Search

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.

Abstract Battery production cost models are critical for evaluating the cost competitiveness of different cell geometries, chemistries, and production processes. To address this need, we present a detailed bottom-up approach for calculating the full cost, marginal cost, and levelized cost of various battery production methods. Our approach ensures comparability across research fields and industries, reflecting capital and imputed interest costs. We showcase the model with case studies of a prismatic PHEV2 hardcase cell and a cylindrical 4680 cell in four different chemistries. Our publicly available browser-based modular tool incorporates up-to-date parameters derived from literature and expert interviews. This work enables researchers to quickly assess the production cost implications of new battery production processes and technologies, ultimately advancing the goal of reducing the cost of electrified mobility.

Abstract Sarcopenia, defined as age-associated loss of skeletal muscle function and muscle mass, is a negative prognostic marker for survival in several tumor entities. However, data evaluating the impact of sarcopenia and fat distribution on penile cancer are rarely described. We performed a retrospective study including 38 patients who were diagnosed with squamous cell carcinoma of the penis. By measuring skeletal muscle mass and fat distribution at axial abdominal computed tomography images at the third lumbar vertebra several body composition parameters including skeletal muscle index (SMI), psoas muscle index (PMI), visceral obesity and visceral-to-subcutaneous fat ratio were determined. Among 38 patients, 26% (n = 10) of the patients with penile cancer were identified as sarcopenic. SMI, age, lymph node metastases, distant metastases and penile cancer of the shaft were identified as significant risk factors for overall survival. PMI and distant metastases were significantly associated with cancer specific survival. None of the analysed adipose tissue parameters could be identified as risk factors for survival in this study. We showed that sarcopenia occurs in a relevant part of patients with penile cancer and is a significant risk factor for overall survival (p = 0.032) and cancer specific survival (p = 0.034) for patients with penile cancer. Regarding fat distribution further studies are needed to evaluate its impact on sarcopenia and survival.

Abstract Radiation-induced morphea (RIM) is a rare complication of radiotherapy presenting as inflammatory fibrosis, most commonly reported in breast cancer patients. As underlying disease mechanisms are not well understood, targeted therapies are lacking. Since fibroblasts are the key mediators of all fibroproliferative diseases, this study aimed to characterize patient-derived fibroblasts to identify therapeutic targets. We studied primary human control and RIM-fibroblasts on a functional and molecular basis, analyzed peripheral blood and tissue samples and conducted, based on our findings, a treatment attempt in one patient. In RIM, we identified a distinct myofibroblast phenotype reflected by increased alpha-smooth-muscle-actin (αSMA) expression, reduced proliferation and migration rates, and overexpression of osteopontin (OPN). Our RNA sequencing identified aberrant Myc activation as a potential disease driver in RIM fibroblasts, similar to previous findings in systemic sclerosis. Treatment with the anti-inflammatory drug mesalazine reversed the myofibroblast phenotype by targeting Myc. Based on these findings, a patient with RIM was successfully treated with mesalazine, resulting in reduced inflammation and pain and tissue softening, while serum OPN was halved. The present study provides a comprehensive characterization of RIM fibroblasts, suggests a disease-driving role for Myc, demonstrates promising antifibrotic effects of mesalazine and proposes OPN as a biomarker for RIM.

Postponing the adoption of genome editing (GE) is costly, with lengthy regulatory processes contributing to postponement. Accelerating agricultural research and development (R&D) transfer is important for stimulating sustainable agricultural transitions and enhancing global food security. Using the MAGNET model, we incorporate dynamic R&D accumulation and compare economic projections in scenarios with accelerated R&D transfer. We calculate the cost of delay (COD) from postponing GE adoption. The results show that accelerating R&D transfer in high-income countries impacts economic performance, welfare, and food affordability globally; the annuity of COD ranges from losses of -$1.1 billion (Brazil) to gains of $18.5 billion (Europe). A 3-year acceleration of R&D transfer in all countries benefits middle and low-income countries the most (e.g. China, India, other Asian countries, and Sub-Saharan African countries), with the annuity of COD ranging from -$4.8 billion (Brazil) to $83.9 billion (China). Therefore, streamlining the GE regulatory framework is essential for enhancing food security and global welfare.

Abstract Despite the astonishing outcomes after chimeric antigen receptor (CAR) T-cell therapy for relapsed refractory multiple myeloma (RRMM), most patients eventually relapse. There are only limited data available on salvage therapies following relapse after BCMA-directed CAR T-cell therapy. Here, we analyzed outcomes of post-CAR T-cell therapy relapse and impact of different salvage strategies in an international cohort of 139 patients (n = 130 ide-cel, n = 9 cilta-cel), receiving talquetamab (n = 28), teclistamab (n = 37), combinations of immunomodulating drugs (IMiDs), proteasome inhibitors (PIs) or CD38 monoclonal antibodies (n = 43), and others (n = 31). The median time to relapse after CAR T-cell therapy was 5 months, 53% had the extramedullary disease (EMD) at relapse, associated with dismal post-relapse outcome (P = 0.005). Overall response and complete response upon salvage therapies were 79% and 39% for talquetamab, 64% and 32% for teclistamab, 30% and 0% for IMiDs/PIs/CD38, and 26% and 3% for others (P

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 The Large Hadron Collider’s high luminosity era presents major computational challenges in the analysis of collision events. Large amounts of Monte Carlo (MC) simulation will be required to constrain the statistical uncertainties of the simulated datasets below these of the experimental data. Modelling of high-energy particles propagating through the calorimeter section of the detector is the most computationally intensive MC simulation task. We introduce a technique combining recent advancements in generative models and quantum annealing for fast and efficient simulation of high-energy particle-calorimeter interactions.

Background: After pylorus-resecting pancreatoduodenectomy (PrPD), delayed gastric emptying (DGE) might partially be attributed to biliary reflux. We investigated whether the incidence of primary DGE is reduced after Roux-en-Y instead of Billroth-II reconstruction. Methods: Patients undergoing PrPD from 2016 to 2019 at a high-volume center were identified. Excluding causes of secondary DGE, we matched patients with Roux-en-Y and Billroth-II reconstruction in a 1:2 ratio and compared primary DGE. Results: In 24 vs. 48 (Roux-en-Y vs. Billroth-II) patients, DGE (grade B/C) incidence (20.8 % vs. 18.8 %; P = 1.000), nasogastric tube requirement (median 2 vs. 2 days; P = 0.844) and time to solid food intake (7 vs. 7 days; P = 0.933) were comparable. Univariable logistic regression showed no association between DGE and Roux-en-Y reconstruction (OR 1.47; P = 0.524), in contrast to age (1.08; P = 0.030) and pancreatic biochemical leak (4.98; P = 0.007). Conclusions: Primary DGE did not differ between Roux-en-Y and Billroth-II reconstruction after PrPD. Instead, age and postoperative pancreatic biochemical leak were associated with higher DGE risk.

The availability of high throughput sequencing tools coupled with the declining costs in the production of DNA sequences has led to the generation of enormous amounts of omics data curated in several databases such as NCBI and EMBL. Identification of similar DNA sequences from these databases is one of the fundamental tasks in bioinformatics. It is essential for discovering homologous sequences in organisms, phylogenetic studies of evolutionary relationships among several biological entities, or detection of pathogens. Improving DNA similarity search is of outmost importance because of the increased complexity of the evergrowing repositories of sequences. Therefore, instead of using the conventional approach of comparing raw sequences, e.g., in fasta format, a numerical representation of the sequences can be used to calculate their similarities and optimize the search process. In this study, we analyzed different approaches for numerical embeddings, including Chaos Game Representation, hashing, and neural networks, and compared them with classical approaches such as principal component analysis. It turned out that neural networks generate embeddings that are able to capture the similarity between DNA sequences as a distance measure and outperform the other approaches on DNA similarity search, significantly.

Abstract GALNT2, also known as polypeptide N-acetylgalactosaminyltransferase 2, is an enzyme that catalyzes the initial step of O-linked glycosylation, a crucial posttranslational modification that affects protein folding, stability, and function. Alterations in GALNT2 activity have been implicated in various diseases, such as cancer, metabolic disorders, and cardiovascular diseases, highlighting its importance in maintaining normal physiological functions. To investigate the impact of GalNT2 overexpression in vivo for the first time, we generated a conditional transgenic mouse line in which GalNT2 was expressed specifically in the pancreas. Heterozygous overexpression leads to a loss of acinar mass and pancreatic steatosis, whereas homozygous overexpression causes complete pancreatic loss and results in a lethal phenotype. Using a reporter gene mouse line, we demonstrated that adipocytes originate through transdifferentiation from pancreatic cells. GalNT2 overexpression results in additional O-glycosylation sites, which we analyzed through PNA lectin enrichment and mass spectrometric proteome analysis.

Abstract Clarifying the underlying mechanisms that govern ordering transitions in condensed matter systems is crucial for comprehending emergent properties and phenomena. While transitions are often classified as electronically driven or lattice-driven, we present a departure from this conventional picture in the case of the double perovskite Ba2MgReO6. Leveraging resonant and non-resonant elastic x-ray scattering techniques, we unveil the simultaneous ordering of structural distortions and charge quadrupoles at a critical temperature of T q ~ 33 K. Using a variety of complementary first-principles-based computational techniques, we demonstrate that, while electronic interactions drive the ordering at T q, it is ultimately the lattice distortions that dictate the specific ground state that emerges. Our findings highlight the crucial interplay between electronic and lattice degrees of freedom, providing a unified framework to understand and predict unconventional emergent phenomena in quantum materials.

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 Extensive research has focused on various dimensions of dropout reasons, yet it often overlooks the importance of considering different dropout directions in the analysis. Our cross-sectional study examines the association of factors of six dimensions of dropout reasons (learner, professional, company, school, activity, and context) with four directions of dropout intention (upwards, downwards, horizontal: occupational change, and horizontal: company change). Stepwise regression analyses using dropout intention as a prior inner condition (before actual dropout behavior) with data from 559 industrial and office management trainees in Germany are conducted. Results indicate that the largest association across different directions of dropout intentions is exerted by the trainees’ occupational identity (professional dimension) and the year in training (context dimension). School factors like the use of outdated teaching equipment and learner factors like trainees’ high professional commitment predict upward dropouts, while a low level of trainees’ workplace social involvement (activity dimension) predicts downward dropouts. Company factors like unfavourable working regulations predict occupational change, and a low level of trainees’ functional involvement (activity dimension) predicts company change. Additionally, we confirm the previously found significant associations of activity and professional factors, particularly the cooperation between learning venues (school and training company) and the alignment between training and the desired occupation. The desired occupation predicts dropout intentions in the upward and horizontal direction (occupational change), and a low level of learning venue cooperation predicts the upward, horizontal (company change), and downward directions. To mitigate dropout rates, we recommend that vocational education and training stakeholders adopt preventive strategies by targeting specific directions of dropout intentions and the factors associated with the six dimensions of dropout reasons.

Abstract Background MAGEL2 is an autism susceptibility gene whose deficiency has been associated with autism-related behaviors in animal models and in syndromic human autism spectrum disorders (ASDs) such as Schaaf-Yang syndrome, but has not been studied in the broader autism spectrum. Given the capabilities of long-read sequencing technologies, this pilot study used a targeted nanopore sequencing approach to simultaneously examine MAGEL2 DNA sequence and methylation in adults with high-functioning autism (HFA) compared to neurotypical controls (NC). Methods Using DNA extracted from peripheral blood, Cas9-targeted nanopore DNA sequencing was used to analyze MAGEL2, including its entire regulatory construct (chr15:23639316–23651466), for sequence variation and 5-methyl-cytosine (5mC) modification in a cohort of adults with HFA compared to sex- and age-matched NC. Given the known sex differences in ASD and MAGEL2 KO animal models, results were further analyzed by sex. Results 20 adults with HFA (10 males, 10 females) and 20 NC were included. While there were no overall differences in MAGEL2 DNA sequence and 5mC modification between HFA and NC, we found a significant difference in MAGEL2 gene promoter methylation between males and females with HFA and NC of both sexes, with HFA males tending to show hypomethylation in a 300 bp long differentially methylated region (chr15:23647640–23647939) around the MAGEL2 transcription start site. Conclusions In this pilot study utilizing nanopore Cas9 targeted DNA sequencing, significant sex-specific differences in MAGEL2 gene promoter methylation were identified in male adults with HFA in comparison to control groups, suggesting the potential for sex-specific epigenetic differences. However, further replication in larger cohorts is required to validate these findings.

Abstract Background Cerebral microbleeds (CMBs) are a possible sequela in human brain tumor patients treated with radiation therapy (RT). No such association is reported in dogs. Objectives To investigate whether CMBs occur in dogs after radiotherapy, and if there is an association between number and dose, and an increase over time. Animals Thirty‐four client‐owned dogs irradiated for primary intracranial neoplasia. ≥2 magnetic resonance imaging (MRI) scans including susceptibility‐weighted imaging (SWI) were required. Methods Retrospective, observational, single‐center study. Cerebral microbleeds identified on 3 T SWI were counted within the entire brain, and within low‐ (30 Gy) dose regions. A generalized linear mixed‐effects model was used to analyze the relationship between the CMBs count and the predictor variables (irradiation dose, time after treatment). Results Median follow‐up time was 12.6 months (range, 1.8‐37.6 months). Eighty‐three MR scans were performed. In 4/15 dogs (27%, 95% CI, 10%‐52%) CMBs were present at baseline. ≥1 CMBs after RT were identified in 21/34 dogs (62%, 95% CI, 45%‐77%). With each month, the number of CMBs increased by 14% (95% CI, 11%‐16%; P

Abstract In the present study, Pušnik et al. investigated whether the XBB.1.5-adapted booster can overcome the persistent imprinting of SARS-CoV-2 immunity by wild-type based vaccines. The findings demonstrate increased plasma neutralization against the homologous variant following the booster vaccination. Formation of de novo humoral response against the mutated epitopes of XBB.1.5 variant’s surface proteins was observed in 3/20 individuals. The booster vaccination had no significant effect on T-cell response.

Abstract Background The ascending or descending extended biplanar tibial cut in open wedge high tibial osteotomy (owHTO) not only changes the lower limb anatomy in the coronal plane but also leads to different three-dimensional (3D) changes in the patellofemoral joint. This study aimed to perform a comprehensive analysis of the dynamic biomechanical changes in the knee joint using a multibody simulation model. Methods Thirteen 3D computer models derived from lower limb computer tomography scans were used for owHTO. Osteotomies with ascending or descending biplanar cut were simulated for each wedge height from 6 to 12 mm (in 1-mm intervals). Multibody simulation was used to analyze differences in patellar shift, patellar tilt, mediolateral patellar rotation, and tibiofemoral rotation during a squat simulation from 5° to 100° knee flexion. Results The main effects of an ascending compared with a descending extended biplanar cut in owHTO were characterized by an increase in lateralization of the patella and rotation, along with reduced tilt. Linear mixed models revealed statistically significant effects of both wedge height and cut variant on knee kinematics at 100° knee flexion, with the influence of the cut variant (ascending/descending) being higher on all analyzed kinematic parameters. Conclusions Significant differences in the changes in patellofemoral shift, tilt, rotation, and tibiofemoral rotation were observed when performing owHTO with an ascending versus a descending biplanar cut. Apart from tibiofemoral rotation, the resulting kinematic changes were greater with an ascending cut.

Abstract Recent research highlights the abundance of floccule (flocs) in rivers, formed by aggregation of clay particles with organic matter. These flocs affect the transport and the eventual fate of clay. Flocs exhibit distinct behaviour from the unflocculated sedimentary counterparts: they can deform and break, and have higher settling velocities, which may in turn cause flocs to deposit and possibly interact with the riverbed. Here, we conducted systematic experiments in a laboratory flume to identify the mechanisms by which flocs and bedforms interact. Flocs showed a saltating (bouncing) behaviour, and were incorporated in the sediment bed as single flocs, clusters, or strings, via deposition and burial in the lee of a dune. Dune geometry was negligibly impacted by the presence of flocs. In natural systems, the burial of flocculated clay particles can affect contaminant spreading, aquatic ecology, the interpretation of deposition patterns, and clay transport.

Abstract Atmospheric new particle formation (NPF) is a naturally occurring phenomenon, during which high concentrations of sub-10 nm particles are created through gas to particle conversion. The NPF is observed in multiple environments around the world. Although it has observable influence onto annual total and ultrafine particle number concentrations (PNC and UFP, respectively), only limited epidemiological studies have investigated whether these particles are associated with adverse health effects. One plausible reason for this limitation may be related to the absence of NPF identifiers available in UFP and PNC data sets. Until recently, the regional NPF events were usually identified manually from particle number size distribution contour plots. Identification of NPF across multi-annual and multiple station data sets remained a tedious task. In this work, we introduce a regional NPF identifier, created using an automated, machine learning based algorithm. The regional NPF event tag was created for 65 measurement sites globally, covering the period from 1996 to 2023. The discussed data set can be used in future studies related to regional NPF.

Abstract Targeted temperature management (TTM) with therapeutic hypothermia (TH) during aortic arch surgery requires valid estimations of core body temperature. The ear canal and epitympanic region might be an easy-to-assess, noninvasive site for the read-out of supra-aortic, cerebral temperature. This observational cohort study comparatively investigated in-ear temperature and different core body temperature (cBT) measurements during TTM/TH for moderate hypothermic circulatory arrest (mHCA) in aortic arch surgery. In total 24 patients (mean age of 56.8 ± 17.5 years; six females) were measured using infrared-thermography of the epitympanic region (BTtym), thermistor-based measurements at the esophagus (BTeso; gold standard), at the ear canal (BTear), at the nasopharynx (BTnas), in the bladder (BTves), and in the rectum (BTrec). The data analysis comprised absolute agreement (AA), bias, intraclass correlation coefficient (ICC), and limit of agreement (LoA). The results revealed high AAs of BTtym, BTear, BTnas in reference to BTeso (biases 0.3–0.6 °C), with also excellent ICCs > 0.9. BTves and BTrec showed lower AAs, higher biases of + 2.5 °C to 3.1 °C with moderate ICCs during mHCA. In the phases of rapid temperature changes, the biases and LoAs were higher throughout all BT measurements. Herein, BTtym performed best of all measurement sites. The study informs about the BT dynamics at different body sites during the mHCA procedure. It supports the approach of using minimally invasive in-ear techniques to estimate core body temperature in an intrahospital TTM/TH setting of mHCA.

Abstract Prostate cancer treatment resistance is a significant challenge facing the field. Genomic and transcriptomic profiling have partially elucidated the mechanisms through which cancer cells escape treatment, but their relation toward the tumor microenvironment (TME) remains elusive. Here we present a comprehensive transcriptomic landscape of the prostate TME at multiple points in the standard treatment timeline employing single-cell RNA-sequencing and spatial transcriptomics data from 120 patients. We identify club-like cells as a key epithelial cell subtype that acts as an interface between the prostate and the immune system. Tissue areas enriched with club-like cells have depleted androgen signaling and upregulated expression of luminal progenitor cell markers. Club-like cells display a senescence-associated secretory phenotype and their presence is linked to increased polymorphonuclear myeloid-derived suppressor cell (PMN-MDSC) activity. Our results indicate that club-like cells are associated with myeloid inflammation previously linked to androgen deprivation therapy resistance, providing a rationale for their therapeutic targeting.

Abstract The activation of the Ca2+-channel Orai1 via the physiological activator stromal interaction molecule 1 (STIM1) requires structural rearrangements within the entire channel complex involving a series of gating checkpoints. Focusing on the gating mechanism operating along the peripheral transmembrane domain (TM) 3/TM4-interface, we report here that some charged substitutions close to the center of TM3 or TM4 lead to constitutively active Orai1 variants triggering nuclear factor of activated T-cell (NFAT) translocation into the nucleus. Molecular dynamics simulations unveil that this gain-of-function correlates with enhanced hydration at peripheral TM-interfaces, leading to increased local structural flexibility of the channel periphery and global conformational changes permitting pore opening. Our findings indicate that efficient dehydration of the peripheral TM-interfaces driven by the hydrophobic effect is critical for maintaining the closed state of Orai1. We conclude that a charge close to the center of TM3 or TM4 facilitates concomitant hydration and widening of peripheral TM interfaces to trigger constitutive Orai1 pore opening to a level comparable to or exceeding that of native activated Orai1.

Abstract Background There is a vicious cycle between unemployment and mental health issues. Unemployed individuals with mental health issues require individualized support at multiple levels in order to promote their mental health, and obtain and retain employment. The 3for1-intervention program aims to provide such support with three components (short-term psychotherapy, job coaching based on the Individual Placement and Support approach, and peer support). This study protocol outlines how the effectiveness of this three-component intervention program in terms of re-employment, mental health, and psychosocial outcomes will be evaluated. Methods The 3for1-intervention program will be evaluated with a non-randomized controlled trial design in a multi-center study. 500 eligible participants aged between 18 and 60 years from six job centers in Southern Germany will be allocated to a control group or an intervention group. Allocation is time-based, with the control group being recruited first, followed by recruitment of the intervention group. The control group will receive treatment as usual, whereas the intervention group will receive treatment as usual as well as access to the three intervention components over a period of 12 months. Assessment will be conducted at baseline (t0), and 12 (t1) and 18 (t3) months later. The primary outcome will be the proportion of participants who are in employment subject to social insurance contributions at t1. Differences between control and intervention group will be tested with logistic regression analysis, controlling for relevant covariates. Analyses of secondary outcomes will relate to group differences regarding re-employment, health and well-being, social integration, help-seeking, and self-stigma at t1 and t2, applying logistic regression analysis or analysis of covariance. Additionally, usage of health services will be measured to evaluate the intervention program’s cost effectiveness. Discussion The 3for1-intervention aims to improve employability and mental health outcomes of a vulnerable population with high need for assistance. Improvements for this population would benefit the German welfare state as well. This study could provide valuable insights into the feasibility, implementation, and sustainability of this individualized, multi-level support program within German job centers. Trial registration This trial is registered with the German Clinical Trials Register: DRKS00029002 (registered on 11 May 2022).

Abstract Objective There is a shortage of established prognostic biomarkers in bladder cancer. One candidate is tumour protein 63 (p63), a transcription factor of the p53 gene family that is expressed in the normal urothelium. Recently proposed RNA expression‐based molecular classifiers of bladder cancer identified high p63 expression as a component of a basal/squamous subtype linked to poor patient prognosis. Methods In this study, p63 protein expression was analysed by immunohistochemistry on more than 2500 urothelial bladder carcinomas in a tissue microarray format to determine its relationship with clinicopathological parameters of disease progression and patient outcome. Results Nuclear p63 staining was seen in all cells of normal urothelium and at elevated levels in pTaG2 tumours. The rate of p63 positive cases and the staining intensity was lower in pTaG3 tumours (93.2%, p

Abstract Background Dual-energy computed tomography (DECT) is a noninvasive diagnostic tool for gouty arthritis. This study aimed to compare two postprocessing techniques for monosodium urate (MSU) detection: conventional two-material decomposition and material map-based decomposition. Methods A raster phantom and an ex vivo biophantom, embedded with four different MSU concentrations, were scanned in two high-end CT scanners. Scanner 1 used the conventional postprocessing method while scanner 2 employed the material map approach. Volumetric analysis was performed to determine MSU detection, and image quality parameters, such as signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR), were computed. Results The material map-based method demonstrated superior MSU detection. Specifically, scanner 2 yielded total MSU volumes of 5.29 ± 0.28 mL and 4.52 ± 0.29 mL (mean ± standard deviation) in the raster and biophantom, respectively, versus 2.35 ± 0.23 mL and 1.15 ± 0.17 mL for scanner 1. Radiation dose correlated positively with detection for the conventional scanner, while there was no such correlation for the material map-based decomposition method in the biophantom. Despite its higher detection rate, material map-based decomposition was inferior in terms of SNR, CNR, and artifacts. Conclusion While material map-based decomposition resulted in superior MSU detection, it is limited by challenges such as increased artifacts. Our findings highlight the potential of this method for gout diagnosis while underscoring the need for further research to enhance its clinical reliability. Relevance statement Advanced postprocessing such as material-map-based two-material decomposition might improve the sensitivity for gouty arthritis in clinical practice, thus, allowing for lower radiation doses or better sensitivity for gouty tophi. Key Points Dual-energy CT showed limited sensitivity for tophi with low MSU concentrations. Materiel-map-based decomposition increased sensitivity compared to conventional two-material decomposition. The advantages of material-map-based decomposition outweigh lower image quality and increased artifact load. Graphical Abstract

Abstract Background Dark-field radiography imaging exploits the wave character of x-rays to measure small-angle scattering on material interfaces, providing structural information with low radiation exposure. We explored the potential of dark-field imaging of bone microstructure to improve the assessment of bone strength in osteoporosis. Methods We prospectively examined 14 osteoporotic/osteopenic and 21 non-osteoporotic/osteopenic human cadaveric vertebrae (L2–L4) with a clinical dark-field radiography system, micro-computed tomography (CT), and spectral CT. Dark-field images were obtained in both vertical and horizontal sample positions. Bone microstructural parameters (trabecular number, Tb.N; trabecular thickness, Tb.Th; bone volume fraction, BV/TV; degree of anisotropy, DA) were measured using standard ex vivo micro-CT, while hydroxyapatite density was measured using spectral CT. Correlations were assessed using Spearman rank correlation coefficients. Results The measured dark-field signal was lower in osteoporotic/osteopenic vertebrae (vertical position, 0.23 ± 0.05 versus 0.29 ± 0.04, p

Abstract Automated blood vessel segmentation is critical for biomedical image analysis, as vessel morphology changes are associated with numerous pathologies. Still, precise segmentation is difficult due to the complexity of vascular structures, anatomical variations across patients, the scarcity of annotated public datasets, and the quality of images. Our goal is to provide a foundation on the topic and identify a robust baseline model for application to vascular segmentation using a new imaging modality, Hierarchical Phase-Contrast Tomography (HiP-CT). We begin with an extensive review of current machine-learning approaches for vascular segmentation across various organs. Our work introduces a meticulously curated training dataset, verified by double annotators, consisting of vascular data from three kidneys imaged using HiP-CT as part of the Human Organ Atlas Project. HiP-CT pioneered at the European Synchrotron Radiation Facility in 2020, revolutionizes 3D organ imaging by offering a resolution of around 20 μm/voxel and enabling highly detailed localised zooms up to 1–2 μm/voxel without physical sectioning. We leverage the nnU-Net framework to evaluate model performance on this high-resolution dataset, using both known and novel samples, and implementing metrics tailored for vascular structures. Our comprehensive review and empirical analysis on HiP-CT data sets a new standard for evaluating machine learning models in high-resolution organ imaging. Our three experiments yielded Dice similarity coefficient (DSC) scores of 0.9523, 0.9410, and 0.8585, respectively. Nevertheless, DSC primarily assesses voxel-to-voxel concordance, overlooking several crucial characteristics of the vessels and should not be the sole metric for deciding the performance of vascular segmentation. Our results show that while segmentations yielded reasonably high scores-such as centerline DSC ranging from 0.82 to 0.88, certain errors persisted. Specifically, large vessels that collapsed due to the lack of hydrostatic pressure (HiP-CT is an ex vivo technique) were segmented poorly. Moreover, decreased connectivity in finer vessels and higher segmentation errors at vessel boundaries were observed. Such errors, particularly in significant vessels, obstruct the understanding of the structures by interrupting vascular tree connectivity. Our study establishes the benchmark across various evaluation metrics, for vascular segmentation of HiP-CT imaging data, an imaging technology that has the potential to substantively shift our understanding of human vascular networks.

Abstract Recent research has identified growth differentiation factor 15 (GDF15) as a crucial factor in various physiological and pathological processes, particularly in energy balance regulation. While the role of GDF15 in modulating energy metabolism through hindbrain GDNF family receptor alpha-like (GFRAL) signaling has been extensively studied, emerging evidence suggests direct peripheral metabolic actions of GDF15. Using knockout mouse models, we investigated GDF15 and GFRAL’s roles in adipose tissue metabolism. Our findings indicate that C57BL/6/129/SvJ Gdf15-KO mice exhibit impaired expression of de novo lipogenesis enzymes in subcutaneous adipose tissue (sWAT). In contrast, C57BL/6J Gfral-KO mice showed no impairments compared to wild-type (WT) littermates. RNA-Seq analysis of sWAT in Gdf15-KO mice revealed a broad downregulation of genes involved in lipid metabolism. Importantly, our study uncovered sex-specific effects, with females being more affected by GDF15 loss than males. Additionally, we observed a fasting-induced upregulation of GDF15 gene expression in sWAT of both mice and humans, reinforcing this factor’s role in adipose tissue lipid metabolism. In conclusion, our research highlights an essential role for GDF15 in sWAT lipid metabolic homeostasis. These insights enhance our understanding of GDF15’s functions in adipose tissue physiology and underscore its potential as a therapeutic target for metabolic disorders.

Abstract The simultaneous charging of many electric vehicles in future mobility scenarios may lead to peaks and overloads threatening grid stability. The necessary infrastructure investments vary by the number and model type of vehicles driven and the residents’ charging preferences. These attributes significantly depend on socio-economic factors such as income. Using power flow simulations based on real-life driving profiles, we predict massive cost asymmetries with an investment demand up to 33-fold in higher-income compared to lower-income neighborhoods. Many grid operators may redistribute these costs through an across-the-board electricity price increase for all households. In times of rising electricity prices, these unwanted inequitable costing allocations could lead to severe challenges and energy poverty. Policymakers should consider countermeasures like dynamic electricity pricing schemes, income-based electric vehicle subsidies, or improved charging network access to ensure energy equity in future mobility scenarios. Our analysis of the impact of socio-economic factors on electric vehicle grid infrastructure and their quantification contributes to the energy equity discussion.

Abstract Macrophages are pleiotropic and diverse cells that populate all tissues of the body. Besides tissue-specific resident macrophages such as alveolar macrophages, Kupffer cells, and microglia, multiple organs harbor at least two subtypes of other resident macrophages at steady state. During certain circumstances, like tissue insult, additional subtypes of macrophages are recruited to the tissue from the monocyte pool. Previously, a recruited macrophage population marked by expression of Spp1, Cd9, Gpnmb, Fabp5, and Trem2, has been described in several models of organ injury and cancer, and has been linked to fibrosis in mice and humans. Here, we show that Notch2 blockade, given systemically or locally, leads to an increase in this putative pro-fibrotic macrophage in the lung and that this macrophage state can only be adopted by monocytically derived cells and not resident alveolar macrophages. Using a bleomycin and COVID-19 model of lung injury and fibrosis, we find that the expansion of these macrophages before lung injury does not promote fibrosis but rather appears to ameliorate it. This suggests that these damage-associated macrophages are not, by themselves, drivers of fibrosis in the lung.

Abstract Background Complex fractures of the trochanteric region, as well as fractures located in the directly subtrochanteric region, are controversially discussed around the world regarding the nail type to be used. A long nail is recommended by manufacturers but requires longer surgical and fluoroscopy times. A possible solution could be a nail with an appropriate length which can be locked in a minimally invasive manner by the main aiming device. We aimed to determine if such a nail model (DCN SL nail, SWEMAC, Linköping, Sweden) offers similar structural stability on biomechanical testing on artificial bone as a standard long nail when used to treat complex trochanteric fractures and compared it to long nails usually used in this setting. Methods An osteoporotic bone model was chosen. The Swemac Hansson DCN Nail System was used as osteosynthesis material. Two types of nails were chosen: a superior lock nail which can be implanted with a singular targeting device, and a long nail with distal locking using free-hand technique. AO31A2.2 fractures were simulated in a standardised manner. Axial height of the construct, varus collapse, and rotational deformity directly after nail insertion were simulated. A Universal Testing Machine was used. Measurements were made with a stereo-optic tracking system. Findings There was a detectable difference in the axial fracture movement resulting in narrowing of the fracture gap. There was no difference in varus collapse or rotational deformity between the nail variants Conclusion We conclude that there are small differences which are clinically insignificant and that a superior locking nail can safely be used to manage complex trochanteric fractures.

Abstract Background In locally advanced rectal cancer, the prediction of tumor response during and after neoadjuvant treatment remains challenging. In terms of organ preservation, adaptive radiotherapy, and intensified (total) neoadjuvant therapies, biomarkers are desirable for patient stratification. Methods In 16 patients, weekly blood samples (n = 86) to detect cell-free tumor DNA (ctDNA) during long-course neoadjuvant chemoradiotherapy were analyzed. Data were correlated with initial tumor volumes, MRI response in week 2 and 5 of radiotherapy as well as with pathologic tumor response after resection and outcome parameters. Results Most patients showed decreasing ctDNA during the course of radiochemotherapy. However, we found heterogenous dynamics of ctDNA and could identify three groups: (1) decline (2) no clear decline and/or late shedding (3) persistence of ctDNA. In seven patients we could detect significant amounts of ctDNA in week 5 or week 6 of treatment. In our pilot cohort, we did not find significant correlations of ctDNA dynamics with pathologic response or outcome parameters. However, patients with distinct decline of ctDNA had larger tumor volumes prior to treatment, and MRI imaging in week 2 and 5 revealed bigger absolute decrease of tumor volumes. If significant levels of ctDNA were found in week 5 and / or 6, patients showed less absolute tumor volume decrease in week 2 and 5. Conclusions Weekly measurement of ctDNA during radiochemotherapy is feasible and might represent a promising biomarker. Bigger initial primary tumors showed different ctDNA shedding profiles compared with smaller primary tumors and correlations of ctDNA dynamics with early imaging response were found.

Abstract Prostate tumor heterogeneity is a major obstacle when studying the biological mechanisms of molecular markers. Increased gene expression levels of secreted frizzled-related protein 4 (SFRP4) is a biomarker in aggressive prostate cancer. To understand how SFRP4 relates to prostate cancer we performed comprehensive spatial and multiomics analysis of the same prostate cancer tissue samples. The experimental workflow included spatial transcriptomics, bulk transcriptomics, proteomics, DNA methylomics and tissue staining. SFRP4 mRNA was predominantly located in cancer stroma, produced by fibroblasts and smooth muscle cells, and co-expressed with extracellular matrix components. We also confirmed that higher SFRP4 gene expression is associated with cancer aggressiveness. Gene expression of SFRP4 was affected by gene promotor methylation. Surprisingly, the high mRNA levels did not reflect SFRP4 protein levels, which was much lower. This study contributes previously unknown insights of SFRP4 mRNA in the prostate tumor environment that potentially can improve diagnosis and treatment.

Abstract Using nanotechnology, while improving the health of broiler chickens, it is possible to control and reduce the conflict of minerals in the intestines, and toxicity of and pollution by these elements. It could be shown that the antioxidant and immune modulation effects of nano selenium are significantly superior compared to other sources of selenium. In addition, improving the quality of meat products with the use of nano selenium has promising results in the future perspective of quality improvement and food safety. Nutrition of permitted and optimal levels is very important in the consumption of nano selenium form and as it can have significant beneficial functional and health effects, in case of errors in the selected levels and doses, irreparable side effects and adverse results can occur. In this review report, an attempt has been made to introduce the position and importance of selenium and the approach of smart consumption of its nano form in the nutrition of broiler chickens. The novelty of using nanotechnology in feeding broiler chickens can be a unique opportunity to improve the bioavailability of important and rare elements such as selenium.

Abstract Understanding the mechanisms of synaptic plasticity is crucial for elucidating how the brain adapts to internal and external stimuli. A key objective of plasticity is maintaining physiological activity states during perturbations by adjusting synaptic transmission through negative feedback mechanisms. However, identifying and characterizing novel molecular targets orchestrating synaptic plasticity remains a significant challenge. This study investigated the effects of tetrodotoxin (TTX)-induced synaptic plasticity within organotypic entorhino-hippocampal tissue cultures, offering insights into the functional, transcriptomic, and proteomic changes associated with network inhibition via voltage-gated sodium channel blockade. Our experiments demonstrate that TTX treatment induces substantial functional plasticity of excitatory synapses, as evidenced by increased miniature excitatory postsynaptic current (mEPSC) amplitudes and frequencies in both dentate granule cells and CA1 pyramidal neurons. Correlating transcriptomic and proteomic data, we identified novel targets for future research into homeostatic plasticity, including cytoglobin, SLIT-ROBO Rho GTPase Activating Protein 3, Transferrin receptor, and 3-Hydroxy-3-Methylglutaryl-CoA Synthase 1. These data provide a valuable resource for future studies aiming to understand the orchestration of homeostatic plasticity by metabolic pathways in distinct cell types of the central nervous system.

Abstract Background Title-abstract screening in the preparation of a systematic review is a time-consuming task. Modern techniques of natural language processing and machine learning might allow partly automatization of title-abstract screening. In particular, clear guidance on how to proceed with these techniques in practice is of high relevance. Methods This paper presents an entire pipeline how to use natural language processing techniques to make the titles and abstracts usable for machine learning and how to apply machine learning algorithms to adequately predict whether or not a publication should be forwarded to full text screening. Guidance for the practical use of the methodology is given. Results The appealing performance of the approach is demonstrated by means of two real-world systematic reviews with meta analysis. Conclusions Natural language processing and machine learning can help to semi-automatize title-abstract screening. Different project-specific considerations have to be made for applying them in practice.

Abstract Antinuclei in our Galaxy may stem either from annihilation or decay of dark matter, or from collisions of cosmic rays with the interstellar medium, which constitute the background of indirect dark matter searches. Understanding the formation mechanism of (anti)nuclei is crucial for setting limits on their production in space. Coalescence models, which describe the formation of light nuclei from final-state interaction of nucleons, have been widely employed in high-energy collisions. In this work, we introduce ToMCCA (Toy Monte Carlo Coalescence Afterburner), which allows for detailed studies of the nuclear formation processes without the overload of general-purpose event generators. ToMCCA contains parameterizations of the multiplicity dependence of the transverse momentum distributions of protons and of the baryon-emitting source size, extracted from ALICE measurements in pp collisions at $$\sqrt{s} = 5 - 13$$ s = 5 - 13 TeV, as well as of the event multiplicity distributions, taken from the EPOS event generator. ToMCCA provides predictions of the deuteron transverse momentum distributions, with agreement of $$\sim 5\%$$ ∼ 5 % with the experimental data. The results of ToMCCA show that the coalescence mechanism in pp collisions depends only on the event multiplicity, not on the collision system or its energy. This allows the model to be utilized for predictions at lower center-of-mass collision energies, which are the most relevant for the production of antinuclei from processes related to dark matter. This model can also be extended to heavier nuclei as long as the target nucleus wavefunction and its Wigner function are known.

Abstract The family of pro-inflammatory and pro-angiogenic chemokines including Interleukin-8 (IL-8, aka CXCL8) and its homologues (CXCL1,2,3,5,6, and 7) exhibit promiscuous binding and activation of several G-protein-coupled receptors (i.e., CXCR2, CXCR1, and the atypical chemokine receptor (ACKR1)). A high proportion of their biological activity is attributed to CXCR2 activation, thus many CXCR2 inhibitors are in clinical trials for several chronic diseases. However, CXCR2 inhibition is often only investigated acutely in these trials or in Cxcr2 −/− mice grown in gnotobiotic conditions. Since humans do not live in germ-free environments, our first goal is to highlight novel retinal and systemic observations in Cxcr2 −/− mice grown in non-gnotobiotic conditions that suggest potential harmful consequences of long-term CXCR2 deficiency or blockade. Beyond confirmation of circulating blood/immune cell-related phenotypes, we report novel findings in Cxcr2 −/− mice including: (1) delayed dye transit to the retinal vasculature, (2) alterations in the density and distribution of retinal vessels, astrocytes and microglia, (3) decreased electroretinogram a- and b-wave amplitudes, (4) reduced visual acuity, and (5) increased polymorphonuclear cell accumulation in vascular lumina abutting venular walls in the retina and in vital non-ocular tissues (lung and liver). Furthermore, PheWAS of CXCR2 CXCR1, and ACKR1 gene variants using data from UK Biobank participants suggest clinical associations with both retinal and vascular disease phenotypes. We conclude that chronic CXCR2 deficiency in mice contributes to functional damage to the retina and that the long-term safety of CXCR1/2 inhibitors designed for chronic use in humans should be explored before clinical adoption to safeguard sight and overall vascular health.

Abstract Phosphorus limits primary productivity in many (Sub-)Arctic ecosystems and may constrain biological carbon sequestration. Iron (III) oxides strongly bind phosphate in soils but can dissolve under flooded, reducing conditions induced by permafrost thaw and ground collapse. The ability for iron to regulate phosphate storage and solubility in thawing permafrost landscapes remains unclear. Here, iron-rich sediments containing iron oxides and organic-bound iron were incubated with or without added phosphate in soils along a permafrost thaw gradient to evaluate how iron-phosphate associations respond to thaw-induced redox shifts. Iron oxides partially dissolved and released sorbed phosphate when incubated in soils underlain by degraded permafrost. Iron complexed by organic matter remained stable but provided no phosphate binding capacity. Phosphate addition enhanced iron oxide dissolution and phosphorus concentrations in associated microbial biomass. Our study demonstrates that the capacity for iron oxides to immobilize and retain phosphate in permafrost peatlands decreases with permafrost thaw.

Abstract Deep brain stimulation (DBS) with electric field steering may avoid areas responsible for side effects. This prospective randomized cross-over trial compared omnidirectional (OS) and directional (DS) subthalamic DBS in 19 patients. Electromyographically measured rigidity was the primary outcome. Motor and non-motor scores were secondary outcomes. There were no significant differences between OS and DS. In the acute setting, both conditions improved motor scores compared to no stimulation. Motor symptoms improved after 3 weeks of OS relative to acute measurements, whereas they worsened under DS. The more ventral the active contact, and the less the motor improvement sweet spot was stimulated, the greater the benefit of DS over OS for executive function. Accurate OS of the dorsal subthalamic nucleus ensures motor and non-motor improvements. While DS can mitigate executive decline stemming from off-target stimulation, it may lead to worse motor outcomes. Larger, long-term studies are needed to confirm these findings. (Registration: subthalamic steering for therapy optimization in Parkinson’s Disease ClinicalTrials.gov: NCT03548506, 2018-06-06).

Abstract In Wuerzburg, Germany, a terrorist attack and a killing rampage occurred five years apart (2016 and 2021). Following a structured evaluation of the rescue mission in 2016, a bundle of quality indicators and ten “lessons learned” were defined. Aim of the presented study was to compare the two rescue missions and to critically review the lessons learned from 2016 for their implementation and feasibility. An interdisciplinary and inter-professional group of experts analyzed the data using predefined quality indicators. All lessons defined in 2016 were critically reviewed and qualified as either lessons learned or lessons identified. While seven out of ten lessons were successfully implemented after 2016 (lessons learned), three lessons didn´t work and were recategorized as lessons identified (communication, zoning and the mutual exchange of different tactical approaches). Our results demonstrate that the conclusions drawn in 2016 have helped to improve the performance of the rescue forces in 2021. In addition, the identified lessons are now the basis for further improving emergency and disaster preparedness. It is important to understand, that the process of preparedness improvement is not completed with the definition of lessons identified. These must first be integrated into response plans and then trained intensively. A lesson identified only becomes a lesson learned once it has been successfully applied.

Abstract A lack of advanced preclinical mouse tumor models impedes the progress in urothelial carcinoma research. We present here a novel fast, robust, reliable, and highly reproducible model for the genetic induction of bladder cancer in immunocompetent mice. Different sets of oncogenic transposons (Cmyc, Kras) and Cre drivers were transfected into the murine bladder wall of two different genetic backgrounds (Trp53 fl/fl and Braf V600E , Pten fl/fl , Ctnnb1 exon3-fl/fl). Transfection was carried out using in vivo electroporation of the bladder after surgical exploration and transmural or transurethral intravesical plasmid injection. Up to 100% of animals developed urothelial carcinomas of the bladder. Time to tumor onset ranged from 16 to 97 days with a median of approximately 23 days in the fastest groups. Histological examination identified orthotopic urothelial carcinomas in most cases, in some experimental groups up to 100%. The resulting tumors were highly invasive and often metastatic. Metastases were found in up to 100% of tumor bearing mice per group. Taken together, this study establishes the proof-of-principle that in vivo electroporation can be versatilely employed as a reliable, fast, and robust method for the highly reproducible induction of urothelial carcinomas in the murine bladder wall. This novel murine tumor model could pave the way towards more easily modelling subtype specific urothelial carcinomas in mice.

Abstract Sensory substitution offers a promising approach to restore lost sensory functions. Here we show that spinal cord stimulation (SCS), typically used for chronic pain management, can potentially serve as a novel auditory sensory substitution device. We recruited 13 patients undergoing SCS implantation and translated everyday sound samples into personalized SCS patterns during their trial phase. In a sound identification task—where chance-level performance was 33.3%—participants ( $$n=8$$ n = 8 ) achieved a mean accuracy of 72.8% using only SCS input. We observed a weak positive correlation between stimulation bitrate and identification accuracy. A follow-up discrimination task ( $$n=5$$ n = 5 ) confirmed that reduced bitrates significantly impaired participants’ ability to distinguish between consecutive SCS patterns, indicating effective processing of additional information at higher bitrates. These findings demonstrate the feasibility of using existing SCS technology to create a novel neural interface for a sound prosthesis. Our results pave the way for future research to enhance stimulation fidelity, assess long-term training effects, and explore integration with other auditory aids for comprehensive hearing rehabilitation.

At this critical juncture in the development of NeuroAI, we outline challenges and training needs of junior researchers working across AI and neuroscience. We also provide advice and resources to help trainees plan their NeuroAI careers.

Abstract Motility coupled to responsive behavior is essential for many microorganisms to seek and establish appropriate habitats. One of the simplest possible responses, reversing the direction of motion, is believed to enable filamentous cyanobacteria to form stable aggregates or accumulate in suitable light conditions. Here, we demonstrate that filamentous morphology in combination with responding to light gradients by reversals has consequences far beyond simple accumulation: Entangled aggregates form at the boundaries of illuminated regions, harnessing the boundary to establish local order. We explore how the light pattern, in particular its boundary curvature, impacts aggregation. A minimal mechanistic model of active flexible filaments resembles the experimental findings, thereby revealing the emergent and generic character of these structures. This phenomenon may enable elongated microorganisms to generate adaptive colony architectures in limited habitats or guide the assembly of biomimetic fibrous materials.

Abstract In this paper we present a deep learning segmentation approach to classify and quantify the two most prevalent primary liver cancers – hepatocellular carcinoma and intrahepatic cholangiocarcinoma – from hematoxylin and eosin (H&E) stained whole slide images. While semantic segmentation of medical images typically requires costly pixel-level annotations by domain experts, there often exists additional information which is routinely obtained in clinical diagnostics but rarely utilized for model training. We propose to leverage such weak information from patient diagnoses by deriving complementary labels that indicate to which class a sample cannot belong to. To integrate these labels, we formulate a complementary loss for segmentation. Motivated by the medical application, we demonstrate for general segmentation tasks that including additional patches with solely weak complementary labels during model training can significantly improve the predictive performance and robustness of a model. On the task of diagnostic differentiation between hepatocellular carcinoma and intrahepatic cholangiocarcinoma, we achieve a balanced accuracy of 0.91 (CI 95%: 0.86-0.95) at case level for 165 hold-out patients. Furthermore, we also show that leveraging complementary labels improves the robustness of segmentation and increases performance at case level.

Abstract Background In adults aged 50 + years, vaccine-preventable diseases (VPDs) pose a significant health burden and can lead to additional ‘downstream effects’ of infection beyond the acute phase e.g., increasing the risk for non-communicable disease and exacerbating chronic conditions. The aim was to understand and quantify the burden of VPD downstream effects in hospitalised adults in the United States. Methods This retrospective observational study analysed hospitalisation claims data (2016–2019) with 1-year follow-up, in adults with a VPD diagnosis versus matched controls (using Optum’s de-identified Clinformatics Data Mart Database). Outcomes included mortality; increase in Charlson Comorbidity Index (CCI) score; new diagnosis of comorbidities; and loss of independence (defined by need for home health/home care and/or move to long-term facility). Results Mortality was significantly increased in VPD cases versus controls at 30-day (risk ratio [RR] of 4.08 [95% CI 3.98–4.18]) and 1-year follow-up (RR 2.76 [2.73–2.80]). Over a 1-year follow-up period, morbidity increased following VPD hospitalisation: 65–86% of VPD cases had new comorbidities diagnosed (versus 13–41% of controls); with a significantly higher mean increase in CCI score versus baseline (3.23 in VPD cases versus 0.89 in controls, p

Abstract Background Although national food guides are designed, ostensibly, to translate scientific evidence with respect to food, dietary patterns, and health, their development has increasingly become a corporate/political process as well as scientific one; often with corporate/political influences overriding science. Our aim was to construct an unbiased, sustainable, evidence-informed Universal Food Guide to serve as a template for countries to develop their unique guides, thereby, provide a valid resource for health professionals, health authorities, and the public. Methods To address our aim, we conducted an integrative review of multiple evidence-informed sources (e.g., established databases, evidence syntheses, scholarly treatises, and policy documents) related to four areas: 1. Food guides’ utility and conflicts of interest; 2. The evidence-based healthiest diet; 3. Constituents of the Universal Food Guide template; and 4. Implications for population health; regulation/governance; environment/climate/planetary health; and ethics. Results The eating pattern that is healthiest for humans (i.e., most natural, and associated with maximal health across the life cycle; reduced non-communicable disease (NCD) risk; and minimal end-of-life illness) is whole food, low fat, plant-based, especially vegan, with the absence of ultra-processed food. Disparities in national food guide recommendations can be explained by factors other than science, specifically, corporate/political interests reflected in heavily government-subsidized, animal-sourced products; and trends toward dominance of daily consumption of processed/ultra-processed foods. Both trends have well-documented adverse consequences, i.e., NCDs and endangered environmental/planetary health. Commitment to an evidence-informed plant-based eating pattern, particularly vegan, will reduce risks/manifestations of NCDs; inform healthy food and nutrition policy regulation/governance; support sustainable environment/climate and planetary health; and is ethical with respect to ‘best’ evidence-based practice, and human and animal welfare. Conclusion The Universal Food Guide that serves as a template for national food guides is both urgent and timely given the well-documented health-harming influences that corporate stakeholders/politicians and advisory committees with conflicts of interest, exert on national food guides. Such influence contributes to the largely-preventable NCDs and environmental issues. Policy makers, health professionals, and the public need unbiased, scientific evidence as informed by the Universal Food Guide, to inform their recommendations and choices.

Abstract Background Misfolding and aggregation of amyloid β (Aβ), along with neurofibrillary tangles consisting of aggregated Tau species, are pathological hallmarks of Alzheimer’s disease (AD) onset and progression. In this study, we hypothesized the clearance of Aβ aggregates from the brain and body into the gut. Methods To investigate this, we used surface-based fluorescence intensity distribution analysis (sFIDA) to determine the Aβ aggregate concentrations in feces from 26 AD patients and 31 healthy controls (HC). Results Aβ aggregates were detectable in human feces and their concentrations were elevated in AD patients compared to HC (specificity 90.3%, sensitivity 53.8%). Conclusion Thus, fecal Aβ aggregates constitute a non-invasive biomarker candidate for diagnosing AD. Whether digestion-resistant Aβ aggregates in feces are secreted via the liver and bile or directly from the enteric neuronal system remains to be elucidated.