interventions, and streamlining research evaluation. At the same time clinicians require concise and feasible measures for routine practice. Considering the heterogeneity of post-COVID-19 condition, a biopsychosocial approach requires sufficient coverage of the psychosocial dimension with assessments. Previous recommendations for core outcome sets have serious limitations regarding the psychosocial aspects of post-COVID-19 condition. This paper specifically focuses on psychosocial outcomes for adults with post-COVID-19 condition, providing both a comprehensive set of outcome domains for research and a streamlined clinical core set tailored for routine clinical use. Methods In a structured Consensus Development Approach, the European Network to improve diagnostic, treatment, and healthcare for patients with persistent somatic symptoms (EURONET-SOMA) developed psychosocial core outcome domains and assessments regarding post-COVID-19 condition. The experts identified variables and instruments which should be considered in studies on adults suffering from post-COVID-19 condition, and which are feasible in the clinical setting and relevant for research. Results We identified three higher-order dimensions with each encompassing several domains: The first higher-order dimension, “outcomes”, encompasses (1) the classification/ diagnostics of post-COVID-19 condition, (2) somatic symptoms (including fatigue), (3) the psychopathological status and mental comorbidities, (4) the physical status and somatic comorbidities, (5) neurocognitive symptoms, and (6) illness consequences. The second higher-order domain “mechanisms” encompasses (7) cognitive components, (8) affective components, (9) behavioral components, (10) social components, and (11) psychobiological bridge markers (e.g., neuroimmunological and psychoneuroendocrinological variables). The third higher-order domain, “risk factors”, includes factors such as (12) socioeconomic status and sociocultural factors, (13) pre-existing mental and somatic health issues, (14) personality factors (e.g., neuroticism), (15) adverse childhood experiences, (16) ongoing disability or pension claim, and (17) social media use. For each domain, specific instruments are suggested for research purposes and clinical use. Conclusions The recommended core domains help to increase consistency in a biopsychosocial approach to post-COVID-19 condition across investigations, improve synergies, and facilitate decision-making when comparing different interventional approaches. It allows to better identify relevant subgroups in heterogeneous post-COVID-19 condition populations offering practical tools for routine clinical practice through the clinical core set.

Abstract Sensori- and psychomotor abnormalities are an inherent part of schizophrenia-spectrum disorders (SSD) pathophysiology and linked to psychopathological symptoms as well as cognitive and global functioning. However, how these different symptom clusters simultaneously interact with each other is still unclear. Here, we examined 192 SSD patients (37.75 ± 12.15 years, 73 females). First, we investigated the cross-sectional prevalence and overlap of individual sensori- and psychomotor abnormalities. Second, we applied network analysis methods to simultaneously model the associations between Neurological Soft Signs (NSS), level of akathisia, parkinsonism symptoms, tardive dyskinesia (TD) and catatonia signs as well as cognition, psychopathology, global functioning and daily antipsychotic dose. The largest centralities were exhibited by NSS (0.90), catatonia signs (0.82) and global functioning (0.79). NSS showed strong partial correlations with cognition and parkinsonism symptoms (edge weight, ew = 0.409 and ew = 0.318, respectively). Catatonia signs showed strong connections with global functioning (ew = 0.333). In contrast, TD, akathisia and daily antipsychotic dose were weakly connected with other variables (e.g., largest ew=0.176 between TD and akathisia). In conclusion, NSS and cognition, parkinsonism symptoms and NSS as well as catatonia signs and global functioning seem to be preferentially connected in SSD. The daily medication had little influence on sensori- and psychomotor abnormalities, indicating that they are features of core SSD pathophysiology. Future studies should incorporate these relationships to enhance the understanding of SSD.

Abstract Pesticides affect a diverse range of non-target species and may be linked to global biodiversity loss. The magnitude of this hazard remains only partially understood. We present a synthesis of pesticide (insecticide, herbicide and fungicide) impacts on multiple non-target organisms across trophic levels based on 20,212 effect sizes from 1,705 studies. For non-target plants, animals (invertebrate and vertebrates) and microorganisms (bacteria and fungi), we show negative responses of the growth, reproduction, behaviour and other physiological biomarkers within terrestrial and aquatic systems. Pesticides formulated for specific taxa negatively affected non-target groups, e.g. insecticidal neonicotinoids affecting amphibians. Negative effects were more pronounced in temperate than tropical regions but were consistent between aquatic and terrestrial environments, even after correcting for field-realistic terrestrial and environmentally relevant exposure scenarios. Our results question the sustainability of current pesticide use and support the need for enhanced risk assessments to reduce risks to biodiversity and ecosystems.

Abstract The optimal management strategy of nutcracker syndrome is debated, especially in the setting of concurrent pelvic congestion syndrome. In this article, we describe our treatment algorithm as illustrated by four different case scenarios. In our experience, renocaval pressure gradients are often inconclusive, but evaluation of the left renal vein waveform as well as a “test PTA” with evidence of a waist in the balloon can be helpful in unmasking a relevant stenosis. We consider nutcracker syndrome not to be a contraindication for ovarian vein embolization. Decision for simultaneous or sequential stenting should be based on angiographic findings and clinical course.

Abstract Recent clinical practice guidelines for diabetes, obesity, cardiovascular disease (CVD) and chronic kidney disease (CKD) emphasise a holistic, person-centred approach to care. However, they do not include recommendations for the assessment of patient-reported outcomes (PROs), which would – dependent on the topic of guideline – be important for improving shared decision-making, patients’ concordance with guideline recommendations, clinical outcomes and health-related quality of life (HRQoL). The Taskforce of the Guideline Workshop discussed PROs in diabetes, obesity, CVD and CKD as well as the relevance of their inclusion in clinical practice guidelines for the management of these conditions.

Abstract Background Schistosomiasis, which is caused by the parasite Schistosoma mansoni as well as other species of the trematode genus Schistosoma, leads to chronic inflammation and finally to liver fibrosis. If untreated, the disease can cause life-threatening complications. The current treatment of schistosomiasis relies on a single drug, praziquantel (PZQ). However, there is increasing concern about emerging resistance to PZQ due to its frequent use. Methods To identify potential alternative drugs for repurposing, the Open Global Health Library (OGHL) was screened in vitro, using two different screening workflows at two institutions, against adult S. mansoni couples and newly transformed schistosomula. This was followed by confirmation of the effects of the lead structures against adult worms. Results In vitro screening at one of the institutions identified two fast-acting substances affecting worm physiology (OGHL00022, OGHL00121). The effects of the two lead structures were investigated in more detail by confocal laser scanning microscopy and 5-ethynyl 2´-deoxyuridine (EdU) assays to assess morphological effects and stem cell effects. Both substances showed negative effects on stem cell proliferation in S. mansoni but no further morphological changes. The EC50values of both compounds were determined, with values for compound OGHL00022 of 5.955 µM for pairing stability, 10.88 µM for attachment, and 18.77 µM for motility, while the values for compound OGHL00121 were 7.088 µM for pairing stability, 8.065 µM for attachment, and 6.297 µM for motility 24 h after treatment. Furthermore, S. mansoni couples were treated in vitro with these two lead structures simultaneously to check for additive effects, which were found with respect to reduced motility. The second in vitro screening, primarily against newly transformed schistosomula and secondarily against adult worms, identified four lead structures in total (OGHL00006, OGHL00022, OGHL00169, OGHL00217). In addition, one of the tested analogues of the hits OGHL00006, OGHL00169, and OGHL00217 showed effects on both stages. Conclusions In two independent in vitro screening approaches against two stages of S. mansoni one common interesting structure with rapid effects was identified, OGHL00022, which provides opportunities for further development. Graphical Abstract

Abstract Being outdoors benefits both humans’ physical and mental well-being, but the reasons for this connection are difficult to pinpoint. This study examines 40 recreational areas to understand their individual characteristics’ impact on mental well-being. We interviewed 1184 visitors on their perception of the place and feeling of mental well-being. In a second survey, 49 participants were shown images of the areas to assess whether they perceived them in the same way as people on-site did. Biologists then evaluated the areas through bird and biotope surveys, also assessing various other landscape characteristics of the study areas. Analysis using a two-level multivariate GLM revealed that perceived naturalness and perceived bird diversity are significant predictors of improved mental well-being. On the flip side, mental well-being declines with increased human impact, as indicated by the amount of infrastructure and the Human Footprint Index value. Notably, perceived naturalness positively correlates with actual bird diversity (p = 0.005) and negatively with human impact (p = 0.006). A strong perception of birds enhances the mental well-being of greenspace visitors (p

Abstract The aryl hydrocarbon receptor (AHR) possesses an extraordinary capacity to sense and respond to a wide range of small-molecule ligands, ranging from polycyclic aromatic hydrocarbons to endogenous compounds. Upon ligand binding, AHR translocates from the cytoplasm to nucleus, forming a transcriptionally active complex with aryl hydrocarbon receptor nuclear translocator (ARNT), for DNA binding and initiation of gene expression programs that include cellular detoxification pathways and immune responses. Here, we examine the molecular mechanisms governing AHR’s high-affinity binding and activation by a diverse group of ligands. Crystal structures of the AHR-ARNT-DNA complexes, bound with each of six established AHR ligands, including Tapinarof, 6-formylindolo[3,2-b]carbazole (FICZ), benzo[a]pyrene (BaP), β-naphthoflavone (BNF), Indigo and Indirubin, reveal an unconventional mode of subunit assembly with intimate association between the PAS-B domains of AHR and ARNT. AHR’s PAS-B domain utilizes eight conserved residues whose dynamic rearrangements account for the ability to bind to ligands through hydrophobic and π-π interactions. Our findings further reveal the structural underpinnings of a ligand-driven activation mechanism, whereby a segment of the AHR protein undergoes a structural transition from chaperone engagement to ARNT heterodimer stabilization, to generate the transcriptionally competent assembly. Our results provide key information for the future development of AHR-targeting drugs.

Abstract Aspirin is a potent lysine acetylation inducer, but its impact on lysine ubiquitination and ubiquitination-directed protein degradation is unclear. Herein, we develop the reversed-pulsed-SILAC strategy to systematically profile protein degradome in response to aspirin. By integrating degradome, acetylome, and ubiquitinome analyses, we show that aspirin impairs proteasome activity to inhibit proteasomal degradation, rather than directly suppressing lysine ubiquitination. Interestingly, aspirin increases lysosomal degradation-implicated K63-linked ubiquitination. Accordingly, using the major pathological protein of Parkinson’s disease (PD), α-synuclein (α-syn), as an example of protein aggregates, we find that aspirin is able to reduce α-syn in cultured cells, neurons, and PD model mice with rescued locomotor ability. We further reveal that the α-syn aggregate clearance induced by aspirin is K63-ubiquitination dependent in both cells and PD mice. These findings suggest two complementary mechanisms by which aspirin regulates the degradation of soluble and insoluble proteins, providing insights into its diverse pharmacological effects that can aid in future drug development efforts.

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.

Abstract Intracerebral hemorrhages (ICH) during implantation of stereo‐EEG electrodes are rare. The impact of tobacco‐free nicotine consumption on periprocedural bleeding is uncertain. We present a 20+ year‐old man with drug‐resistant epilepsy who underwent stereo‐EEG with 17 depth electrodes. Within a few days after insertion, the patient developed multiple ICHs in the electrode trajectories and an intradural hemorrhage after a diagnostic spinal tap. We performed the investigation of the clotting system and whole‐exome sequencing (WES). WES identified a heterozygous mutation c.4698G>T, p.(Trp1566Cys) in COL4A2 (NM_001846.4) encoding a collagen type‐IV alpha‐2 chain inherited from his seemingly healthy mother. As COL4A2 mutations had been identified in four adult patients with ICH we postulated that the identified variant presents a potential risk factor. Notably, mutations encoding other collagens have been linked to cerebral hemorrhages (COL4A1) and increased propensity to trigger ICH upon smoking (COL1A2). Our patient consumed at least 24 oral nicotine pouches (containing 11 mg nicotine each) per day. We consider the patient's COL4A2 mutation in combination with his substantial nicotine consumption as likely predisposition to multiple ICHs precipitated by stereo‐EEG. Patients with nicotine consumption and any collagen mutation may have a substantially higher risk for hemorrhagic complications in SEEG and other neurosurgical procedures. Plain Language Summary A young man with drug‐resistant epilepsy experienced multiple intracerebral hemorrhages after implantation of SEEG electrodes for presurgical evaluation and concomitantly a intradural hemorrhage after a lumbar spinal tap. A collagen IV mutation of unclear significance and heavy use of oral nicotine pouches were the only potential risk factors identified. As collagen mutations were previously described risk factors and smoking in particular worsens the bleeding risk in collagen mutations, further research is warranted to prevent hemorrhages in neurosurgical procedures. Nicotine consumption in any form is a preventable risk factor.

Reconfigurable electromagnetic structures (REMSs), such as reconfigurable reflectarrays (RRAs) or reconfigurable intelligent surfaces (RISs), hold significant potential to improve the spectral efficiency of wireless communication systems and the accuracy of wireless sensing systems. Even though several REMS modeling approaches have been proposed in recent years, the literature lacks models that are both computationally efficient and physically consistent. As a result, algorithms that control the reconfigurable elements of REMSs (e.g., the phase shifts of a RIS) are often built on simplistic and thus inaccurate models. To enable physically accurate REMS-parameter tuning, we present a new framework for efficient and physically consistent modeling of general REMSs. Our modeling method combines a circuit-theoretic approach with a new formalism that describes a REMS’s interaction with the electromagnetic (EM) waves in its far-field region. Our modeling method enables efficient computation of the entire far-field radiation pattern for arbitrary configurations of the REMS reconfigurable elements once a single full-wave EM simulation of the non-reconfigurable parts of the REMS has been performed. The predictions made by our framework align with the physical laws of classical electrodynamics and model effects caused by inter-antenna coupling, non-reciprocal materials, polarization, ohmic losses, matching losses, influence of metallic housings, noise from low-noise amplifiers, and noise arising in or received by antennas. In order to validate the efficiency and accuracy of our modeling approach, we (i) compare our modeling method to EM simulations and (ii) conduct a case study involving an RRA that enables simultaneous multiuser beam- and null-forming using a new, computationally efficient, and physically accurate parameter tuning algorithm.

Hand gestures are a natural form of human communication, making gesture recognition a sensible approach for intuitive human-computer interaction. Wearable sensors on the forearm can be used to detect the muscle contractions that generate these gestures, but classification approaches relying on a single measured modality lack accuracy and robustness. In this work, we analyze sensor fusion of force myography (FMG) and electromyography (EMG) for gesture recognition. We employ piezoelectric FMG sensors based on ferroelectrets and a commercial EMG system in a user study with 13 participants to measure 66 distinct hand movements with 10ms labelling precision. Three classification tasks, namely flexion and extension, single finger, and all finger movement classification, are performed using common handcrafted features as input to machine learning classifiers. Subsequently, the evaluation covers the effectiveness of the sensor fusion using correlation analysis, classification performance based on leave-one-subject-out-cross-validation and 5x2cv-t-tests, and its effects of involuntary movements on classification. We find that sensor fusion leads to significant improvement (42% higher average recognition accuracy) on all three tasks and that both sensor modalities contain complementary information. Furthermore, we confirm this finding using reduced FMG and EMG sensor sets. This study reinforces the results of prior research about the effectiveness of sensor fusion by performing meticulous statistical analyses, thereby paving the way for multi-sensor gesture recognition in assistance systems.

Soil nitrogen (N) is the main limiting nutrient for plant growth, which is sensitive to variations in the soil oxygen environment. To provide insights into plant N accumulation and yield under aerated and drip irrigation, a greenhouse tomato experiment was conducted with six treatments, including three fertilization types: inorganic fertilizer (NPK); organic fertilizer (OM); chemical (75% of applied N)+organic fertilizer (25%) (NPK+OM) under drip irrigation (DI) and aerated irrigation (AI) methods. Under AI, total soil carbon mineralization (Cmin) was significantly higher (by 5.7–7.0%) than under DI irrigation. Cmin in the fertilizer treatments followed the order NPK+OM>OM>NPK under both AI and DI. Potentially mineralizable C (C0) and N (N0) was greater under AI than under DI. Gross N mineralization, gross nitrification, and NH4+ immobilization rates were significantly higher under the AINPK treatment than the DINPK treatment by 2.58–3.27-, 1.25–1.44-, and 1–1.26-fold, respectively. These findings demonstrated that AI and the addition of organic fertilizer accelerated the turnover of soil organic matter and N transformation processes, thereby enhancing N availability. Moreover, the combination of AI and organic fertilizer application was found to promote root growth (8.4–10.6%), increase the duration of the period of rapid N accumulation (ΔT), and increase the maximum N accumulation rate (Vmax), subsequently encouraging aboveground dry matter accumulation. Consequently, the AI treatment yield was significantly greater (by 6.3–12.4%) than under the DI treatment. Further, N partial factor productivity (NPFP) and N harvest index (NHI) were greater under AI than under DI, by 6.3 to 12.4%, and 4.6 to 8.1%, respectively. The rankings of yield and NPFP remained consistent, with NPK+OM>OM>NPK under both AI and DI treatments. These results highlighted the positive impacts of AI and organic fertilizer application on soil N availability, N uptake, and overall crop yield in tomato. The optimal management measure was identified as the AINPK+OM treatment, which led to more efficient N management, better crop growth, higher yield, and more sustainable agricultural practices.

Vehicle-to-everything (V2X) communications is an important part of future driver assistance and traffic control systems that will reduce accidents and congestion. The millimeter-wave (mmWave) band shows great promise to enable the high-data-rate links that are required or at least beneficial for such systems. To design such systems, we first need a detailed understanding of the vehicle-to-vehicle (V2V) and vehicle-to-infrastructure (V2X) propagation channels. This paper provides a systematic account of a series of measurement campaigns for such channels, conducted by the four research institutions of the authors over the past year. After a description of the similarities and differences of the channel sounders used in the campaigns, a description of the measurements in two European and one American city is given, and the scenarios of convoy, opposite-lane passing, and overtaking, are described. This is then followed by key results, presenting both sample results of power delay profiles and delay Doppler (or angular) spectra, as well as the statistical description such as delay spread and size of stationarity region. We also discuss the availability of spatial diversity in V2I connections and the correlation of the channels between different frequency bands.

Abstract Background Supervisor–subordinate relationship is high relevant in dealing with work-related stress and providing a compassionate, high-quality, and safe nursing care while meeting the needs of the hospital. Our aim was to assess the predisposing risk and resilience factors of the stress of nursing staff as well as to explore the common and distinctive perceptions of these factors between nurses without a managerial position (nursing staff) and employees in a supervising position (nurse managers, ward nurses). Design Generic qualitative study using half-standardized interviews. Methods Fifty nurses and supervisors from different departments from a German hospital of maximum medical care participated in this study between August and November 2018. Nineteen face-to-face interviews and five focus groups were conducted. Transcripts were subjected to structured qualitative content analysis. Results Systematised in Lazarus’s transactional model, nurses, and supervisors mentioned similar risk and resilience factors of stress. Disagreement in suggested responsibility for nurses’ stress or health and an evaluation of implemented measures meeting the nurses’ needs are discussed. Conclusion Nursing staff and supervisors should enforce exchange to reduce disagreements in perceptions and to improve mutual understanding. Furthermore, measures to meet nurses’ needs to minimize stress and to improve collaboration and job satisfaction should be developed in close coordination with the target group. The focus should be placed on restructuring training and education programs with supplementation of self-responsibility promotion. Trail registration The study was registered with the German Register for Clinical Studies (DRKS 00013482) on 09 March 2018.

Abstract Patient-derived xenografts (PDXs) provide biologically relevant models and potential platforms for the development of treatment strategies for precision medicine in pancreatic cancer. Furthermore, circulating epithelial tumor cells (CETCs/CTCs) are released into the bloodstream by solid tumors and a rare subpopulation—circulating cancer stem cells (cCSCs) – is considered to be responsible for recurrence and plays a key role in metastasis. For the identification of cCSCs, an innovative in vitro assay to generate tumorspheres was established in this study. The number of tumorspheres and CETCs/CTCs was analyzed perioperatively in 25 pancreatic cancer patients. Additionally, an individual in vivo chorioallantoic membrane (CAM) culture system was used to generate PDXs from these tumorspheres. While overall correlations of CETCs/CTCs with clinicopathological parameters did not reach statistical significance, a significant difference in the number of tumorspheres was observed between patient subgroups with lower and higher UICC stages. This finding underscores their potential as biomarkers, providing valuable insights into clinical decision-making and tumor progression. The application of tumorspheres on the CAM successfully established PDXs within 7 days. These xenografts closely resembled the histological features of the primary tumor. Hence, this model represents a novel and fast option for individualized testing of new therapies for PDAC.

Abstract During the omicron wave of the COVID-19 pandemic and with SARS-CoV-2 vaccines becoming available, seroprevalence rates rose in children and adolescents. This study investigated the impact of both SARS-CoV-2 infections and vaccinations on the incidence of acute and prolonged symptoms in real-world conditions during the transition from the pandemic to the endemic phase. Participants from a pediatric population based seroprevalence study (CorKID study) were followed up at least two and for almost four years by survey of health status features and symptoms suggestive of post-COVID syndrome (PCS). In a subgroup (n = 259) SARS-CoV-2 antibody serology was further investigated. 789 participants of the original CorKID study cohort (n = 2.121; 37.2%) were included. 67.9% reported at least one SARS-CoV2 infection. 46.6% had received one or more SARS-CoV-2 vaccinations. In the vast majority of serologically tested participants antibodies again SARS-CoV-2 spike (98.9%) or nucleocapsid (93.3%) antigen were detected following infection and/or vaccination. At least 30% experienced one unrecognized SARS-CoV-2 infection. The overall health status was comparable between children, irrespective of SARS-CoV-2 infections and similar to pre-pandemic assessment. However, a subset of young adolescents exhibited a decline in physical performance compared to pre-pandemic conditions. After infection, PCS-like symptoms persisted in 7% of the respondents for more than three months and up to four years. SARS-CoV-2 vaccinated participants (47%) reported 12% less acute flu-like infections other than SARS-CoV-2. Nearly all participants developed SARS-CoV-2 antibodies in this longitudinal study through either vaccination or infection during the Omicron wave. About 7% of participants suffered from PCS symptoms, predominately fatigue and exhaustion. Furthermore, participants who received vaccinations against SARS-CoV-2 reported a lower frequency of acute infections during follow-up.

Abstract The impact of diabetes on incident cardiovascular disease in relation to the extent of atherosclerotic disease remains unclear. We aimed to investigate major adverse cardiovascular events (MACE) in patients with or without type 2 diabetes (T2DM) presenting with two extremes of atherosclerotic disease, those with angiographically documented minor coronary atherosclerotic lesions and those with symptomatic peripheral artery disease. We included 1238 patients from two prospective, long-term cohort studies. Patients underwent coronary angiography and/or sonography in order to assess the grade of atherosclerosis and were defined as having no signs of Atherosclerosis (n = 332; Group I), minor atherosclerosis (n = 425; Group II) and major atherosclerosis (n = 481; Group III). Cardiovascular events were recorded over a median follow-up period of 7.1 years (Q1 = 3.6 years, Q2 = 7.1 years, Q3 = 11.3 years), covering a total of 9533 patient years. We tested the hypothesis that T2DM infers the same relative risk increase irrespective of the atherosclerosis stage, considering 3-point MACE as the primary endpoint. Incident MACE was reported in 681 patients (51%). MACE occurred more frequently in patients with T2DM than in patients without T2DM (p

Abstract Diffraction-before-destruction imaging with ultrashort X-ray pulses can visualize non-equilibrium processes, such as chemical reactions, with sub-femtosecond precision in the native environment. Here, a nanospecimen diffracts a single X-ray flash before it disintegrates. The sample structure can be reconstructed from the coherent diffraction image (CDI). State-of-the-art X-ray snapshots lack high spatial resolution because of weak diffraction signal. Bleaching effects from photo-ionization significantly restrain image brightness scaling. We find that non-linear transient ion resonances can overcome this barrier if X-ray laser pulses are shorter than in most experiments. We compared snapshots from individual ≈ 100 nm Xe nanoparticles as a function of pulse duration and incoming X-ray fluence. Our experimental results and Monte Carlo simulations suggest that transient resonances can increase ionic scattering cross sections significantly beyond literature values. This provides a novel avenue towards substantial improvement of the spatial resolution in CDI in combination with sub-femtosecond temporal precision at the nanoscale.

Abstract Invasive infections with Aspergillus fumigatus in ICU patients are linked to high morbidity and mortality. Diagnosing invasive pulmonary aspergillosis (IPA) in non-immunosuppressed patients is difficult, as Aspergillus antigen (galactomannan [GM]) may have other causes. This retrospective study analyzed 160 ICU surgical patients with positive GM in broncho-alveolar lavage fluid (BALF), classifying them based on AspICU criteria for suspected IPA (pIPA) or aspiration. Patients with pIPA had higher disease severity than those with aspiration, including higher dialysis rates, organ transplantation, corticosteroid use, and Sequential Organ Failure Assessment (SOFA) score. Aspergillus culture was positive in 47.0% of pIPA cases but only 2.6% of aspiration cases (p