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Abstract $$\varLambda $$ Λ -Cold Dark Matter ( $$\varLambda $$ Λ CDM) has been successful at explaining the large-scale structures in the universe but faces severe issues on smaller scales when compared to observations. Introducing self-interactions between dark matter particles claims to provide a solution to the small-scale issues in the $$\varLambda $$ Λ CDM simulations while being consistent with the observations at large scales. The existence of the energy region in which these self-interactions between dark matter particles come close to saturating the S-wave unitarity bound can result in the formation of dark matter bound states called darkonium. In this scenario, all the low energy scattering properties are determined by a single parameter, the inverse scattering length $$\gamma $$ γ . In this work, we set bounds on $$\gamma $$ γ by studying the impact of darkonium on the observations at direct detection experiments using data from CRESST-III and XENON1T. The exclusion limits on $$\gamma $$ γ are then subsequently converted to exclusion limits on the self-interaction cross-section and compared with the constraints from astrophysics and N-body simulations.

Abstract Neurodegenerative diseases are often accompanied by neuroinflammation and impairment of the blood-brain barrier (BBB) mediated by activated glial cells through their release of proinflammatory molecules. To study the effects of glial cells on mouse brain endothelial cells (mBECs), we developed an in vitro BBB model with inflammation by preactivating mixed glial cells (MGCs) with lipopolysaccharide (LPS) before co-culturing with mBECs to study the influence of molecules released by activated MGCs. The response of the mBECs to activated MGCs was compared to direct stimulation with LPS. The cytokine profile of activated MGCs was analyzed together with their effects on the mBEC’s integrity, expression of tight junction proteins, adhesion molecules, and BBB-specific transport proteins. Stimulation of MGCs significantly upregulated mRNA expression and secretion of several pro-inflammatory cytokines. Co-culturing mBECs with pre-stimulated MGCs significantly affected the barrier integrity of mBECs similar to direct stimulation with LPS. The gene expression levels of tight junction proteins were unaltered, but tight junction proteins revealed rearrangements with respect to subcellular distribution. Compared to direct stimulation with LPS, the expression of cell-adhesion molecules was significantly increased when mBECs were co-cultured with prestimulated MGCs and thus pre-activating MGCs transforms mBECs into a proinflammatory phenotype.

Abstract In recent times, the sensitivity of low-mass direct dark matter searches has been limited by unknown low energy backgrounds close to the energy threshold of the experiments known as the low energy excess (LEE). The CRESST experiment utilises advanced cryogenic detectors constructed with different types of crystals equipped with Transition Edge Sensors (TESs) to measure signals of nuclear recoils induced by the scattering of dark matter particles in the detector. In CRESST, this low energy background manifests itself as a steeply rising population of events below 200 eV. A novel detector design named doubleTES using two identical TESs on the target crystal was studied to investigate the hypothesis that the events are sensor-related. We present the first results from two such modules, demonstrating their ability to differentiate between events originating from the crystal’s bulk and those occurring in the sensor or in its close proximity.

Abstract Cryogenic scintillating calorimeters are ultra- sensitive particle detectors for rare event searches, particularly for the search for dark matter and the measurement of neutrino properties. These detectors are made from scintillating target crystals generating two signals for each particle interaction. The phonon (heat) signal precisely measures the deposited energy independent of the type of interacting particle. The scintillation light signal yields particle discrimination on an event-by-event basis. This paper presents a likelihood framework modeling backgrounds and a potential dark matter signal in the two-dimensional plane spanned by phonon and scintillation light energies. We apply the framework to data from CaWO $$_4$$ 4 -based detectors operated in the CRESST dark matter search. For the first time, a single likelihood framework is used in CRESST to model the data and extract results on dark matter in one step by using a profile likelihood ratio test. Our framework simultaneously fits (neutron) calibration data and physics (background) data and allows combining data from multiple detectors. Although tailored to CaWO $$_4$$ 4 -targets and the CRESST experiment, the framework can easily be expanded to other materials and experiments using scintillating cryogenic calorimeters for dark matter search and neutrino physics.

Abstract RNAs are often modified to invoke new activities. While many modifications are limited in frequency, restricted to non-coding RNAs, or present only in select organisms, 5-methylcytidine (m5C) is abundant across diverse RNAs and fitness-relevant across Domains of life, but the synthesis and impacts of m5C have yet to be fully investigated. Here, we map m5C in the model hyperthermophile, Thermococcus kodakarensis. We demonstrate that m5C is ~25x more abundant in T. kodakarensis than human cells, and the m5C epitranscriptome includes ~10% of unique transcripts. T. kodakarensis rRNAs harbor tenfold more m5C compared to Eukarya or Bacteria. We identify at least five RNA m5C methyltransferases (R5CMTs), and strains deleted for individual R5CMTs lack site-specific m5C modifications that limit hyperthermophilic growth. We show that m5C is likely generated through partial redundancy in target sites among R5CMTs. The complexity of the m5C epitranscriptome in T. kodakarensis argues that m5C supports life in the extremes.

Abstract Many different platforms have been used to develop highly protective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in humans. However, protection has eroded over time due to the emergence of antigenically diverse viral variants, especially the Omicron subvariants. One successful platform for the generation of SARS-CoV-2 vaccines are recombinant spike protein vaccines, of which two are licensed in the United States and Europe. Typically, purified recombinant protein antigens are poorly immunogenic and adjuvants must be included in the formulation. Here, we adjuvanted recombinant ancestral SARS-CoV-2 Wuhan-Hu-1 spike proteins with an emulsion formulation combined with synthetic Toll-like receptor (TLR) 4 and 7/8 agonists. This combination led to the induction of a Th1-skewed immune response that included high titers of antibodies against Wuhan-Hu-1 spike. These serum antibodies included neutralizing and cross-reactive antibodies that recognized the spike from multiple SARS-CoV-2 variants, as well as the receptor binding domain (RBD) from SARS-CoV-1. Despite an absence of robust cross-neutralization, vaccination against Wuhan-Hu-1 spike in the context of TLR-containing emulsions provided complete cross-protection against disease from a lethal challenge with XBB.1 in a stringent K18-hACE2 mouse model. We believe that the combination of recombinant spike antigens with TLR agonist-based emulsion formulations could lead to the development of next-generation SARS-CoV-2 vaccines that provide significant protection from future emerging variants.

Introduction: Graduate medical education is being reformed in many countries, with a focus on the principles of competency-based medical education (CBME). A main novel aspect in this context is the implementation of entrustable professional activities (EPAs). The introduction of EPAs aims to better align training curricula with clinical practice, provide individualized supervision, and enhance the quality of feedback.Project description: This project report presents the development of a national strategy and the initial results of implementing entrustable professional activities in the Swiss context.Results: Affiliated with the Swiss Institute of Medical Education (SIME), an EPA-Commission was established with the mandate to develop a strategy and provide guidance to medical specialty societies. To date, 28 out of 45 specialty societies have sought advice from the EPA-Commission and have begun developing EPAs. Concurrently, the Commission has expanded the national faculty development courses, adapted the content, started offering multilingual courses, and has published a series of articles on CBME and EPAs. Selected pilot hospitals are now planning to implement EPA-based graduate medical education curricula. Additionally, the introduction of a nationwide electronic solution (app) for assessing EPAs is planned.Conclusion: The introduction of EPAs in graduate medical education is a multilayered project. In addition to medical education aspects, various social, organizational, and professional-political factors are crucial for the transformation processes. In the Swiss context, such a reform has been successfully initiated. Continuous evaluations of the ongoing projects will provide further insights for competency-based graduate medical education reforms.

ObjectivesThe purpose of this systematic review is to provide an overview of published follow-up care programs of primary and secondary health conditions (SHCs) in spinal cord injury/disorder (SCI/D) and spina bifida and describe recommendations on content, frequency, setting of follow-up care programs for persons with SCI/D and spina bifida.MethodsAccording to the sequence of procedures of the AWMF (Association of the Scientific Medical Societies in Germany) a systematic literature search was performed (in PubMed, Cochrane Library and nine additional databases for guidelines) between 5 September 2019 and 22 September 2019. Publications (Jan. 2008–Dec. 2018) and guidelines (up to 2018) published in English or German and describing an evidence-based follow-up care program for persons with SCI/D or spina bifida were included.ResultsThe systematic literature search found 1973 publications in PubMed and Cochrane Library, resulting in 19 papers for SCI/D and 6 for Spina bifida. Additionally, we included 34 guidelines developed by reputable committees or medical associations. All eligible guidelines, and publications, were rated and classified according to the guidance of AWMF. Of the retrieved publications, and guidelines, level of evidence of follow-up care programs was mostly based on informal procedures and expert opinion or formally consent based expert opinion. None of the guidelines, or publications described an evidence based comprehensive clinical practice guideline (CPG) for follow-up care for people with SCI/D or spina bifida.ConclusionBased on the comprehensive and extensive literature research conducted, regular (annual) follow-up care appointments at specialized SCI clinics are recommended. There is a notable absence of a comprehensive CPG covering all relevant health conditions for long-term follow-up in SCI/D or spina bifida. In order to provide persons with SCI/D with up-to-date and best possible medical and rehabilitative care, a CPG for follow-up care is urgently needed. In response to this gap, the German-speaking Medical Society of Paraplegia (DMGP) has commissioned its members to establish a guideline for follow-up care for individuals with SCI/D. The current review serves as an evidence-based framework for the development of this guideline.

Abstract Background Neutrophils play a crucial role in inflammation and in the increased thrombotic risk in myeloproliferative neoplasms (MPNs). We have investigated how neutrophil-specific expression of JAK2-V617F or CALRdel re-programs the functions of neutrophils. Methods Ly6G-Cre JAK2-V617F and Ly6G-Cre CALRdel mice were generated. MPN parameters as blood counts, splenomegaly and bone marrow histology were compared to wild-type mice. Megakaryocyte differentiation was investigated using lineage-negative bone marrow cells upon in vitro incubation with TPO/IL-1β. Cytokine concentrations in serum of mice were determined by Mouse Cytokine Array. IL-1α expression in various hematopoietic cell populations was determined by intracellular FACS analysis. RNA-seq to analyse gene expression of inflammatory cytokines was performed in isolated neutrophils from JAK2-V617F and CALR-mutated mice and patients. Bioenergetics of neutrophils were recorded on a Seahorse extracellular flux analyzer. Cell motility of neutrophils was monitored in vitro (time lapse microscopy), and in vivo (two-photon microscopy) upon creating an inflammatory environment. Cell adhesion to integrins, E-selectin and P-selection was investigated in-vitro. Statistical analysis was carried out using GraphPad Prism. Data are shown as mean ± SEM. Unpaired, two-tailed t-tests were applied. Results Strikingly, neutrophil-specific expression of JAK2-V617F, but not CALRdel, was sufficient to induce pro-inflammatory cytokines including IL-1 in serum of mice. RNA-seq analysis in neutrophils from JAK2-V617F mice and patients revealed a distinct inflammatory chemokine signature which was not expressed in CALR-mutant neutrophils. In addition, IL-1 response genes were significantly enriched in neutrophils of JAK2-V617F patients as compared to CALR-mutant patients. Thus, JAK2-V617F positive neutrophils, but not CALR-mutant neutrophils, are pathogenic drivers of inflammation in MPN. In line with this, expression of JAK2-V617F or CALRdel elicited a significant difference in the metabolic phenotype of neutrophils, suggesting a stronger inflammatory activity of JAK2-V617F cells. Furthermore, JAK2-V617F, but not CALRdel, induced a VLA4 integrin-mediated adhesive phenotype in neutrophils. This resulted in reduced neutrophil migration in vitro and in an inflamed vessel. This mechanism may contribute to the increased thrombotic risk of JAK2-V617F patients compared to CALR-mutant individuals. Conclusions Taken together, our findings highlight genotype-specific differences in MPN-neutrophils that have implications for the differential pathophysiology of JAK2-V617F versus CALR-mutant disease.

Abstract Predicting the course of neurodegenerative disorders early has potential to greatly improve clinical management and patient outcomes. A key challenge for early prediction in real-world clinical settings is the lack of labeled data (i.e., clinical diagnosis). In contrast to supervised classification approaches that require labeled data, we propose an unsupervised multimodal trajectory modeling (MTM) approach based on a mixture of state space models that captures changes in longitudinal data (i.e., trajectories) and stratifies individuals without using clinical diagnosis for model training. MTM learns the relationship between states comprising expensive, invasive biomarkers (β-amyloid, grey matter density) and readily obtainable cognitive observations. MTM training on trajectories stratifies individuals into clinically meaningful clusters more reliably than MTM training on baseline data alone and is robust to missing data (i.e., cognitive data alone or single assessments). Extracting an individualized cognitive health index (i.e., MTM-derived cluster membership index) allows us to predict progression to AD more precisely than standard clinical assessments (i.e., cognitive tests or MRI scans alone). Importantly, MTM generalizes successfully from research cohort to real-world clinical data from memory clinic patients with missing data, enhancing the clinical utility of our approach. Thus, our multimodal trajectory modeling approach provides a cost-effective and non-invasive tool for early dementia prediction without labeled data (i.e., clinical diagnosis) with strong potential for translation to clinical practice.

Abstract Background Researchers have highlighted the importance of early access to concussion care within one week of injury in reducing recovery times. However, a persisting question for concussion researchers is “just how early is important?” The purpose of this study was to examine differences in recovery time as predicted by the number of days elapsed since injury (DSI) to initial evaluation among patients who had access to a specialty concussion clinic within seven days. We hypothesized that DSI group membership, even within seven days, would significantly predict risk of protracted recovery (i.e., beyond 21 days). Methods In this archival study, retrospective data were gathered from electronic medical records between September 2020 to March 2022. Records of participants between ages 12–18, those diagnosed with a sports-related concussion based on initial clinic visit diagnosis by a medical provider and those who established care within seven days of injury at a large pediatric specialty concussion clinic were examined. Participants were divided into three DSI groups (patients seen in 21 recovery days). Results A total of 856 participants were eligible. Adolescents in the acute group (M = 15.12, SD = 8.04) had shorter recovery times in days compared to those in the sub-acute (M = 17.98, SD = 10.18) and post-acute (M = 21.12, SD = 10.12; F = 26.00, p

IntroductionWhile it is well-established that follow-up care programs play a crucial role in preventing and early detecting secondary health conditions (SHCs) in persons with spinal cord injury [SCI, including spina bifida (SB)], the availability of evidence-based follow-up care programs remains limited. Under the leadership of the German-speaking Medical Society for Paraplegiology (DMGP), we have developed an evidence based clinical practice guideline for follow-up care of SHCs in persons with SCI and identify research gaps.MethodsThis guideline was developed in accordance with the regulations of the Association of the Scientific Medical Societies in Germany (AWMF e.V.). To ensure an evidence-based guidance, we utilized the International Classification of Functioning, Disability and Health (ICF) generic core set and ICF Core Set for individuals with SCI in long-term context as our foundational framework. We conducted a comprehensive literature review to identify existing recommendations for follow-up care and graded the level of evidence according to relevant instruments. Subsequently, we formulated recommendations and achieved consensus through a structured nominal group process involving defined steps and neutral moderation, while adhering to the criteria outlined in the German guideline development instrument (DELBI).ResultsAlthough there is a fair number of literatures describing prevalence and severity of SHCs after SCI, the amount of literature including recommendations was low (19 for SCI and 6 for SB). Based on the current evidence on prevalence and severity of SHCs and available recommendations, a clinical practice guideline on follow-up care of most relevant SHCs was defined. The recommendations for follow-up care are described in the following chapters: (1) Nervous system; (2) (Neuropathic) pain; (3) Cardiovascular diseases; (4) Respiratory System; (5) Immunological system, vaccination and allergies; (6) Gastrointestinal tract and function; (7) Endocrinological system and nutrition; (8) Urogenital system; (9) Contraception, pregnancy, birth and postpartum care; (10) Musculoskeletal system; (11) Pressure injuries; (12) Psychological health; (13) Medication and polypharmacy.ConclusionWe could successfully establish an evidence based clinical practice guideline for follow-up care of SHCs in individuals with SCI. There is however a notable lack of high-quality recommendations for SCI follow-up care.

Musculoskeletal modeling is a powerful tool to quantify biomechanical factors typically not feasible to measure in vivo, such as hip contact forces and deep muscle activations. While technological advancements in musculoskeletal modeling have increased accessibility, selecting the appropriate modeling approach for a specific research question, particularly when investigating pathological populations, has become more challenging. The purposes of this review were to summarize current modeling and simulation methods in structural hip disorder research, as well as evaluate model validation and study reproducibility. MEDLINE and Web of Science were searched to identify literature relating to the use of musculoskeletal models to investigate structural hip disorders (i.e., involving a bony abnormality of the pelvis, femur, or both). Forty-seven articles were included for analysis, which either compared multiple modeling methods or applied a single modeling workflow to answer a research question. Findings from studies comparing methods were summarized, such as the effect of generic versus patient-specific modeling techniques on model-estimated hip contact forces or muscle forces. The review also discussed limitations in validation practices, as only 11 of the included studies conducted a validation and used qualitative approaches only. Given the lack of information related to model validation, additional details regarding the development and validation of generic models were retrieved from references and modeling software documentation. To address the wide variability and under-reporting of data collection, data processing, and modeling methods highlighted in this review, we developed a template that researchers can complete and include as a table within the methodology section of their manuscripts. The use of this table will help increase transparency and reporting of essential details related to reproducibility and methods without being limited by word count restrictions. Overall, this review provides a comprehensive synthesis of modeling approaches that can help researchers make modeling decisions and evaluate existing literature.

Abstract Recent outbreaks of highly pathogenic avian influenza have devastated poultry production across the United States, with more than 77 million birds culled in 2022–2024 alone. Wild waterfowl, including various invasive species, host numerous pathogens, including highly pathogenic avian influenza virus (HPAIV), and have been implicated as catalysts of disease outbreaks among native fauna and domestic birds. In major poultry‐producing states like Arkansas, USA, where the poultry sector is responsible for significant economic activity (>$4 billion USD in 2022), understanding the risk of invasive waterfowl interactions with domestic poultry is critical. Here, we assessed the risk of invasive waterfowl‐poultry interaction in Arkansas by comparing the density of poultry production sites (chicken houses) to areas of high habitat suitability for two invasive waterfowl species, (Egyptian Goose [Alopochen aegyptiaca] and Mute Swan [Cygnus olor]), known to host significant pathogens, including avian influenza viruses. The percentage of urban land cover was the most important habitat characteristic for both invasive waterfowl species. At the 95% confidence interval, chicken house densities in areas highly suitable for both species (Egyptian Goose = 0.91 ± 0.11 chicken houses/km2; Mute Swan = 0.61 ± 0.03 chicken houses/km2) were three to five times higher than chicken house densities across the state (0.17 ± 0.01 chicken houses/km2). We show that northwestern and western Arkansas, both areas of high importance for poultry production, are also at high risk of invasive waterfowl presence. Our results suggest that targeted monitoring efforts for waterfowl‐poultry contact in these areas could help mitigate the risk of avian pathogen exposure in Arkansas and similar regions with high poultry production.