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Frontotemporal Lobar Degeneration (FTLD) encompasses progressive neurodegeneration primarily affecting the frontal and/or temporal lobes, presenting in varied pathological entities. These pathologies lead to diverse clinical syndromes collectively known as Frontotemporal Dementia (FTD), which includes a behavioral variant, and primary progressive aphasia, with its non-fluent and semantic variants, and related conditions with parkinsonism or motoneuron disease features. The historical development of FTD concept is rooted in the pioneering work of Arnold Pick, who first described clinical cases of focal brain atrophy. Oskar Fischer significantly advanced this field by detailing the histopathological features of these conditions, such as the spongiform cortical wasting, and identifying characteristic neuronal changes such as the ballooned cells. Fischers contributions, alongside those of contemporaries like Alois Alzheimer, laid the foundation for understanding FTLD histopathology. Here, Fischers overlooked work is spotlighted, advocating for a greater recognition, which he rightfully deserves for his contributions to the field of neurodegenerative diseases.

Abstract Background The endogenous nucleotide adenosine 5′-tetraphosphate (Ap4) is a potent vasoconstrictor. Despite its structural similarity to the danger signal adenosine 5’-triphosphate (ATP), the immunomodulatory effects of Ap4 remain unclear. Methods Modulation of interleukin (IL)-1β secretion by Ap4 was studied in both immune cells lines (THP-1, U937) and primary immune cells. Genetic and pharmacological approaches were used to characterize signaling. Cytokine production was measured using ELISA and multiplex assays, while cell viability was determined by MTT and LDH assays. Calcium influx and YO-PRO-1 uptake were assessed via microplate assays and flow cytometry, respectively. RNA sequencing and Western blotting were performed to analyze global gene expression and protein levels. Results We demonstrate that Ap4 stimulates IL-1β release in primed immune cells without affecting the levels of other cytokines, suggesting specificity in its immunomodulatory actions. Mechanistically, Ap4-induced IL-1β release was partially modulated by the P2X7 receptor, a key mediator of inflammation. However, unlike canonical inflammasome activators, this process was independent of potassium efflux, the NLRP3 inflammasome, and caspase-1. Ap4 specifically increased LDH release in macrophages irrespective of priming. Furthermore, Ap4-mediated calcium influx, crucial for immune cell activation, predominantly occurred through P2Y receptors rather than P2X7 receptors. Transcriptomic analysis highlighted Ap4-induced upregulation of metallothioneins, implicating metal ion homeostasis in Ap4-mediated responses. Conclusions Collectively, our findings suggest Ap4 as a novel pro-inflammatory mediator capable of inducing IL-1β release in innate immune cells through distinct mechanisms from classical NLRP3 inflammasome activators, shedding light on its potential role in inflammatory diseases and vascular disorders.

Abstract Remimazolam is a novel ultra-short-acting benzodiazepine gaining attention for its rapid onset, predictable pharmacokinetics, and favorable safety profile in adult procedural sedation and anesthesia. Early pediatric data suggest it may offer significant advantages over traditional sedatives, including enhanced predictability, improved safety, and faster recovery times. Despite these promising attributes, its routine use in pediatric populations remains underexplored and unestablished. This narrative review examines remimazolam’s pharmacological properties, including its mechanism of action, metabolism, and elimination, and evaluates its safety and efficacy in pediatric sedation. Potential clinical applications are highlighted, such as procedural sedation, intensive care, and anesthesia induction, with comparisons to conventional agents. While initial studies suggest benefits, critical gaps remain in understanding its use in children. These include age-specific dosing strategies, long-term safety considerations, and its efficacy in children with comorbid conditions or undergoing complex procedures. Addressing these gaps will require robust clinical trials and large-scale observational studies. This review synthesizes current evidence and explores the potential of remimazolam to enhance pediatric sedation and anesthesia practices. By identifying key knowledge gaps and proposing future research directions, it aims to inform clinicians and researchers about the role of remimazolam in improving safety and outcomes in pediatric anesthesia.

Abstract Background Women diagnosed with breast cancer undergoing a mastectomy often have the option to undergo breast reconstruction (BR). BR decisions are complex and have considerable impact. We developed a patient decision aid (pDA) to support patients’ BR decision-making. Here, we assess patients’ and physicians’ use of the BR pDA and their views on the barriers and facilitators for widespread implementation. Methods Participants completed a questionnaire, and back-end data of the pDA was analyzed. Results Of 116 eligible patients, 113 patients accessed the BR pDA (median age: 50 years and 50% were highly educated. Most patients (72%) were satisfied with the pDA and 74% would recommend the BR pDA to other women facing the same choice. Patients’ preferences regarding how much, what kind and how to present information varied. Plastic surgeons (N = 22; 71% response) were satisfied with the pDA. Their key factors for implementation included the perceived match between information and clinical practice, costs, impact on patients, and support from peers and management for the tool. Conclusions As the BR pDA was highly valued by its end users, the identified factors for implementation should be taken into account.

Abstract Federated learning is a renowned technique for utilizing decentralized data while preserving privacy. However, real-world applications often face challenges like partially labeled datasets, where only a few locations have certain expert annotations, leaving large portions of unlabeled data unused. Leveraging these could enhance transformer architectures’ ability in regimes with small and diversely annotated sets. We conduct the largest federated cardiac CT analysis to date (n = 8, 104) in a real-world setting across eight hospitals. Our two-step semi-supervised strategy distills knowledge from task-specific CNNs into a transformer. First, CNNs predict on unlabeled data per label type and then the transformer learns from these predictions with label-specific heads. This improves predictive accuracy and enables simultaneous learning of all partial labels across the federation, and outperforms UNet-based models in generalizability on downstream tasks. Code and model weights are made openly available for leveraging future cardiac CT analysis.

Background: Previous research has shown that temporal prediction processes are associated with phase resets of low-frequency delta oscillations in a network of parietal, sensory and frontal areas during non-rhythmic sensory stimulation. Transcranial alternating current stimulation (tACS) modulates perceptually relevant brain oscillations in a frequency and phase-specific manner, allowing the assessment of their functional qualities in certain cognitive functions like temporal prediction. Objective: We addressed the relation between oscillatory activity and temporal prediction by using tACS to manipulate brain activity in a sinusoidal manner. This enables the investigation of the relevance of low-frequency oscillations’ phase for temporal prediction. Methods: Delta tACS was applied over the left and right parietal cortex in two separate unimodal and crossmodal temporal prediction experiments. Participants judged either the visual or the tactile reappearance of a uniformly moving visual stimulus, which shortly disappeared behind an occluder. tACS was applied with six different phase shifts relative to sensory stimulation in both experiments. Additionally, a computational model was developed and analysed to elucidate oscillation-based functional principles for the generation of temporal predictions. Results: Only in the unimodal experiment, the application of delta tACS resulted in a phase-dependent modulation of temporal prediction performance. By considering the effect of sustained tACS in the computational model, we demonstrate that the entrained dynamics can phase-specifically modulate temporal prediction accuracy. Conclusion: Our results suggest that delta oscillatory phase contributes to unimodal temporal prediction. Crossmodal prediction may involve a broader brain network or cross-frequency interactions, extending beyond parietal delta phase and the scope of our current stimulation design.

Diese Vignettenstudie hatte zum Ziel, den Einfluss von ChatGPT auf die aktuelle Lernmotivation von Studierenden sowie den Einfluss der aktuellen Lernmotivation auf die Technologieakzeptanz der Nutzung von ChatGPT im Studium zu untersuchen. Es wurden Studierende mittels einer Online-Umfrage im Zeitraum von Juli bis November 2023 befragt. Die Befragung umfasste Skalen zur aktuellen Motivation (FAM) sowie ausgewählte Skalen des TAM 3. Insgesamt wurden 111 vollständige Datensätze ausgewertet. Es zeigte sich ein geringer Effekt der ChatGPT-Nutzung auf die aktuelle Lernmotivation, welche wiederum die Akzeptanz von ChatGPT im Studium beeinflusste.

The symptoms of active systemic lupus erythematosus (SLE) potentially lead to inactivity, muscle loss and social isolation. In addition to medical treatment, the current EULAR recommendations describe the relevance of physical activity, exercise and training as a non-pharmacological management option in patients with SLE. A positive interaction between fatigue and the basic health-promoting effects of exercise is well established. Still unclear is what kind of training, setting, and intensity show optimal objective and subjective outcomes. The study will include 40 adult SLE patients with moderate to severe fatigue. The study lasts 28 weeks and is divided into a 12-week “real-world” monitoring phase before rehabilitation, a 4-week inpatient rehabilitation phase, and a 12-week maintenance activity and training phase after the rehabilitation. The parameters consisted of physical performance parameters, laboratory parameters, physician and patient-related questionnaires and activity data based on a fitness watch. During rehabilitation, patients receive individual high-intensity interval training (HIIT), basic endurance training and functional interval training. This proof-of-concept trial aims to investigate if high-intensity interval training is feasible and how VO2peak is increased. Additionally, the effect of the severity of fatigue measured by patient-related outcomes and the number of anti-NR2 antibodies is focussed. This study was approved by the Ethics Committee of the Medical Association of Rhineland-Palatinate and complies with the standards of the Declaration of Helsinki. All participants will sign a written informed consent. Trial registration number: DRKS00022933.

ABSTRACT Frontotemporal Lobar Degeneration (FTLD) encompasses progressive neurodegeneration primarily affecting the frontal and/or temporal lobes, presenting in varied pathological entities. These pathologies lead to diverse clinical syndromes collectively known as Frontotemporal Dementia (FTD), which includes a behavioral variant, and primary progressive aphasia, with its non-fluent and semantic variants, and related conditions with parkinsonism or motoneuron disease features. The historical development of FTD concept is rooted in the pioneering work of Arnold Pick, who first described clinical cases of focal brain atrophy. Oskar Fischer significantly advanced this field by detailing the histopathological features of these conditions, such as the ‘spongiform cortical wasting’, and identifying characteristic neuronal changes such as the ‘ballooned cells’. Fischer’s contributions, alongside those of contemporaries like Alois Alzheimer, laid the foundation for understanding FTLD histopathology. Here, Fischer’s overlooked work is spotlighted, advocating for a greater recognition, which he rightfully deserves for his contributions to the field of neurodegenerative diseases.

IntroductionComplex in vitro respiratory models, including air-liquid interface (ALI) transwell cultures and airway organoids, have emerged as promising tools for studying human respiratory virus infections. These models address several limitations of conventional two-dimensional cell line and animal models. However, the lack of standardized protocols for the application of these models in infection studies limits the possibilities for comparing results across different research groups. Therefore, we applied a collaborative approach to harmonize several aspects of experimental methodology between different research laboratories, aiming to assess the comparability of different models of human airway epithelium in the context of respiratory viral infections.MethodsIn this study, we compared three different models of human respiratory epithelium: a primary human bronchial epithelial cell-derived ALI transwell model, and two airway organoid models established from human airway- and lung-derived adult stem cells. We first assessed the presence of various differentiated cell types using immunofluorescence microscopy. Using a shared stock of influenza A virus, we then assessed viral growth kinetics, epithelial cytokine responses, and serum-mediated inhibition of infection.ResultsThe presence of club, goblet, and ciliated cells was confirmed in all models. We observed similar viral replication kinetics with a >4-log increase in virus titre across all models using a TCID50 assay. Following infection, a reproducible antiviral cytokine response, including a consistent increase in CXCL10, IL-6, IFN-λ1, IFN-λ2/3, and IFN-β, was detected across all models. Finally, neutralization was assessed by pre-incubation of virus with human serum. Reduced viral replication was observed across all models, resulting in a 3- to 6-log decrease in virus titres as quantified by TCID50.DiscussionIn conclusion, all three models produced consistent results regardless of the varying cell sources, culturing approaches, and infection methods. Our collaborative efforts to harmonize infection experiments and compare ALI transwell and airway organoid models described here aid in advancing our understanding and improving the standardization of these complex in vitro respiratory models for future studies.

The axon initial segment (AIS) constitutes not only the site of action potential initiation, but also a hub for activity-dependent modulation of output generation. Recent studies shedding light on AIS function used predominantly post-hoc approaches since no robust murine in vivo live reporters exist. Here, we introduce a reporter line in which the AIS is intrinsically labeled by an ankyrin-G-GFP fusion protein activated by Cre recombinase, tagging the native Ank3 gene. Using confocal, superresolution, and two-photon microscopy as well as whole-cell patch-clamp recordings in vitro, ex vivo, and in vivo, we confirm that the subcellular scaffold of the AIS and electrophysiological parameters of labeled cells remain unchanged. We further uncover rapid AIS remodeling following increased network activity in this model system, as well as highly reproducible in vivo labeling of AIS over weeks. This novel reporter line allows longitudinal studies of AIS modulation and plasticity in vivo in real-time and thus provides a unique approach to study subcellular plasticity in a broad range of applications.

Per- and polyfluoroalkyl substances (PFAS) have been detected worldwide, from the deep seas to polar regions. A previous review showed that PFAS are risk drivers of the chemical mixture present in human blood. This study focused on establishing the PFAS exposure of a Swedish subpopulation and investigated whether the exposure poses a risk of adverse health effects. Human serum from 60 blood donors in Stockholm, Sweden, was analyzed. A target method including 32 PFAS analytes and over 270 suspect features was used to detect and quantify PFAS. Twenty-six PFAS were quantified, and 7 suspect PFAS features (6 H-PFCAs and PFECHS) were semi-quantified. Nine mixture risk assessment (MRA) strategies were used to assess the risk of health outcomes. Fifteen effect levels were derived and used, along with 15 already established values. The certainty of various derivation techniques was discussed. The MRAs showed that the entire studied population exceeded some of the risk thresholds, with effects including high cholesterol and immune suppression. However, the certainty was lower when deriving these two effect levels. The MRA, using human biomonitoring guidance values (high certainty), concluded that for 63 % of the individuals, a risk for adverse health effects cannot be excluded. This study has demonstrated that there is a reason for concern regarding PFAS exposure in the general population of Sweden. To our knowledge, this is the first time the H-PFCAs have been semi-quantified in human blood using a reference standard.

Accurate preoperative mapping is crucial for maximizing tumor removal while minimizing damage to critical brain functions during brain tumor surgery. Navigated transcranial magnetic stimulation (nTMS), magnetoencephalography (MEG), and functional magnetic resonance imaging (fMRI) are established methods for assessing motor and language function. Following PRISMA guidelines, this systematic review analyzes the reliability, clinical utility, and accessibility of these techniques. A total of 128 studies (48 nTMS, 56 fMRI, 24 MEG) were identified from various databases. The analysis finds nTMS to be a safe, standardized method with high accuracy compared to direct cortical stimulation for preoperative motor mapping. Combining nTMS with tractography allows for preoperative assessment of short-term and long-term motor deficits, which may not be possible with fMRI. fMRI data interpretation requires careful consideration of co-activated, non-essential areas (potentially leading to false positives) and situations where neural activity and blood flow are uncoupled (potentially leading to false negatives). These limitations restrict fMRI’s role in preoperative planning for both motor and language functions. While MEG offers high accuracy in motor mapping, its high cost and technical complexity contribute to the limited number of available studies. Studies comparing preoperative language mapping techniques with direct cortical stimulation show significant variability across all methods, highlighting the need for larger, multicenter studies for validation. Repetitive nTMS speech mapping offers valuable negative predictive value, allowing clinicians to evaluate whether a patient should undergo awake or asleep surgery. Language function monitoring heavily relies on the specific expertise and experience available at each center, making it challenging to establish general recommendations.

This paper describes a collaborative, community-based research development process in Southern California, named TRACtion – Transformative Research and Collaboration. TRACtion draws from community-based participatory research (CPBR) methods used in medicine and environmental research, but it applies these methods to the collaborative development of social problems and research questions in transportation, rather than the development or execution of a single research project. Academic researchers were paired with members of community-based organizations in five working groups, and were charged with identifying research gaps and barriers to a just transition for transportation. We then used the working group priorities as the starting point for focused literature reviews, identifying questions that are already well researched and those where future research could address the themes raised by the working groups. We highlight how the research priorities uncovered through TRACtion systematically differ from the thrust of most current transportation research. Specifically, TRACtion produced research priorities that are more people-centric compared to the current transportation research landscape. By detailing the TRACtion process, and comparing its outcomes to traditional transportation research subjects, this paper aims to provide a model for future CPBR methods in transportation research, and highlight how this model could uncover important, unaddressed research topics.