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Abstract Background Non-malignant chronic diseases remain a major public health concern. Given the alterations in lipid metabolism and deposition in the lung and its association with fibrotic interstitial lung disease (fILD) and chronic obstructive pulmonary disease (COPD), this study aimed to detect those alterations using computed tomography (CT)-based analysis of pulmonary fat attenuation volume (CTpfav). Methods This observational retrospective single-center study involved 716 chest CT scans from three subcohorts: control (n = 279), COPD (n = 283), and fILD (n = 154). Fully automated quantification of CTpfav based on lung segmentation and HU-thresholding. The pulmonary fat index (PFI) was derived by normalizing CTpfav to the CT lung volume. Statistical analyses were conducted using Kruskal–Wallis with Dunn’s post hoc tests. Results Patients with fILDs demonstrated a significant increase in CTpfav (median 71.0 mL, interquartile range [IQR] 59.7 mL, p

While there is much knowledge about local neuronal circuitry, considerably less is known about how neuronal input is integrated and combined across neuronal networks to encode higher order brain functions. One challenge lies in the large number of complex neural interactions. Neural networks use oscillating activity for information exchange between distributed nodes. To better understand building principles underlying the observation of synchronized oscillatory activity in a large-scale network, we developed a reductionistic neuronal network model. Fundamental building principles are laterally and temporally interconnected virtual nodes (microcircuits), wherein each node was modeled as a local oscillator. By this building principle, the neuronal network model can integrate information in time and space. The simulation gives rise to a wave interference pattern that spreads over all simulated columns in form of a travelling wave. The model design stabilizes states of efficient information processing across all participating neuronal equivalents. Model-specific oscillatory patterns, generated by complex input stimuli, were similar to electrophysiological high-frequency signals that we could confirm in the primate visual cortex during a visual perception task. Important oscillatory model pre-runners, limitations and strength of our reductionistic model are discussed. Our simple scalable model shows unique integration properties and successfully reproduces a variety of biological phenomena such as harmonics, coherence patterns, frequency-speed relationships, and oscillatory activities. We suggest that our scalable model simulates aspects of a basic building principle underlying oscillatory, large-scale integration of information in small and large brains.

Abstract Background Human induced pluripotent stem cells represent a scalable source of youthful tissue progenitors and secretomes for regenerative therapies. The aim of our study was to investigate the potential of conditioned medium (CM) from hiPSC-mesenchymal progenitors (hiPSC-MPs) to stimulate osteogenic differentiation of human bone marrow-derived mesenchymal stromal cells (MSCs). We also investigated whether prolonged cultivation or osteogenic pre-differentiation of hiPSC-MPs could enhance the stimulatory activity of CM. Methods MSCs were isolated from 13 donors (age 20–90 years). CM derived from hiPSC-MPs was added to the MSC cultures and the effects on proliferation and osteogenic differentiation were examined after 14 days and 6 weeks. The stimulatory activity of hiPSC-MP-CM was compared with the activity of MSC-derived CM and with the activity of CM prepared from hiPSC-MPs pre-cultured in growth or osteogenic medium for 14 days. Comparative proteomic analysis of CM was performed to gain insight into the molecular components responsible for the stimulatory activity. Results Primary bone marrow-derived MSC exhibited variability, with a tendency towards lower proliferation and tri-lineage differentiation in older donors. hiPSC-MP-CM increased the proliferation and alkaline phosphatase activity of MSC from several adult/aged donors after 14 days of continuous supplementation under osteogenic conditions. However, CM supplementation failed to improve the mineralization of MSC pellets after 6 weeks under osteogenic conditions. hiPSC-MP-CM showed greater enhancement of proliferation and ALP activity than CM derived from bone marrow-derived MSCs. Moreover, 14-day cultivation but not osteogenic pre-differentiation of hiPSC-MPs strongly enhanced CM stimulatory activity. Quantitative proteomic analysis of d14-CM revealed a distinct profile of components that formed a highly interconnected associations network with two clusters, one functionally associated with binding and organization of actin/cytoskeletal components and the other with structural constituents of the extracellular matrix, collagen, and growth factor binding. Several hub proteins were identified that were reported to have functions in cell-extracellular matrix interaction, osteogenic differentiation and development. Conclusions Our data show that hiPSC-MP-CM enhances early osteogenic differentiation of human bone marrow-derived MSCs and that prolonged cultivation of hiPSC-MPs enhances CM-stimulatory activity. Proteomic analysis of the upregulated protein components provides the basis for further optimization of hiPSC-MP-CM for bone regenerative therapies. Graphical Abstract

Abstract Introduction Medical education, especially in ultrasound training, is undergoing significant changes. This study examines practical issues in ultrasound medical education, emphasizing state-of-the-art teaching methods, their effectiveness, and implementation challenges. Methods The study analyzed advancements in ultrasound education, including randomized controlled trials comparing peer-to-peer teaching with traditional faculty-led instruction. It evaluated the effectiveness of collaborative small-group training and group size impact in simulation-based training. The study also assessed practical training components outlined in the WFUMB Position Paper Part II. Results Findings indicate that peer-to-peer and collaborative small-group training are effective and cost-efficient. Group size did not significantly affect training outcomes. Key practical training elements, including early hands-on sessions and exposure to various equipment, substantially improved learning outcomes. Simulation tools like virtual reality (VR), augmented reality (AR), and phantoms were crucial for teaching standardized procedures and rare pathologies. Challenges identified include developing robust image acquisition skills, scarcity of qualified student tutors, and the need for reliable ultrasound skill assessment methods. Conclusion Integrating peer-to-peer teaching and advanced simulation technologies significantly advances ultrasound medical education. These methods enhance cognitive and psychomotor skills but also present challenges such as ensuring quality education and developing effective assessment methods. Future research should compare different simulation tools and establish objective ultrasound proficiency assessment criteria. Continual method evaluation and improvement are essential for effective and standardized ultrasound training, ultimately enhancing patient care and clinical outcomes.

Abstract N-glycosylation is one of the most common protein modifications in eukaryotes, with immense importance at the molecular, cellular, and organismal level. Accurate and reliable N-glycan analysis is essential to obtain a systems-wide understanding of fundamental biological processes. Due to the structural complexity of glycans, their analysis is still highly challenging. Here we make publicly available a consistent N-glycome dataset of 20 different mouse tissues and demonstrate a multimodal data analysis workflow that allows for unprecedented depth and coverage of N-glycome features. This highly scalable, LC-MS/MS data-driven method integrates the automated identification of N-glycan spectra, the application of non-targeted N-glycome profiling strategies and the isomer-sensitive analysis of glycan structures. Our delineation of critical sub-structural determinants and glycan isomers across the mouse N-glycome uncovered tissue-specific glycosylation patterns, the expression of non-canonical N-glycan structures and highlights multiple layers of N-glycome complexity that derive from organ-specific regulations of glycobiological pathways.

Abstract Behavioral variant frontotemporal dementia (bvFTD) is characterized by profound and early deficits in social cognition (SC) and executive functions (EF). To date it remains unclear whether deficits of the respective cognitive domains are based on the degeneration of distinct brain regions. In 103 patients with a diagnosis of bvFTD (possible/probable/definite: N = 40/58/5) from the frontotemporal lobar degeneration (FTLD) consortium Germany cohort (age 62.5±9.4 years, gender 38 female/65 male) we applied multimodal structural imaging, i.e. voxel-based morphometry, cortical thickness (CTH) and networks of structural covariance via source based morphometry. We cross-sectionally investigated associations with performance in a modified Reading the Mind in the Eyes Test (RMET; reflective of theory of mind - ToM) and five different tests reflective of EF (i.e. Hamasch-Five-Point Test, semantic and phonemic Fluency, Trail Making Test, Stroop interference). Finally, we investigated the conjunction of RMET correlates with functional networks commonly associated with SC respectively ToM and EF as extracted meta-analytically within the Neurosynth database. RMET performance was mainly associated with gray matter volume (GMV) and CTH within temporal and insular cortical regions and less within the prefrontal cortex (PFC), whereas EF performance was mainly associated with prefrontal regions (GMV and CTH). Overlap of RMET and EF associations was primarily located within the insula, adjacent subcortical structures (i.e. putamen) and the dorsolateral PFC (dlPFC). These patterns were more pronounced after adjustment for the respective other cognitive domain. Corroborative results were obtained in analyses of structural covariance networks. Overlap of RMET with meta-analytically extracted functional networks commonly associated with SC, ToM and EF was again primarily located within the temporal and insular region and the dlPFC. In addition, on a meta-analytical level, strong associations were found for temporal cortical RMET correlates with SC and ToM in particular. These data indicate a temporo-frontal dissociation of bvFTD related disturbances of ToM and EF, with atrophy of the anterior temporal lobe being critically involved in ToM deficits. The consistent overlap within the insular cortex may be attributable to the multimodal and integrative role of this region in socioemotional and cognitive processing.

Abstract Literature suggests that intravenous prophylaxis exceeding 48 h offers no additional benefit in preventing surgical site infections (SSI) in patients with microvascular head and neck reconstruction. However, protocols for antibiotic therapy duration post-reconstruction are not standardized. This study identifies factors predicting prolonged intravenous antibiotic use and antibiotic escalation in patients receiving free flap head neck reconstruction. A retrospective analysis of 446 patients receiving free flap reconstruction was conducted, examining predictors for antibiotic therapy > 10 days and postoperative escalation. 111 patients (24.8%) experienced escalation, while 159 patients (35.6%) received prolonged therapy. Multivariate regression analysis revealed predictors for escalation: microvascular bone reconstruction (p = 0.008, OR = 2.0), clinically suspected SSI (p

Abstract Aims Few randomized trials assessed the changes over time in the chronotropic heart rate (HR) reactivity (CHR), HR recovery (HRR) and exercise endurance (EE) in response to the incremental shuttle walk test (ISWT). We addressed this issue by analysing the open HOMAGE (Heart OMics in Aging) trial. Methods In HOMAGE, 527 patients prone to heart failure were randomized to usual treatment with or without spironolactone (25–50 mg/day). The current sub‐study included 113 controls and 114 patients assigned spironolactone (~70% on beta‐blockers), who all completed the ISWT at baseline and at Months 1 and 9. Within‐group changes over time (follow‐up minus baseline) and between‐group differences at each time point (spironolactone minus control) were analysed by repeated measures ANOVA, unadjusted or adjusted for sex, age and body mass index, and additionally for baseline for testing 1 and 9 month data. Results Irrespective of randomization, the resting HR and CHR did not change from baseline to follow‐up, with the exception of a small decrease in the HR immediately post‐exercise (−3.11 b.p.m.) in controls at Month 9. In within‐group analyses, HR decline over the 5 min post‐exercise followed a slightly lower course at the 1 month visit in controls and at the 9 month visits in both groups, but not at the 1 month visit in the spironolactone group. Compared with baseline, EE increased by two to three shuttles at Months 1 and 9 in the spironolactone group but remained unchanged in the control group. In the between‐group analyses, irrespective of adjustment, there were no HR differences at any time point from rest up to 5 min post‐exercise or in EE. Subgroup analyses by sex or categorized by the medians of age, left ventricular ejection fraction or glomerular filtration rate were confirmatory. Combining baseline and Months 1 and 9 data in both treatment groups, the resting HR, CHR and HRR at 1 and 5 min averaged 61.5, 20.0, 9.07 and 13.8 b.p.m. and EE 48.3 shuttles. Conclusions Spironolactone on top of usual treatment compared with usual treatment alone did not change resting HR, CHR, HRR and EE in response to ISWT. Beta‐blockade might have concealed the effects of spironolactone. The current findings demonstrate that the ISWT, already used in a wide variety of pathological conditions, is a practical instrument to measure symptom‐limited exercise capacity in patients prone to developing heart failure because of coronary heart disease.

The concept of precision oncology, the application of targeted drugs based on comprehensive molecular profiling, has revolutionized treatment strategies in oncology. This review summarizes the current status of precision oncology in glioblastoma (GBM), the most common and aggressive primary brain tumor in adults with a median survival below 2 years. Targeted treatments without prior target verification have consistently failed. Patients with BRAF V600E‐mutated GBM benefit from BRAF/MEK‐inhibition, whereas targeting EGFR alterations was unsuccessful due to poor tumor penetration, tumor cell heterogeneity, and pathway redundancies. Systematic screening for actionable molecular alterations resulted in low rates (

Abstract We study a non-relativistic limit of 11-dimensional supergravity. This limit leads to a theory with an underlying membrane Newton-Cartan geometry. Consistency of the non-relativistic limit requires the imposition of constraints, requiring that certain bosonic and fermionic torsions and curvatures vanish. We investigate the implications of two versions of these constraints. In one version, we keep only 16 supersymmetry transformations, leading to a simple (purely bosonic) constraint structure but an unusual realisation of the supersymmetry algebra which does not close into diffeomorphisms. In the other, we keep all 32 supersymmetry transformations. This requires a complicated sequence of bosonic and fermionic constraints, eventually involving three derivatives of bosonic fields. We argue, with a linearised calculation, that this sequence of constraints terminates. Furthermore, we show that there exists a family of supersymmetric solutions satisfying these constraints, containing the non-relativistic limit of the M2 supergravity solution recently obtained by Lambert and Smith as a background relevant for non-relativistic holography.

Abstract Background Genomic instability and evading apoptosis are two fundamental hallmarks of cancer and closely linked to DNA damage response (DDR). By analyzing expression quantitative trait loci (eQTL) upon cell stimulation (called exposure eQTL (e2QTL)) it is possible to identify context specific gene regulatory variants and connect them to oncological diseases based on genome-wide association studies (GWAS). Results We isolate CD8+ T cells from 461 healthy donors and stimulate them with high doses of 5 different carcinogens to identify regulatory mechanisms of DNA damage-induced apoptosis. Across all stimuli, we find 5,373 genes to be differentially expressed, with 85% to 99% of these genes being suppressed. While upregulated genes are specific to distinct stimuli, downregulated genes are shared across conditions but exhibit enrichment in biological processes depending on the DNA damage type. Analysis of eQTL reveals 654 regulated genes across conditions. Among them, 47 genes are significant e2QTL, representing a fraction of 4% to 5% per stimulus. To unveil disease relevant genetic variants, we compare eQTL and e2QTL with GWAS risk variants. We identify gene regulatory variants for KLF2, PIP4K2A, GPR160, RPS18, ARL17B and XBP1 that represent risk variants for oncological diseases. Conclusion Our study highlights the relevance of gene regulatory variants influencing DNA damage-induced apoptosis in cancer. The results provide new insights in cellular mechanisms and corresponding genes contributing to inter-individual effects in cancer development.

Abstract The uniqueness in each person’s cancer cells and variation in immune infiltrates means that each tumor represents a unique problem, but therapeutic targets can be found among their shared features. Radiation therapy alters the interaction between the cancer cells and the stroma through release of innate adjuvants. The extranuclear DNA that can result from radiation damage of cells can result in production of the second messenger cyclic guanosine monophosphate–adenosine monophosphate (cGAMP) by cyclic GMP-AMP synthase (cGAS). In turn, cGAMP can activate the innate sensor stimulator of interferon genes (STING), resulting in innate immune activation. Ectonucleotide pyrophosphatase/phosphodiesterase 1 (Enpp1) is a phosphodiesterase that can be expressed by cancer cells that can degrade cGAMP, thus can decrease or block STING activation following radiation therapy, impairing the innate immunity that is critical to support adaptive immune control of tumors. We observed that many human and murine cancer cells lack Enpp1 expression, but that Enpp1 is expressed in cells of the tumor stroma where it limits tumor control by radiation therapy. We demonstrate in preclinical models the efficacy of a novel Enpp1 inhibitor and show that this inhibitor improves tumor control by radiation even where the cancer cells lack Enpp1. This mechanism requires STING and type I interferon (IFN) receptor expression by non-cancer cells and is dependent on CD8 T cells as a final effector mechanism of tumor control. This suggests that Enpp1 inhibition may be an effective partner for radiation therapy regardless of whether cancer cells express Enpp1. This broadens the potential patient base for whom Enpp1 inhibitors can be applied to improve innate immune responses following radiation therapy.

Abstract Background Mindfulness has been studied as a treatment option for a large range of psychological disorders and is associated with a multitude of positive psychological outcomes. There are now several scales for measuring mindfulness as both a trait and a state. As mindfulness potentially plays a critical role in maintaining physical activity habits, the State Mindfulness Scale for Physical Activity (SMS-PA) was developed to specifically measure mindfulness in a physical activity context. This study aimed to provide validity evidence for a German version of the SMS-PA (henceforth called SMS-PA-G) in a clinical sample. Methods We used baseline data from 129 participants in the randomised controlled trial ‘New Ways to Cope with Depression’. The sample, which was screened for clinical depression symptoms, completed the SMS-PA-G and several other psychometric scales for capturing state mindfulness, self-efficacy, sense of coherence, anxiety, depression, and physical activity. We conducted reliability and item analyses and ran a confirmatory factor analysis. Also, we assessed construct validity through correlations with the abovementioned scales and through differences in SMS-PA scores between physically active and nonactive participants. Results The mean SMS-PA-G score in our sample was 25.3 with a standard deviation of 8.5. The item and reliability analyses provided satisfactory Cronbach’s alpha and discriminatory power values. The confirmatory factor analysis showed that physical activity mindfulness can best be described via a bifactor model, with specific mind and body factors and a general mindfulness factor. We found the expected relationships with the attention subscale of state mindfulness, self-efficacy, and sense of coherence but did not find them with the awareness subscale of state mindfulness, depression, and anxiety. As hypothesised, physically active participants exhibited higher SMS-PA-G values than nonactive participants. Conclusions The SMS-PA-G is an internally consistent test instrument that captures respondents’ general physical activity mindfulness and their attention to mental and bodily events. Whereas validity evidence was generally supportive of the SMS-PA-G, its relationships with other constructs require further investigation. Trial registration ISRCTN, ISRCTN12347878. Registered 28 March 2022, https://www.isrctn.com/ISRCTN12347878 .

Abstract Neoantigen-specific T cell receptors (neoTCRs) promise safe, personalized anti-tumor immunotherapy. However, detailed assessment of neoTCR-characteristics affecting therapeutic efficacy is mostly missing. Previously, we identified diverse neoTCRs restricted to different neoantigens in a melanoma patient. In this work, we now combine single-cell TCR-sequencing and RNA-sequencing after neoantigen-specific restimulation of peripheral blood-derived CD8+ T cells of this patient. We detect neoTCRs with specificity for the previously detected neoantigens and perform fine-characterization of neoTCR-transgenic (tg) T cells in vitro and in vivo. We describe a heterogeneous spectrum of TCR-intrinsic activation patterns in response to a shared neoepitope ranging from previously detected more highly frequent neoTCRs with moderate activation to rare ones with initially stronger activation. Experimental restimulation of adoptively transferred neoTCR-tg T cells in a xenogeneic rechallenge tumor model demonstrates superior anti-tumor responses of moderate neoTCR-tg T cells upon repeated tumor contact. These insights have significant implications for the selection of TCRs for therapeutic engineering of TCR-tg T cells.

Abstract Single-cell multiomics provides comprehensive insights into gene regulatory networks, cellular diversity, and temporal dynamics. Here, we introduce nanoSPLITS (nanodroplet SPlitting for Linked-multimodal Investigations of Trace Samples), an integrated platform that enables global profiling of the transcriptome and proteome from same single cells via RNA sequencing and mass spectrometry-based proteomics, respectively. Benchmarking of nanoSPLITS demonstrates high measurement precision with deep proteomic and transcriptomic profiling of single-cells. We apply nanoSPLITS to cyclin-dependent kinase 1 inhibited cells and found phospho-signaling events could be quantified alongside global protein and mRNA measurements, providing insights into cell cycle regulation. We extend nanoSPLITS to primary cells isolated from human pancreatic islets, introducing an efficient approach for facile identification of unknown cell types and their protein markers by mapping transcriptomic data to existing large-scale single-cell RNA sequencing reference databases. Accordingly, we establish nanoSPLITS as a multiomic technology incorporating global proteomics and anticipate the approach will be critical to furthering our understanding of biological systems.

Abstract Background Spondyloarthritides (SpAs) are a group of common rheumatic diseases that often cause limited mobility and lower back pain. Physiotherapy is an integral part of treatment, but access to physiotherapy limits treatment success. Digital health applications (DHAs) enable home-based physiotherapy and could significantly improve access for SpAs patients. The aim is to investigate the clinical effects of the DHA ViViRA compared with those of standard physiotherapy. Methods SpAs patients with chronic back pain were enrolled in a randomized controlled trial. The intervention group received ViViRA DHA, whereas the control group received standard physiotherapy. Pain (verbal rating scale, PAIN-Detect), quality of life (SF-36) and mobility (BASMI) were assessed at baseline and after 12 weeks as the primary outcomes. Results Data from 59 participants (71.2% female, mean age 45.2 years) were analyzed. The intervention group showed a significant improvement in mobility (average BASMI score: baseline: 1.1 [range 0.7–1.5]; follow-up: 1.0 [range 0.5–1.4]; p = 0.05), whereas the control group showed a significant decrease in mobility (baseline: 1.5 [range 1.1–1.9]; follow-up: 1.8 [range 1.4–2.2]; p = 0.00). The intervention group demonstrated lower pain intensity (VRS pain level at week 3.5 ± 2.8) than did the control group (VRS pain level at week 4.5 ± 2) after 12 weeks. Conclusion Our results highlight the efficacy of DHAs such as ViViRA in the treatment of lower back pain in SpAs patients. Compared with the current gold standard, physiotherapy, DHA use results in superior outcomes. However, further larger studies are needed to confirm these promising results. Trial registration The study is registered in the German clinical trial registry (DRKS) under the following ID: DRKS00031254.

Abstract Background Alcohol use disorder (AUD) poses severe health risks, yet many affected individuals opt out of complete abstinence. Therefore, harm reduction strategies have become more prominent in treatment guidelines for AUD. Our two case reports illustrate how disulfiram, initially intended to enforce abstinence, was repurposed to support reduced drinking. Case Presentations A 41-year-old patient with a history of severe AUD successfully reduced his alcohol consumption to a low-risk level by leveraging the effects of the disulfiram-alcohol aversive reaction. Another patient, a 63-year-old woman with long histories of AUD and major depressive disorder, experienced fewer depressive episodes and hospitalizations with disulfiram therapy despite periodically intentional discontinuation of medication. Conclusion Individualized treatment strategies are critical in optimizing outcomes for patients with AUD. Continuous disulfiram therapy, despite its limitations in directly reducing alcohol intake, might offer a new avenue for harm reduction in exceptional cases even if alcohol consumption continues. The cases suggest that maintaining therapy, aiming at reduced drinking, can enhance the therapeutic alliance and help manage comorbid conditions. Regular medical monitoring is essential for safety and efficacy, warranting further study of possible long-term consequences and psychotropic effects of elevated acetaldehyde levels related to the disulfiram-alcohol interaction.

Abstract Background To assess fatigue in cancer patients, several patient-reported outcome measures (PROMs) are available that differ in content. To support the selection of suitable measures for specific applications and to evaluate possibilities of quantitative linking, the present study provides a content comparison of common fatigue measures, scales, and item banks. We included the EORTC CAT Core, EORTC QLQ-FA12, EORTC QLQ-C30, FACIT-F, PROMIS Fatigue (Cancer item bank v1.0), Brief Fatigue Inventory (BFI), Multidimensional Fatigue Inventory (MFI-20), Piper Fatigue Scale (PFS-12), and PRO-CTCAE. Methods All items of the included measures were linked to the International Classification of Functioning, Disability and Health (ICF). Additionally, they were categorized as assessing general, physical, emotional, or cognitive fatigue. Descriptive statistics were used to display the contents covered in each measure and to allow for a qualitative comparison. Results The measures consist of 160 items in total and covered primarily contents of the ICF components ‘Body functions’, ‘Activities and participation’, and ‘Environmental Factors’. Most ICF codings refer to ‘b1300 Energy level’ (9–67% of the codings per instrument; 47% of all coded content). Within the broad categorization of types of fatigue, most items were classified as general fatigue (33–100% of the codings per instrument; 49% of the overall item pool). While the EORTC CAT Core focuses exclusively on physical and general fatigue, FACIT and BFI additionally assess emotional fatigue. The EORTC QLQ-FA12, PROMIS, MFI-20, and PFS-12 cover all fatigue components, including cognitive fatigue. Discussion The review provides an in-depth content comparison of PROMs assessing cancer-related fatigue. This can inform the selection of suitable measures in different clinical contexts. Furthermore, it will inform quantitative analyses to facilitate comparison of scores obtained with different PROMs.

Abstract: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is the best curative treatment modality for many malignant hematologic disorders. In the absence of a matched related donor, matched unrelated donors (MUDs) and haploidentical donors are the most important stem cell sources. In this registry-based retrospective study, we compared the outcomes of allo-HSCTs from 10/10 MUDs with antithymocyte globulin (ATG)–based regimens (n = 7050) vs haploidentical transplants (Haplo-Tx) using posttransplant cyclophosphamide (PT-CY Haplo; n = 487) in adult patients with hematologic malignancies between 2010 and 2020. Cox proportional hazard-and competing risks regression models were formed to compare the outcomes. Overall survival (OS), Disease-free survival (DFS), and graft-versus-host disease (GVHD)–free and relapse-free survival (GRFS) were superior for 10/10 MUDs (OS [hazard ratio (HR), 1.27; 95% confidence interval (CI), 1.10-1.47; P = .001]; DFS [HR, 1.17; CI, 1.02-1.34; P = .022]; GRFS [HR, 1.34; CI, 1.19-1.50; P

Background: Historically, patients with metastatic renal cell carcinoma (mRCC) have been offered upfront cytoreductive nephrectomy (CN) followed by systemic therapy. Currently, CN is no longer the standard of care (SOC) based on the randomised phase 3 CARMENA study performed in the vascular endothelial growth factor receptor tyrosine kinase inhibitor era. With the advent of immune checkpoint inhibitor (ICI) combination therapy in first line, the role of CN needs to be reassessed. There is indirect evidence from small retrospective series that deferred CN after ICI combination therapy may lead to better outcomes. To reassess the role of CN, we designed PrimerX, a randomised controlled trial following the Trial within Cohorts (TwiCs) study design. The primary objective of this study is to re-evaluate the benefit of deferred local treatment in the current era of immunotherapy. Study design: This PrimerX study has been designed as a TwiCs study within the Dutch Prospective Renal Cell Carcinoma (PRO-RCC) cohort. The PRO-RCC cohort includes patients with mRCC and nonmetastatic RCC, and has been set up for prospective collection of long-term clinical data and as an infrastructure for initiating TwiCs studies. The PrimerX TwiCs trial follows a Bayesian adaptive multistage design to allow for early discontinuation due to futility or efficacy. PrimerX has appropriate ethics approval and is registered at clinical.trials.gov (NCT05941169). End points: The primary clinical endpoint is overall survival, defined as the time from randomisation to death from any cause. The secondary endpoint is the objective response rate within the primary tumour prior to local therapy, as assessed by a computed tomography scan. Patients and methods: A maximum of 700 patients with synchronous mRCC and absence of progression at metastatic sites following at least 6 mo of standard first-line ICI combination therapy will be assigned randomly to receive local treatment of the primary tumour (experimental arm) or SOC (control arm). The experimental intervention consists of (partial) CN, any form of ablative local therapy, or magnetic resonance imaging guided ablative stereotactic radiotherapy, performed within 6 mo and 1.5 yr after the start of systemic treatment.

Background and objective: Prostate-specific membrane antigen (PSMA) radioguided salvage pelvic lymph node dissection (S-PLND) has emerged as a feasible treatment option for prostate cancer recurrence following initial surgery. This study aims to evaluate the feasibility and short-term outcomes of PSMA radioguided S-PLND. Methods: From a prospective trial of 99mTc-PSMA-I&S followed by PSMA radioguided robotic surgery, we evaluated patients treated for node-only recurrence following radical therapy. The primary outcome was serum prostate-specific antigen (PSA) response 3 mo after surgery. Key findings and limitations: Among 14 patients (enrolled from June 2021 to June 2023), the median age was 65 yr. One patient had undergone primary whole gland ultrasound ablation, while the rest received prior prostatectomy. The median (interquartile range) time from primary treatment to PSMA positron emission tomography (PET) was 4.1 (2.9–8.3) yr, and 21 total pelvic targets were noted on PSMA PET: one in eight patients (67%), two in five patients (29%), and three in one patient (7%). Targets were successfully detected intraoperatively and removed in 13/14 (93%) patients. Cancer was noted on histopathology in 90% (19/21) of PSMA PET targets, 94% (17/18) of single-photon emission computed tomography targets, and 82% (14/17) of gamma probe targets. There were no adverse effects due to the radiotracer, and there were no complications after surgery. PSA at 3 mo was

Background and objective: With advancement in technology, it has been possible to use minimally invasive surgical approaches for performing pyeloplasty for the treatment of ureteral strictures. This study aims to investigate the current trends of pyeloplasty and reconstructive ureteral procedures. Methods: We analyzed the nationwide German hospital billing database (Destatis) from 2006 to 2022. Linear regression models were utilized for the identification of trends over time. Key findings and limitations: A total of 34 975 pyeloplasties and 37 470 cases with ureteral reconstruction procedures were analyzed. The total number of pyeloplasties increased from 1990 procedures in 2006 to 2251 in 2019, before declining again down to 1916 procedures in 2022 (p = 0.783). Open pyeloplasty cases decreased from 79.5% in 2006 to 17.6% in 2022, while those using the robotic approach increased from 0.3% in 2006 to 35.9% in 2022 (p

Abstract Water is characterized by strong intermolecular hydrogen bonds (H-bonds) between molecules. The two hydrogen atoms in one water molecule can form H-bonds of dissimilar length. Although intimately connected to water’s anomalous properties, the details and the origins of the asymmetry have remained elusive. We study water’s H-bonds using the O-D stretching vibrations as sensitive reporters of H-bonding of D2O and HOD in dimethylformamide. Broader inhomogeneous linewidths of the OD band of HOD compared to the symmetric and asymmetric OD stretching modes of D2O together with density functional theory calculations provide evidence for markedly anti-correlated H-bonds: water preferentially forms one weak and one strong H-bond. Coupling peaks in the spectra for D2O directly demonstrate anti-correlated H-bonds and these anti-correlations are modulated by thermal motions of water on a sub-picosecond timescale. Experimentally inferred H-bond distributions suggest that the anti-correlations are a direct consequence of the H-bonding potential of XH2 groups, which we confirm for the ND2 group of urea. These structural and dynamic insights into H-bonding are essential for understanding the relationship between the H-bonded structure and phase behavior of water.

Compliance checking is an essential part of a construction project. The recent rapid uptake of building information models (BIM) in the construction industry has created more opportunities for automated compliance checking (ACC). BIM enable sharing of digital building design data that can be used to check compliance with legal requirements, which are conventionally conveyed in natural language and not intended for machine processing. Creating a computable representation of legal requirements suitable for ACC is complex, costly, and time-consuming. Large language models (LLMs) such as the generative pre-trained transformers (GPT), GPT-3.5 and GPT-4, powering OpenAI’s ChatGPT, can generate logically coherent text and source code responding to user prompts. This capability could be used to automate the conversion of building regulations into a semantic and computable representation. This paper evaluates the performance of LLMs in translating building regulations into LegalRuleML in a few-shot learning setup. By providing GPT-3.5 with only a few example translations, it can learn the basic structure of the format. Using a system prompt, we further specify the LegalRuleML representation and explore the existence of expert domain knowledge in the model. Such domain knowledge might be ingrained in GPT-3.5 through the broad pre-training but needs to be brought forth by careful contextualisation. Finally, we investigate whether strategies such as chain-of-thought reasoning and self-consistency could apply to this use case. As LLMs become more sophisticated, the increased common sense, logical coherence and means to domain adaptation can significantly support ACC, leading to more efficient and effective checking processes.

Healthcare integrated biobanking describes the annotation and collection of residual samples from hospitalized patients for research purposes. The central idea of the current work is to establish an automated workflow for sample annotation, selection and storage for diabetes mellitus. This is challenging due to incomplete data at the time of sample selection. The study evaluates a machine learning (ML) and natural language processing (NLP) based two-step procedure for timely and precise sample annotation for diabetes mellitus. Electronic health record data of 785 persons were extracted from the hospital information system. In the first step, a conditional inference forest (CIF) model was trained and tested based on laboratory values from the first 72 h of the hospital stay using test- (n = 550) and training data sets (n = 235). Performance was compared with a simple laboratory cut-off classifier (LCC) and a logistic regression (LR) model. Algorithms based on laboratory values, ICD-10 codes or information from discharge summaries extracted by a natural language processing software (NLP-DS) were evaluated as a second (review) step designed to increase the precision of annotations. For the first step, recall/precision/F1-score/accuracy were 71 %/86 %/0.78/0.82 for CIF and 77 %/70 %/0.74/0.75 for LR compared to 73 %/68 %/0.70/0.72 for LCC. NLP-DS was the best-performing second (review) step (93 %/100 %/0.97/0.97). Combining first-step models with NLP-DS increased precision to 100 % for all procedures (66 %/100 %/0.80/0.85 for CIF&NLP-DS, 72 %/100 %/0.84/87.2 for LR&NLP-DS and 66 %/100 %/0.80/0.85 for LCC&NLP-DS). The number of samples removed by NLP-DS was higher for LR&NLP-DS and LCC&NLP-DS (removal rate 35 % and 38 % of initially selected samples) compared to CIF&NLP-DS (removal rate of 20 %). The developed two-step procedure is an efficient implementable method for timely and precise annotation of samples from diabetic hospitalized patients.

Identifying potential cancer-associated genes and drug targets from omics data is challenging due to its diverse sources and analyses, requiring advanced skills and large amounts of time. To facilitate such analysis, we developed Cat-E (Cancer Target Explorer), a novel R/Shiny web tool designed for comprehensive analysis with evaluation according to cancer-related omics data. Cat-E is accessible at https://cat-e.bioinfo-wuerz.eu/. Cat-E compiles information on oncolytic viruses, cell lines, gene markers, and clinical studies by integrating molecular datasets from key databases such as OvirusTB, TCGA, DrugBANK, and PubChem. Users can use all datasets and upload their data to perform multiple analyses, such as differential gene expression analysis, metabolic pathway exploration, metabolic flux analysis, GO and KEGG enrichment analysis, survival analysis, immune signature analysis, single nucleotide variation analysis, dynamic analysis of gene expression changes and gene regulatory network changes, and protein structure prediction. Cancer target evaluation by Cat-E is demonstrated here on lung adenocarcinoma (LUAD) datasets. By offering a user-friendly interface and detailed user manual, Cat-E eliminates the need for advanced computational expertise, making it accessible to experimental biologists, undergraduate and graduate students, and oncology clinicians. It serves as a valuable tool for investigating genetic variations across diverse cancer types, facilitating the identification of novel diagnostic markers and potential therapeutic targets.

A tool to help Italian dairy farmers choosing the most suitable replacement strategy has been developed. The approach aimed to identify yearly female replacement needs based on herd performance level and combination of different semen type (conventional, sex-sorted, and beef semen), with the ultimate goal of enhancing farm profit. A case study based on a 350-cow Holstein herd was used and three levels of herd fertility (high, medium, and low) were simulated to define the yearly number of dairy female replacements needed and the number of females yielded under different semen utilisation scenario. The number of annual dairy replacements was obtained as the number of cows multiplied by the replacement rate and adjusted by the age at first calving. Number of animals yielded was used to evaluate the replacement cost per 100 L of milk. Then, four strategies of sexed semen utilisation were combined with five strategies of beef semen use. Animals that were not inseminated with sexed or beef semen were bred with conventional semen. Regardless of fertility level, the number of dairy female replacement heifers that the farm needs are 110. Increasing beef semen use allows farmer to yield less replacement heifers. Furthermore, as beef semen use increases and the number of replacement heifers decreases, replacement cost per 100 L of milk reduces. Therefore, our results highlighted that replacement costs increase with increasing number of yielded heifers. Hence, combining beef and sexed semen to reach heifer balance close to zero, decreased the replacement cost.

Abstract Eukaryotic mRNAs are transcribed, processed, translated, and degraded in different subcellular compartments. Here, we measured mRNA flow rates between subcellular compartments in mouse embryonic stem cells. By combining metabolic RNA labeling, biochemical fractionation, mRNA sequencing, and mathematical modeling, we determined the half-lives of nuclear pre-, nuclear mature, cytosolic, and membrane-associated mRNAs from over 9000 genes. In addition, we estimated transcript elongation rates. Many matured mRNAs have long nuclear half-lives, indicating nuclear retention as the rate-limiting step in the flow of mRNAs. In contrast, mRNA transcripts coding for transcription factors show fast kinetic rates, and in particular short nuclear half-lives. Differentially localized mRNAs have distinct rate constant combinations, implying modular regulation. Membrane stability is high for membrane-localized mRNA and cytosolic stability is high for cytosol-localized mRNA. mRNAs encoding target signals for membranes have low cytosolic and high membrane half-lives with minor differences between signals. Transcripts of nuclear-encoded mitochondrial proteins have long nuclear retention and cytoplasmic kinetics that do not reflect co-translational targeting. Our data and analyses provide a useful resource to study spatiotemporal gene expression regulation.

Abstract Van der Waals (vdW) magnetic materials are comprised of layers of atomically thin sheets, making them ideal platforms for studying magnetism at the two-dimensional (2D) limit. These materials are at the center of a host of novel types of experiments, however, there are notably few pathways to directly probe their magnetic structure. We confirm the magnetic order within a single crystal of NiPS3 and show it can be accessed with resonant elastic X-ray diffraction along the edge of the vdW planes in a carefully grown crystal by detecting structurally forbidden resonant magnetic X-ray scattering. We find the magnetic order parameter has a critical exponent of β ~ 0.36, indicating that the magnetism of these vdW crystals is more adequately characterized by the three-dimensional (3D) Heisenberg universality class. We verify these findings with first-principles density functional theory, Monte-Carlo simulations, and density matrix renormalization group calculations.

Abstract Background The garden dormouse (Eliomys quercinus) has experienced a significant population decline across Europe in recent decades. While habitat loss and climate change are often cited as primary factors, pathogen exposure, either to novel or to previously known, may play a role in such a decline. This study aimed to investigate the presence of polyomaviruses in garden dormice, given that these viruses are highly prevalent and can cause disease, particularly in immunocompromised individuals. Methods The carcasses of garden dormice (n = 89) were collected throughout Germany. Kidney samples were tested for the presence of polyomavirus DNA using nested degenerate and specific diagnostic PCRs. Seroprevalence was assessed from chest cavity fluid samples through an enzyme-linked immunosorbent assay using polyomavirus VP1 virus-like particles produced in yeast. Results A new polyomavirus, related to chimpanzee (Pan troglodytes) polyomaviruses 4 and 5 and human Merkel cell polyomavirus, was identified in the garden dormouse. Two 5,380 bp-length complete viral genomes were sequenced from dormice kidney samples (sequences PQ246041 and PQ246042). Genes encoding the putative structural proteins VP1, VP2, and VP3, as well as the Large, Middle, and small T antigens, containing conserved functional domains were identified. Polyomavirus DNA was detected in 2 of 74 dormice (2.7%, 95% confidence interval: 0-6.4%) through PCR, while 12 of 69 animals (17.4%, 95% confidence interval: 8.4-26.3%) tested positive for polyomavirus-specific antibodies. Conclusions In conclusion, here we describe a novel polyomavirus in the garden dormouse with molecular and serological detection. Pairwise sequence comparison and phylogenetic analysis suggest that this novel virus may represent a novel species within the genus Alphapolyomavirus. Future work should examine if this virus is garden dormouse-specific and whether it is associated with disease in dormice.

Abstract Owing to the simultaneous increase in the risk of thrombosis and bleeding in critically ill patients, point-of-care-available diagnostic tests to guide parenteral anticoagulation are warranted. We evaluated the detection of enoxaparin and argatroban, two commonly used parenteral anticoagulants, using the novel ClotPro viscoelastic coagulometer. For this experimental in vitro study at a tertiary care academic center, blood samples were drawn from twelve (six female, six male) healthy volunteers without intake of antithrombotic medication and no history of hemostatic disorders. Blood samples were spiked with enoxaparin (IU.ml− 1) and argatroban (µg.ml− 1) at increasing concentrations ranging from 0 to 1. The ClotPro Russell’s viper venom (RVV)-test and the ClotPro ecarin (ECA)-test clotting time were performed in parallel with conventional coagulation tests (anti-Xa activity, activated partial thromboplastin time, and diluted thrombin time). We observed a strong correlation between anti-Xa activity and the RVV-test clotting time (r = 0.88 (95% confidence interval (CI) 0.8–0.92; p

Abstract Resting heart rate (RHR) has prognostic implications in heart failure with reduced ejection fraction, where ≤ 70 bpm is targeted. Whether a RHR > 70 bpm assessed within clinical practice goes along with elevated cardiovascular risk in implantable cardioverter-defibrillator (ICD) / cardiac resynchronization therapy-defibrillator (CRT-D) recipients remains incompletely understood. A total of 1589 patients (ICD n = 1172 / CRT-D n = 417, median age 65 years, 22.6% female) undergoing ICD/CRT-D implantation or revision in the prospective German DEVICE multicenter registry were analyzed. RHR was assessed via a 12-channel electrocardiogram at enrollment. 1-year outcomes (all-cause mortality, major cardio- and cerebrovascular events (MACCE), all-cause hospital admission) were compared between patients with a RHR ≤ 70 bpm and > 70 bpm. 733 patients (46.1%) showed a RHR > 70 bpm. Median RHR was 63 (interquartile range 59; 68) bpm (≤ 70 bpm group) and 80 (75; 89) bpm (> 70 bpm group). Heart failure with reduced ejection fraction was present in 76.3%, a prior myocardial infarction in 32.4% and non-ischemic heart disease in 44.9%. One-year all-cause mortality was similar between RHR groups (≤ 70 bpm 5.4% vs. > 70 bpm 5.4%, p = 0.96), and subgroup analysis regarding patient characteristics and comorbidities revealed only a significantly higher rate of patients with dual chamber ICD in the > 70 bpm group (0.8% vs. 9.2%, p = 0.003). MACCE (5.9% vs. 6.1%, p = 0.87) and defibrillator shock rates (9.9% vs. 9.8%, p = 1.0) were similar. Higher all-cause hospital admission rates were observed in patients with > 70 bpm RHR (23.1% vs. 29.0%, p = 0.027) driven by non-cardiovascular events (6.0% vs. 11.7%, p = 0.001). In conclusion, in ICD and CRT-D recipients a RHR at admission > 70 bpm may indicate patients at increased risk of all-cause hospital admission but not of other adverse cardiovascular events or death at 1-year follow-up.

Abstract Metal–organic framework nanosheets (MONs) have proved themselves to be useful additives for enhancing the performance of a variety of thin film solar cell devices. However, to date only isolated examples have been reported. In this work we take advantage of the modular structure of MONs in order to resolve the effect of their different structural and optoelectronic features on the performance of organic photovoltaic (OPV) devices. Three different MONs were synthesized using different combinations of two porphyrin-based ligands meso-tetracarboxyphenyl porphyrin (TCPP) or tetrapyridyl-porphyrin (TPyP) with either zinc and/or copper ions and the effect of their addition to polythiophene-fullerene (P3HT-PC71BM) OPV devices was investigated. The power conversion efficiency (PCE) of devices was found to approximately double with the addition of MONs of Zn2(ZnTCPP) -4.7% PCE, 10.45 mA/cm2 short-circuit current density (J SC), 0.69 open-circuit voltage (V OC), 64.20% fill-factor (FF), but was unchanged with the addition of Cu2(ZnTPyP) (2.6% PCE, 3.68 mA/cm2 J SC, 0.59 V OC, 46.27% FF) and halved upon the addition of Cu2(CuTCPP) (1.24% PCE, 6.72 mA/cm2 J SC, 0.59 V OC, 56.24% FF) compared to devices without nanosheets (2.6% PCE, 6.61 mA/cm2 J SC, 0.58 V OC, 56.64% FF). Our analysis indicates that there are three different mechanisms by which MONs can influence the photoactive layer – light absorption, energy level alignment, and morphological changes. Analysis of external quantum efficiency, UV–vis and photoelectron spectroscopy data found that MONs have similar effects on light absorption and energy level alignment. However, atomic force and Raman microscopy studies revealed that the nanosheet thickness and lateral size are crucial parameters in enabling the MONs to act as beneficial additives resulting in an improvement of the OPV device performance. We anticipate this study will aid in the design of MONs and other 2D materials for future use in other light harvesting and emitting devices.

Abstract Recent research in patients with functionally univentricular hearts (UVH) is focusing on pathologies of the lymphatic vessels. Morphology of the abdominal lymphatic vessels was analyzed by MRI in patients with UVH following total cavopulmonary connection (TCPC) and it was examined, if clinical and laboratory parameters correlate with changes after TCPC. We prospectively examined 33 patients at the age of 19.8 (14.6;30.2) years [median (Q1;Q3)] after TCPC (follow-up 14.3 years (9.7;24.9) with a heavily T2-weighted MRI sequence on a 3.0 T scanner. Examinations in coronal orientation were performed with respiratory gating, slice thickness 0.6 mm, TR 2400 ms, TE 692 ms, FoV 460 mm (covering thoracic and abdominal regions), scan time 14:41 min (13:18;16:30) after a solid meal and a cup of pineapple juice. The findings were classified according to delineation of abdominal lymphatic vessels. Type 1: 6 av and/or oedematous changes or ascites. The results were correlated with parameters obtained at the annual routine check-up. Statistical analysis was performed using U-test and Chi-square test. Fifteen patients (group 1) showed type 3 lymphatic morphologies, two of which had ascites. Eighteen patients (group 2) showed lower grade morphologies (type 1–2). Image quality was rated considering the delineation of the common hepatic duct and did not differ between groups (p = 0.134). “Lymphatic burden” was automatically examined and was indexed to the number of delineated abdominal vessels and showed quantification according to the chosen categories type 1–3. Patients in group 1 were younger at MRI examination (17.4;14.3/18.9 vs. 26.2;18.2/32.3 years, p = 0.03). Superior cavopulmonary connection (SCPC) had been performed earlier in group 1 (9.9;7.9/25.5 vs. 29.2;13.7/66.6 months, p = 0.018). Laboratory examinations in group 1 showed lower levels for Immunoglobulin G (IgG), Lipase, α-Antitrypsin, Cystatin C and TSH. There were no significant differences for total protein, NTproBNP, lymphocytes or platelets. A history of chylothorax was present in 7/15 versus 2/18 p = 0.022. Protein-losing enteropathy (PLE) occurred in 4/15 versus 1/18 (p = 0.092). T2 weighted MRI is feasible for noninvasive delineation of abdominal lymphatic vessel in patients following TCPC. In the long-term follow-up, patients with more pronounced changes of the abdominal lymphatic vessels were younger at SCPC and were more likely to show a history of chylothorax and lower IgG values.

Abstract Background As ultrasound is one of the most utilized imaging procedures in clinical practice in Germany, its integration into undergraduate medical education is imperative. Thereby, the limited availability of qualified instructors is a major challenge. Peer tutors, who are trained to instruct their peers collaboratively, could resolve staff constraints. This systematic review explores the literature on peer teaching in undergraduate ultrasound education, aiming to provide an overview of methodologies, outcomes, and peer teacher training concepts. Methods Following the PRISMA guidelines, a systematic literature review was conducted on the subject of peer teaching in undergraduate ultrasound education. Using PubMed and Google Scholar as databases, studies in English or German involving training concepts for peer teachers in undergraduate ultrasound education, published up to November 21, 2023, were included. Data extraction of original studies followed the PICOS schema with special respect to didactic concepts of peer tutor training programs and the effectiveness of peer teachers compared to faculty instructors. A modified version of the Newcastle–Ottawa Scale (NOS) was used to assess the quality of included studies. Results Finally, the search resulted in 20 relevant original studies, including 16 studies exploring peer teacher training concepts. Predominantly, peer teachers studied in their 4th year of medical school and on average one year further compared to their students. Peer teacher training was integrated into curricula by course-based concepts (93.8%) and internships (50.0%). Didactic modalities varied, encompassing laboratory rotations including the scanning of patients, the scanning of fellow students, lectures, and didactic training. The median training duration was about ten days. Of six comparative studies, five found peer-assisted learning to be comparably effective and one even better than faculty-led courses. Conclusion Despite the growing amount of literature underlining the effectiveness and wide application of peer teaching in ultrasound education, training concepts stay heterogenous without a standardized system for training and qualifying peer teachers. Developing comprehensive guidelines for peer tutor education could increase acceptance and recognition of peer-assisted learning and ensure minimum training standards.

Abstract Wildfires emit solid-state strongly absorptive brown carbon (solid S-BrC, commonly known as tar ball), critical to Earth’s radiation budget and climate, but their highly variable light absorption properties are typically not accounted for in climate models. Here, we show that from a Pacific Northwest wildfire, over 90% of particles are solid S-BrC with a mean refractive index of 1.49 + 0.056i at 550 nm. Model sensitivity studies show refractive index variation can cause a ~200% difference in regional absorption aerosol optical depth. We show that ~50% of solid S-BrC particles from this sample uptake water above 97% relative humidity. We hypothesize these results from a hygroscopic organic coating, potentially facilitating solid S-BrC as nuclei for cloud droplets. This water uptake doubles absorption at 550 nm and the organic coating on solid S-BrC can lead to even higher absorption enhancements than water. Incorporating solid S-BrC and water interactions should improve Earth’s radiation budget predictions.

Abstract Recent successes in developing small molecule degraders that act through the ubiquitin system have spurred efforts to extend this technology to other mechanisms, including the autophagosomal-lysosomal pathway. Therefore, reports of autophagosome tethering compounds (ATTECs) have received considerable attention from the drug development community. ATTECs are based on the recruitment of targets to LC3/GABARAP, a family of ubiquitin-like proteins that presumably bind to the autophagosome membrane and tether cargo-loaded autophagy receptors into the autophagosome. In this work, we rigorously tested the target engagement of the reported ATTECs to validate the existing LC3/GABARAP ligands. Surprisingly, we were unable to detect interaction with their designated target LC3 using a diversity of biophysical methods. Intrigued by the idea of developing ATTECs, we evaluated the ligandability of LC3/GABARAP by in silico docking and large-scale crystallographic fragment screening. Data based on approximately 1000 crystal structures revealed that most fragments bound to the HP2 but not to the HP1 pocket within the LIR docking site, suggesting a favorable ligandability of HP2. Through this study, we identified diverse validated LC3/GABARAP ligands and fragments as starting points for chemical probe and ATTEC development.

Abstract Background Titanium plantar plates have proven successful in the fixation of the first tarsometatarsal arthrodesis (TMT). However, a second surgery is typically needed for implant removal, and potential adverse effects, carried by the conventional implantations, are not uncommon. The purpose of this study was to determine whether a novel magnesium-based plantar plate system provides similar fusion stability to a titanium-based plantar plate system under various loading conditions. Methods Six matched-pair human cadaveric specimens underwent TMT fusions using either a magnesium plantar plate system prototype or a titanium plantar plate system. Specimens were cyclically loaded with a force ranging from 5 N to 50 N for 5,000 cycles, and displacement was recorded. Axial stiffness (N/mm) was calculated from load-displacement curves. Each specimen was loaded to failure at a rate of 5 mm/min, and the ultimate load was recorded. Results No significant difference was found in the vertical displacement between Ti group and Mg group after 100 cycles (2.4 ± 1.0 mm vs. 1.3 ± 1.4 mm, p = 0.196), 500 cycles (3.3 ± 1.3 mm vs. 1.7 ± 1.7 mm, p = 0.142), 1,000 cycles (3.7 ± 1.5 mm vs. 1.9 ± 1.9 mm, p = 0.128), 2,500 cycles (4.2 ± 1.7 mm vs. 2.3 ± 2.2 mm, p = 0.172) and 5,000 cycles (4.5 ± 1.8 mm vs. 2.3 ± 3.3 mm, p = 0.125), Additionally, no significant differences were observed in initial stiffness (53.1 ± 19.2 N/mm vs. 82.2 ± 53.9 N/mm, p = 0.257), final stiffness (90.6 ± 48.9 N/mm vs. 120.0 ± 48.3 N/mm, p = 0.319), or maximum load-to-failure (259.8 ± 98.2 N vs. 323.9 ± 134.9 N, p = 0.369). Conclusions Based on the performed biomechanical testing, the magnesium plantar plate system provides mechanical stability equivalent to the titanium plantar plate system in fixation for the first TMT joint fusion.

Abstract Light profoundly impacts many aspects of human physiology and behaviour, including the synchronization of the circadian clock, the production of melatonin, and cognition. These effects of light, termed the non-visual effects of light, have been primarily investigated in laboratory settings, where light intensity, spectrum and timing can be carefully controlled to draw associations with physiological outcomes of interest. Recently, the increasing availability of wearable light loggers has opened the possibility of studying personal light exposure in free-living conditions where people engage in activities of daily living, yielding findings associating aspects of light exposure and health outcomes, supporting the importance of adequate light exposure at appropriate times for human health. However, comprehensive protocols capturing environmental (e.g., geographical location, season, climate, photoperiod) and individual factors (e.g., culture, personal habits, behaviour, commute type, profession) contributing to the measured light exposure are currently lacking. Here, we present a protocol that combines smartphone-based experience sampling (experience sampling implementing Karolinska Sleepiness Scale, KSS ratings) and high-quality light exposure data collection at three body sites (near-corneal plane between the two eyes mounted on spectacle, neck-worn pendant/badge, and wrist-worn watch-like design) to capture daily factors related to individuals’ light exposure. We will implement the protocol in an international multi-centre study to investigate the environmental and socio-cultural factors influencing light exposure patterns in Germany, Ghana, Netherlands, Spain, Sweden, and Turkey (minimum n = 15, target n = 30 per site, minimum n = 90, target n = 180 across all sites). With the resulting dataset, lifestyle and context-specific factors that contribute to healthy light exposure will be identified. This information is essential in designing effective public health interventions.

Abstract CDKN2A/B deletions are prognostically relevant in low- and high-grade gliomas. Data on this is derived from heterogeneous series, an accurate estimation of survival risk from homozygous CDKN2A/B deletion is missing. Besides genetic testing, p16-immunohistochemistry (IHC) as a less cost intensive means for indirect detection of CDKN2A/B alterations is possible but not validated in larger datasets. The present meta-analysis aimed to (1) reconstruct individual patient data (IPD) and estimate overall survival (OS) stratified by CDKN2A/B status from all literature and to (2) determine accuracy of p16 testing for CDKNA2/B detection from published studies. For survival analysis according to CDKN2A/B status 460 records were screened, four articles with 714 participants were included. In IDH-wildtype (IDH-wt) gliomas, 57.07% harbored the deletion compared to 9.76% in IDH-mutant (IDH-mut) gliomas. Median OS of patients with IDH-wt gliomas and homozygous CDKN2A/B deletion was 13.0 months compared to 18.0 months with non-deleted CDKN2A/B (p = 0.014, Log-Rank). With homozygous deletion of CDKN2A/B the risk of death was increased by 1.5 (95%-CI 1.1–2.1). Median OS in patients with IDH-mut gliomas without CDKN2A/B deletion was 92.0 months compared to 40.0 months with CDKN2A/B deletion (p 5% and within IDH-mut glioma.

The integration of artificial intelligence, particularly Large Language Models (LLMs), has the potential to significantly enhance therapeutic decision-making in clinical oncology. Initial studies across various disciplines have demonstrated that LLM-based treatment recommendations can rival those of multidisciplinary tumor boards (MTBs); however, such data are currently lacking for urological cancers. This preparatory study establishes a robust methodological foundation for the forthcoming CONCORDIA trial, including the validation of the System Causability Scale (SCS) and its modified version (mSCS), as well as the selection of LLMs for urological cancer treatment recommendations based on recommendations from ChatGPT-4 and an MTB for 40 urological cancer scenarios. Both scales demonstrated strong validity, reliability (all aggregated Cohen’s K > 0.74), and internal consistency (all Cronbach’s Alpha > 0.9), with the mSCS showing superior reliability, internal consistency, and clinical applicability (p < 0.01). Two Delphi processes were used to define the LLMs to be tested in the CONCORDIA study (ChatGPT-4 and Claude 3.5 Sonnet) and to establish the acceptable non-inferiority margin for LLM recommendations compared to MTB recommendations. The forthcoming ethics-approved and registered CONCORDIA non-inferiority trial will require 110 urological cancer scenarios, with an mSCS difference threshold of 0.15, a Bonferroni corrected alpha of 0.025, and a beta of 0.1. Blinded mSCS assessments of MTB recommendations will then be compared to those of the LLMs. In summary, this work establishes the necessary prerequisites prior to initiating the CONCORDIA study and validates a modified score with high applicability and reliability for this and future trials.

Background/Objectives: This study was conducted to compare two modes of computed tomography fluoroscopy (CTF) and two gastropexy techniques used in CT-guided percutaneous radiologic gastrostomy (CT-PRG) aiming to identify the optimal techniques for image guidance and gastropexy and, thus, to overcome the current lack of consensus on the preferred modalities. Methods: We retrospectively identified 186 successful CT-PRG procedures conducted evenly across two university hospitals from January 2019 to December 2023. Patients were divided into two groups (intermittent multislice CT biopsy mode-guided technique (MS-CT BM) and retention anchor suture (T-fastener) versus real-time (RT-)CTF and gastropexy device) for descriptive analysis of demographics, indication for PRG, radiation exposure (DLP), procedural time, number of CT scans, gastropexy time, and complications. Differences were assessed for statistical significance using Fisher’s exact test and the Mann–Whitney U-test. Results: Our final study population comprised 100 patients (50 from each center; 62.52 ± 12.36 years, 73 men). There was a significant difference in radiation exposure between MS-CT BM (group 1) and RT-CTF (group 2), with an average dose-length product (DLP) of 56.28 mGycm×m ± 67.89 and 30.91 ± 27.53 mGycm×cm, respectively (p < 0.001). PRG with RT-CTF guidance was significantly faster than PRG with MS-CT BM, with an average difference of 10.28 min (p < 0.001). No significant difference in duration was found between the two gastropexy methods compared (retention anchor suture, 11.50 ± 5.239 s vs. gastropexy device, 11.17 ± 6.015 s; p = 0.463). Complication rates did not differ significantly either (p = 0.458). Conclusions: Our findings indicate comparable efficacy and safety of the two gastropexy methods and underscore that the choice of CTF mode for image guidance has only a small role in reducing radiation exposure in patients undergoing CT-PRG. Instead, it is essential to avoid control scans.

Abstract We compute the far-field time-domain waveform of the gravitational waves produced in the scattering of two spinning massive objects. The results include linear-in-spin (S) couplings and first-order gravitational corrections (G 3), and are valid for encounters in the weak-field regime. Employing a field-theory framework based on the scattering of massive scalar and vector particles coupled to Einstein-Hilbert gravity, we derive results for leading and the next-to-leading spectral waveforms. We provide analytic expressions for the required scattering data, which include trees, one-loop amplitudes and their cuts. The expressions are extracted from numerical amplitude evaluations with the Caravel program, using analytic reconstruction techniques applied in the classical limit. We confirm a recent prediction for infrared physics of the classical observable, and observe the surprising appearance of a ultraviolet singularity, which drops out in the far-field waveform.

Abstract Background For several decades, the European wildcat (Felis silvestris) has gradually been returning to the forests of Germany, mainly in the central and southwestern regions. To increase the knowledge about this threatened species, the endoparasite status of dead found specimens from Germany was surveyed. Methods A total of 118 wildcats were examined for endoparasites in peritoneal organs and skeletal muscles. Owing to decomposition or incomplete carcasses, 104 gastrointestinal tracts (stomachs and intestines), 101 livers with gallbladders, 99 urinary bladders, as well as kidneys of 95 and skeletal muscles of 112 specimens were available for examination. All detected parasites were identified morphologically to genus or species level, followed by molecular examinations of one to ten specimens of each parasite species. Results Overall endoparasite prevalence in peritoneal organs was 99.0% (103/104). Among the 99.0% (103/104) infected gastrointestinal tracts, the most frequent species were Toxocara cati (95.2% [99/104]), Hydatigera kamiyai (84.6% [88/104]), Mesocestoides litteratus (69.2% [72/104]), Strongyloides spp. (58.7% [61/104]), Cylicospirura petrowi (37.5% [39/104]), Ancylostoma tubaeforme (31.7% [33/104]), Capillaria putorii (24.0% [25/104]), and Echinococcus multilocularis (18.3% [19/104]). In 77.8% (77/99) of the urinary bladders, Capillaria plica and/or Capillaria feliscati were detected. Moreover, the liver fluke Metorchis bilis occurred in 2.0% (2/101) of the livers, and roundworm larvae (presumably Toxocara spp.) were detected in 33.0% (37/112) of the muscle samples. Conclusions These results show a broad spectrum of endoparasite species infecting European wildcats in Germany. It might be assumed that some of the endoparasites could pose a risk to domestic cats (Felis catus) and humans through spillover events, or may be transmitted from domestic cats to the free-ranging population, posing a potential risk to wildcats. Graphical Abstract

Abstract Current legislation and market dynamics require and encourage systems to become more open and interoperable. Given this shift, the challenge arises as to how service providers can navigate such environments and whether and how known platform economics are affected by that change. In this context, our work investigates behavior when users interact with services in highly interoperable environments, examining the influence of service attributes and platform economics on service selection and switching decisions, with a focus on the role of transaction cost and time, onboarding time, privacy, ownership, and community. For this purpose, we designed and conducted an extensive survey study with more than 500 respondents that combined a conjoint study with an experimental part on switching scenarios. Our findings suggest that transaction features such as cost, time, and privacy are the main factors in service selection with part-worth utilities being 2.1 to 14.7 times higher than non-transactional features. Additionally, building a strong community and offering ownership opportunities to users are effective strategies for customer retention. Further, we observe that rational choice theory does not explain switching decisions in many cases. Our study has important implications for both industry practitioners and policymakers. Practitioners can use our results to carefully manage effective customer retention strategies, while policymakers can use them to better regulate digital markets.

Abstract Alterations in subcortical brain regions are linked to motor and non-motor symptoms in Parkinson’s disease (PD). However, associations between clinical expression and regional morphological abnormalities of the basal ganglia, thalamus, amygdala and hippocampus are not well established. We analyzed 3D T1-weighted brain MRI and clinical data from 2525 individuals with PD and 1326 controls from 22 global sources in the ENIGMA-PD consortium. We investigated disease effects using mass univariate and multivariate models on the medial thickness of 27,120 vertices of seven bilateral subcortical structures. Shape differences were observed across all Hoehn and Yahr (HY) stages, as well as correlations with motor and cognitive symptoms. Notably, we observed incrementally thinner putamen from HY1, caudate nucleus and amygdala from HY2, hippocampus, nucleus accumbens, and thalamus from HY3, and globus pallidus from HY4–5. Subregions of the thalami were thicker in HY1 and HY2. Largely congruent patterns were associated with a longer time since diagnosis and worse motor symptoms and cognitive performance. Multivariate regression revealed patterns predictive of disease stage. These cross-sectional findings provide new insights into PD subcortical degeneration by demonstrating patterns of disease stage-specific morphology, largely consistent with ongoing degeneration.

Abstract Ship traffic substantially contributes to air pollution, thus affecting climate and human health. Recently introduced regulations by the International Maritime Organization (IMO) on the fuel sulfur content (FSC) caused a shift in marine fuel onsumption from heavy fuel oils (HFO) to diesel-like distillate fuels, but also to alternative hybrid fuels and the operation of sulfur scrubbers. Using multi-wavelength thermal-optical carbon analysis (MW-TOCA), our study provides emission factors (EF) of carbonaceous aerosol particles and link the fuel composition to features observed in the soot microstructure, which may be exploited in online monitoring by single-particle mass spectrometry (SPMS). Particulate matter from distillate fuels absorbs stronger light of the visible UV and near-infrared range than HFO. However, Simple Forcing Efficiency (SFE) of absorption weighted by EF of total carbon compensated the effect, leading to a net reduction by >50% when changing form HFO to distillate fuels.

Abstract Non-invasive brain stimulation (NIBS) techniques such as transcranial direct current stimulation (tDCS) or transcranial magnetic stimulation (TMS) have made great progress in recent years and offer boundless potential for the neuroscientific research and treatment of disorders. However, the possible use of NIBS devices for neuro-doping and neuroenhancement in healthy individuals and the military are poorly regulated. The great potentials and diverse applications can have an impact on the future development of the technology and society. This participatory study therefore aims to summarize the perspectives of different stakeholder groups with the help of qualitative workshops. Nine qualitative on-site and virtual workshops were conducted in the study with 91 individuals from seven stakeholder groups: patients, students, do-it-yourself home users of tDCS, clinical practitioners, industry representatives, philosophers, and policy experts. The co-creative and design-based workshops were tailored to each group to document the wishes, fears, and general comments of the participants. The outlooks from each group were collected in written form and summarized into different categories. The result is a comprehensive overview of the different aspects that need to be considered in the field of NIBS. For example, several groups expressed the wish for home-based tDCS under medical supervision as a potential therapeutic intervention and discussed the associated technical specifications. Other topics that were addressed were performance enhancement for certain professional groups, training requirements for practitioners, and questions of agency, among others. This qualitative participatory research highlights the potential of tDCS and repetitive TMS as alternative therapies to medication, with fewer adverse effects and home-based use for tDCS. The ethical and societal impact of the abuse of NIBS for non-clinical use must be considered for policy-making and regulation implementations. This study adds to the neuroethical debate on the responsible use and application of NIBS technologies, taking into consideration the different perspectives of important stakeholders in the field.

Abstract Choroidal nevi are common benign melanocytic lesions often incidentally found during routine ophthalmic examinations. Patients with choroidal nevi are frequently referred to ocular oncology centers to differentiate these from choroidal melanoma and to exclude a malignant transformation which rarely occurs. However, this causes a high workload for referral centers and may delay diagnosis and treatment of patients with potentially severe conditions. To overcome this, the MOLES score was previously developed which may empower non-specialists to differentiate choroidal nevi from melanoma. In this retrospective study, the performance of the MOLES score was assessed in 695 patients with choroidal nevi and 53 with choroidal melanoma. With a specificity of 96% (choroidal nevi) and a sensitivity of 100% (melanoma) the MOLES score was highly successful in differentiating choroidal nevi from melanoma and may offer great potential to optimize monitoring and referral decisions, and for teleophthalmology applications. Furthermore, the TFSOM-DIM score using risk factors for determining tumor progression was applied and showed a good correlation with MOLES. A complementary use of MOLES and TFSOM-DIM may be beneficial for clinical routine: MOLES for screening by non-experts with limited diagnostic tools and TFSOM-DIM in a referral setting to counsel also regarding potential transformation.

Abstract Epistasis refers to changes in the effect on phenotype of a unit of genetic information, such as a single nucleotide polymorphism or a gene, dependent on the context of other genetic units. Such interactions are both biologically plausible and good candidates to explain observations which are not fully explained by an additive heritability model. However, the search for epistasis has so far largely failed to recover this missing heritability. We identify key challenges and propose that future works need to leverage idealized systems, known biology and even previously identified epistatic interactions, in order to guide the search for new interactions.