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Abstract Background Randomised controlled trials (RCTs) are considered the gold standard for generating clinical evidence. The focus on high internal validity in RCTs challenges the external validity and generalisability of findings, potentially hindering their application in routine care. In neurorehabilitation, limited literature addresses conducting RCTs feasibly and efficiently. We investigated barriers and facilitators to conducting RCTs within routine care of neurorehabilitation centres from the perspective of stakeholders in neurorehabilitation in Germany and Austria. Methods We conducted semi-structured interviews with stakeholders in neurorehabilitation from four centres in Germany and Austria, informed by the Theoretical Domains Framework (TDF) and the Capability, Opportunity, Motivation and Behaviour model (COM-B). Employing a hybrid approach, the interview analysis integrated both deductive, theory-driven analysis based on the TDF domains and COM-B model and inductive, reflexive thematic analysis. Results Twelve stakeholders (4 physicians, 4 therapy managers, 4 therapists; 5 females, 7 males; with research experience spanning 0–40 years) were interviewed. Key barriers to conducting RCTs in neurological rehabilitation centres include limited financial, human, and time resources, high clinical workloads, and a lack of interest of some therapists. Ineffective leadership, perceived lack of research expertise, and communication issues were also significant barriers. Social influence factors such as lack of employer support and inadequate training access further contributed to the challenges. Additionally, barriers included insufficient research infrastructure, limited space, internal power struggles, and rigid cost bearer specifications. Key facilitators included physicians’ and therapists’ motivation to advance the field, contribute to knowledge, and to prioritise patient health. Support from supervisors, joint decision-making, and efficient organisation were crucial facilitators. Flexible therapy planning, mutual support, and interdisciplinary collaboration also played important roles. Conclusion Our results suggest that increasing professional development and understanding, along with providing adequate financial, human, time, and spatial resources to support research endeavours, implementing effective communication strategies to enhance interdisciplinary collaboration and coordination among team members may contribute to increased motivation and facilitate RCTs within the setting of neurorehabilitation centres. Trial registration This study was prospectively registered with the German Clinical Trials Register (08.04.2021 DRKSID DRKS00024982).

This retrospective cross-sectional study investigates determinants on follicular development, oocyte retrieval and pregnancy outcome. It assessed the clinical practicability of monitoring parameters in relation to predict a successful treatment. Analysis of serum-estradiol (E2), sonographic follicle count, number of oocytes and optimizable parameters have therefore been carried out based on patient files from the IVF outpatient clinic at the Department of Gynecology, Obstetrics and Reproductive Medicine, Homburg/Saar, Germany. Equidirectional connection occurred between serum-E2, sonographic follicle count and number of oocytes (p < 0.001). There was no significant difference between sonographic and punctured follicle count (p = 0.428), but between sonographic/punctured follicle count and number of oocytes obtained (p < 0.01). Increasing endometrial thickness was associated with increasing serum-E2 (p = 0.003) and number of oocytes (p < 0.001), but not with the follicle count (p > 0.05). Additionally, age was inversely associated with sonographic follicle count and number of oocytes (p < 0.001) but not with E2 (p > 0.05). BMI, nicotine and stimulation protocol had no association with the observed parameters (p > 0.05). Mean differences in follicle numbers can be used for predicting expectable numbers of oocytes. Due to comparable numbers of follicles visualized on the day of ovulation induction and the number of follicles punctured, more emphasis should be placed in optimizing oocyte retrieval procedures.

Abstract Acute transverse myelitis (ATM) is a disease characterized by inflammation of the spinal cord and may have various causes. In the context of this work, the distinction between isolated ATM and initial manifestation of autoimmune-mediated diseases of the central nervous system such as multiple sclerosis (MS) is crucial. Hence, the aim of this work was to identify predictive factors associated with the conversion to definite MS in a collective of individuals after their initial episode of isolated ATM (no initial identified cause). In this retrospective data analysis from the Vienna MS Database, all patients from Jan. 1, 1999, to Dec. 31, 2019, with a diagnosis of isolated ATM (according to the criteria of the Transverse Myelitis Consortium Working Group) who underwent lumbar puncture were extracted. Electronic medical records were reviewed on the availability of clinical data including therapy and follow-up, laboratory results including cerebrospinal fluid (CSF) analysis, evoked potentials (EP) as well as magnetic resonance imaging data. Among 42 patients with the diagnosis of isolated ATM, 12 (29%) were subsequently diagnosed with MS over a median follow-up period of 7.7 years. Univariately, MS converters were younger (32 years [25–39] vs. 42 years [31–50], p = 0.032), had a lower CSF/serum albumin ratio (29 [24–35] vs 37 [27–52], p = 0.037), lower CSF total protein (4.5 [2.8–4.8] vs. 5.5 [3.4–8.5], p = 0.023) and a higher proportion of CSF-specific oligoclonal bands (OCB; 83% vs. 30%, p = 0.002). In the multivariate regression analysis, the presence of CSF-specific OCB emerged as the sole predictive factor of subsequent MS diagnosis (OR: 14.42, 95% CI 1.39 to 149.48, p = 0.03). In a collective of 42 patients with isolated ATM and an MS conversion rate of nearly 30%, the only but highly predictive factor were CSF-specific OCB. This emphasizes the significance of conducting timely CSF analysis in such patients and underscores the need for tailored monitoring and follow-up strategies in this specific group.

Abstract Background Canine mammary tumours (CMT) are among the most common types of tumours in female dogs. Diagnosis currently requires invasive tissue biopsies and histological analysis. Tumour cells shed extracellular vesicles (EVs) containing RNAs and proteins with potential for liquid biopsy diagnostics. We aimed to identify CMT subtype-specific proteome profiles by comparing the proteomes of EVs isolated from epithelial cell lines derived from morphologically normal canine mammary tissue, adenomas, and carcinomas. Methods Whole-cell protein lysates (WCLs) and EV-lysates were obtained from five canine mammary cell lines: MTH53A (non-neoplastic); ZMTH3 (adenoma); MTH52C (simple carcinoma); 1305, DT1406TB (complex carcinoma); and their proteins identified by LC-MS/MS analyses. Gene Ontology analysis was performed on differentially abundant proteins from each group to identify up- and down-regulated biological processes. To establish CMT subtype-specific proteomic profiles, weighted gene correlation network analysis (WGCNA) was carried out. Results WCL and EVs displayed distinct protein abundance signatures while still showing the same increase in adhesion, migration, and motility-related proteins in carcinoma-derived cell lines, and of RNA processing and RNA splicing factors in the adenoma cell line. WGCNA identified CMT stage-specific co-abundant EV proteins, allowing the identification of adenoma and carcinoma EV signatures not seen in WCLs. Conclusions EVs from CMT cell lines exhibit distinct protein profiles reflecting malignancy state, allowing us to identify potential biomarkers for canine mammary carcinomas, such as biglycan. Our dataset could therefore potentially serve as a basis for the development of a less invasive clinical diagnostic tool for the characterisation of CMT.

Abstract Background Pre-existing comorbidities increase the likelihood of post-stroke dysphagia. This study investigates comorbidity prevalence in patients with dysphagia after ischemic stroke. Methods The data of patients with acute ischemic stroke from two large representative cohorts (STROKE-CARD trial 2014–2019 and STROKE-CARD registry 2020–2022 – both study center Innsbruck, Austria) were analyzed for the presence of dysphagia at hospital admission (clinical swallowing examination). Comorbidities were assessed using the Charlson Comorbidity Index (CCI). Results Of 2054 patients with ischemic stroke, 17.2% showed dysphagia at hospital admission. Patients with dysphagia were older (77.8 ± 11.9 vs. 73.6 ± 14.3 years, p

Abstract Purpose Childhood cancer survivors (CCS) have an increased risk of developing late chronic diseases, which can be influenced by the cancer type and its treatment. These chronic diseases can be severe and disabling, typically emerging years to decades after treatment. These deficits negatively impact quality of life, intelligence quotient, and memory. This study investigated how much the cancer type and treatment could affect the neurological hospitalisations in the French Childhood Cancer Survivors Study (FCCSS). Methods We included 5579 childhood cancer survivors (CCS), diagnosed with solid tumours or lymphoma between 1945 and 2000, treated before 2001 and below the age of 21 years at initial treatment. The follow-up period was from 2006 to 2018. Hospitalisation data were obtained by linkage with the National Health Data System. We calculated the relative hospitalisation rate (RHRs) and absolute excess rate (AERs). Multivariable analyses were conducted using a Generalized Linear Model (GLM) with a Poisson distribution to estimate the association between neurological hospitalisation and patient characteristics. The expected number of hospitalisations served as an offset to compare the risk for FCCSS survivors with that of the reference population. Risk estimates were reported as relative risk (RR) with 95% confidence intervals. Results The hospitalisation rate for CCS was 114.2 per 10,000 person-years (PY), compared to 48.4 in the reference population. The highest hospitalisation rates were observed for epilepsy (AER = 27.1 per 10000 PY, 95%CI: 23.5–31.2 and RHR = 5.1, 95%CI 4.4–5.7). In multivariable analyses, central nervous system (CNS) tumours survivors had the highest relative risk (RR) of hospitalisation (RR = 9.4, 95%CI: 6.7–13.1) followed by neuroblastoma survivors (RR = 2.5, 95%CI: 1.7–3.7). In the whole population, survivors who received radiation to the head and neck had a significantly higher risk of hospitalisation (RR = 3.9, 95%CI: 3.3–4.7) compared to those who did not receive radiotherapy. Conclusions Head and neck irradiation was identified as a strong risk factor for hospitalisation. This underlines the importance of implementing specific neurologic surveillance programs for at-risk individuals.

Abstract We study the production of dineutrinos in proton-proton collisions, with large missing transverse energy and an energetic jet as the experimental signature. Recasting a search from the ATLAS collaboration we work out constraints on semileptonic four-fermion operators, gluon and electroweak dipole operators and Z-penguins in the SMEFT. All but the Z-penguin operators experience energy-enhancement. Constraints on gluon dipole operators are the strongest, probing new physics up to 14 TeV, and improve over existing ones from collider studies. Limits on FCNC four-fermion operators are competitive with Drell-Yan production of dileptons, and improve on those for tau final states. For left-handed |∆s| = |∆d| = 1 and right-handed |∆c| = |∆u| = 1 transitions these are the best available limits, also considering rare kaon and charm decays. We estimate improvements for the 3000 fb−1 High Luminosity Large Hadron Collider.

Errors in variable subscripts, equations and Fig. 8 in Section 3.2 of the article by Lotze et al. [(2024). J. Synchrotron Rad. 31, 42–52] are corrected.

Abstract Efficient intracellular delivery is crucial for biotherapeutics, such as proteins, oligonucleotides, and CRISPR/Cas9 gene-editing systems, to achieve their efficacy. Despite the great efforts of developing new intracellular delivery carriers, the lack of straightforward methods for intracellular delivery quantification limits further development in this area. Herein, we designed a simple and versatile bioorthogonal luminescent reaction (BioLure assay) to analyze intracellular delivery. Our results suggest that BioLure can be used to estimate the amount of intracellularly delivered molecules after electroporation, and the estimation by BioLure is in good correlation with the results from complementary methods. Furthermore, we used BioLure assay to correlate the intracellularly-delivered RNase A amount with its tumoricidal activity. Overall, BioLure is a versatile tool for understanding the intracellular delivery process on live cells, and establishing the link between the cytosolic concentration of intracellularly-delivered biotherapeutics and their therapeutic efficacy.

Abstract Parkinson’s disease (PD) is a debilitating neurodegenerative disorder and its rising global incidence highlights the need for the identification of modifiable risk factors. In a gene-based burden test of rare variants (8647 PD cases and 777,693 controls) we discovered a novel association between loss-of-function variants in ITSN1 and PD. This association was further supported with burden data from the Neurodegenerative Disease Knowledge Portal and the Accelerating Medicines Partnership Parkinson’s Disease Knowledge Platform. Our findings show that Rho GTPases and disruptions in synaptic vesicle transport may be involved in the pathogenesis of PD, pointing to the possibility of novel therapeutic approaches.

Abstract Electrochemotherapy (ECT) combines the reversible electroporation (rEP) with intravenous (i.v.) or intratumoral (i.t.) administration of chemotherapeutic drugs. We conducted this study to compare the efficacy of i.v., i.t., and i.v. + i.t. injection of bleomycin (BLM) in ECT treatment of colorectal hepatic metastases in a rat model. WAG/Rij rats were randomized into three groups and underwent ECT with i.v., i.t., or i.v. + i.t. injection of BLM. Tumor volumes and oxygenation were measured by means of ultrasound and photoacoustic imaging. Moreover, liver and tumor tissue were analyzed by histology and immunohistochemistry. The i.v. and i.v. + i.t. groups exhibited a 44.0% and 46.6% reduction in oxygen saturation of the tumor tissue when compared to pretreatment values, whereas the i.t. group only showed a reduction of 35.2%. The extent of tumor tissue necrosis did not statistically differ between the groups. However, the i.t. group showed a tendency towards a lower necrosis rate. Cell proliferation, apoptotic cell death, vascularization, and immune cell infiltration were comparable in the treated tumors of the three groups. ECT with i.v. administration of BLM should be preferred in clinical practice, as the combined i.v. + i.t. therapy did not show superior oncological outcomes in the present study.

Abstract Background Transitioning to end-of-life care and thereby changing the focus of treatment directives from life-sustaining treatment to comfort care is important for neurological patients in advanced stages. Late transition to end-of-life care for neurological patients has been described previously. Objective To investigate whether previous treatment directives, primary medical diagnoses, and demographic factors predict the transition to end-of-life care and time to eventual death in patients with neurological diseases in an acute hospital setting. Method All consecutive health records of patients diagnosed with stroke, amyotrophic lateral sclerosis (ALS), and Parkinson’s disease or other extrapyramidal diseases (PDoed), who died in an acute neurological ward between January 2011 and August 2020 were retrieved retrospectively. Descriptive statistics and multivariate Cox regression were used to examine the timing of treatment directives and death in relation to medical diagnosis, age, gender, and marital status. Results A total of 271 records were involved in the analysis. Patients in all diagnostic categories had a treatment directive for end-of-life care, with patients with haemorrhagic stroke having the highest (92%) and patients with PDoed the lowest (73%) proportion. Cox regression identified that the likelihood of end-of-life care decision-making was related to advancing age (HR = 1.02, 95% CI: 1.007–1.039, P = 0.005), ischaemic stroke (HR = 1.64, 95% CI: 1.034–2.618, P = 0.036) and haemorrhagic stroke (HR = 2.04, 95% CI: 1.219–3.423, P = 0.007) diagnoses. End-of-life care decision occurred from four to twenty-two days after hospital admission. The time from end-of-life care decision to death was a median of two days. Treatment directives, demographic factors, and diagnostic categories did not increase the likelihood of death following an end-of-life care decision. Conclusions Results show not only that neurological patients transit late to end-of-life care but that the timeframe of the decision differs between patients with acute neurological diseases and those with progressive neurological diseases, highlighting the particular significance of the short timeframe of patients with the progressive neurological diseases ALS and PDoed. Different trajectories of patients with neurological diseases at end-of-life should be further explored and clinical guidelines expanded to embrace the high diversity in neurological patients.

Abstract Geological information is required to parameterize hydrogeological properties in groundwater flow models. Our aim was to provide a hydrogeological model for the island of Norderney, Northwest Germany and the surrounding Wadden Sea for this purpose. The model focuses on Holocene, Pleistocene and Pliocene deposits which are the most relevant to groundwater flow in and around the island's freshwater lens. For these geological units, borehole data was available that allowed us to distinguish between sediments acting as aquifers and aquitards. Conceptual units were derived that comprise the most common stratigraphic and petrographic features into discrete entities. The borehole data was supplemented by maps of the pre‐Holocene surface as well as data from an existing stratigraphic model for deeper geological units. The model was developed and created using the open‐source geological modelling software GemPy. The resulting model contains major hydrogeological units that can be assumed continuous over a larger extent of the model area based on the available data. From the deeper geology, a possible range of locations of the aquifer base below Norderney was extracted. By integrating borehole data, existing geological models and geological interpretations available in the literature, this dataset complements the so far mainly cross‐sectional and partial descriptions of the hydrogeology below Norderney.

Abstract Background The co-occurrence of C4 and CAM photosynthesis in a single species seems to be unusual and rare. This is likely due to the difficulty in effectively co-regulating both pathways. Here, we conducted a comparative transcriptomic analysis of leaves and cotyledons of the C4-like species Sesuvium sesuvioides (Aizoaceae) using RNA-seq. Results When compared to cotyledons, phosphoenolpyruvate carboxylase 4 (PEPC4) and some key C4 genes were found to be up-regulated in leaves. During the day, the expression of NADP-dependent malic enzyme (NADP-ME) was significantly higher in cotyledons than in leaves. The titratable acidity confirmed higher acidity in the morning than in the previous evening indicating the induction of weak CAM in cotyledons by environmental conditions. Comparison of the leaves of S. sesuvioides (C4-like) and S. portulacastrum (C3) revealed that PEPC1 was significantly higher in S. sesuvioides, while PEPC3 and PEPC4 were up-regulated in S. portulacastrum. Finally, potential key regulatory elements involved in the C4-like and CAM pathways were identified. Conclusions These findings provide a new species in which C4-like and CAM co-occur and raise the question if this phenomenon is indeed so rare or just hard to detect and probably more common in succulent C4 lineages.

Abstract Autoimmune thyroid disease (AITD) is a common autoimmune disease. In a GWAS meta-analysis of 110,945 cases and 1,084,290 controls, 290 sequence variants at 225 loci are associated with AITD. Of these variants, 115 are previously unreported. Multiomics analysis yields 235 candidate genes outside the MHC-region and the findings highlight the importance of genes involved in T-cell regulation. A rare 5’-UTR variant (rs781745126-T, MAF = 0.13% in Iceland) in LAG3 has the largest effect (OR = 3.42, P = 2.2 × 10−16) and generates a novel start codon for an open reading frame upstream of the canonical protein translation initiation site. rs781745126-T reduces mRNA and surface expression of the inhibitory immune checkpoint LAG-3 co-receptor on activated lymphocyte subsets and halves LAG-3 levels in plasma among heterozygotes. All three homozygous carriers of rs781745126-T have AITD, of whom one also has two other T-cell mediated diseases, that is vitiligo and type 1 diabetes. rs781745126-T associates nominally with vitiligo (OR = 5.1, P = 6.5 × 10−3) but not with type 1 diabetes. Thus, the effect of rs781745126-T is akin to drugs that inhibit LAG-3, which unleash immune responses and can have thyroid dysfunction and vitiligo as adverse events. This illustrates how a multiomics approach can reveal potential drug targets and safety concerns.

Abstract Background Pediatric headache is an increasing medical problem that has adverse effects on children’s quality of life, academic performance, and social functioning. Children with primary headaches exhibit enhanced sensory sensitivity compared to their healthy peers. However, comprehensive investigations including multimodal sensory sensitivity assessment are lacking. This study aimed to compare sensory sensitivity of children with primary headaches with their healthy peers across multiple sensory domains. Methods The study included 172 participants aged 6 to 17 years (M = 13.09, SD = 3.02 years; 120 girls). Of these 80 participants were patients with migraine, 23 were patients with tension-type headache, and 69 were healthy controls. The following sensory measures were obtained: Mechanical Detection Threshold (MDT), Mechanical Pain Threshold (MPT), Mechanical Pain Sensitivity (MPS), detection and pain threshold for Transcutaneous Electrical Nerve Stimulation (TENS), olfactory and intranasal trigeminal detection threshold, and odor identification ability. Sensory sensitivity was compared between groups with a series of Kruskal-Wallis tests. Binomial regression models were used to compare the relative utility of sensory sensitivity measures in classifying participants into patients and healthy controls, as well as into patients with migraine and tension-type headache. Results Patients with migraine had lower MPT measured at the forearm than patients with tension-type headaches and healthy controls. MPS was higher in patients with migraine than in healthy controls. All patients with headaches had lower detection threshold of TENS and higher olfactory sensitivity. Healthy controls showed increased intranasal trigeminal sensitivity. Scores in MPS, TENS, and olfactory and trigeminal thresholds were significantly predicting presence of primary headaches. Additionally, scores in MPT, olfactory and trigeminal threshold were positive predictors of type of headache. Conclusions Children with primary headaches exhibit different sensory profiles than healthy controls. The obtained results suggest presence of increased overall, multimodal sensitivity in children with primary headaches, what may negatively impact daily functioning and contribute to further pain chronification. Trial registration The study was registered in the German Registry of Clinical Trials (DRKS) DRKS00021062.

Abstract An international collection of Staphylococcus aureus of clonal complex (CC) 398 from diverse hosts spanning all continents and a 30 year-period is studied based on whole-genome sequencing (WGS) data. The collection consists of publicly available genomic data from 2994 strains and 134 recently sequenced Swiss methicillin-resistant S. aureus (MRSA) CC398 strains. A time-calibrated phylogeny reveals the presence of distinct phylogroups present in Asia, North and South America and Europe. European MRSA diverged from methicillin-susceptible S. aureus (MSSA) at the beginning of the 1950s. Two major European phylogroups (EP4 and EP5), which diverged approximately 1974, are the main drivers of MRSA CC398 spread in Europe. Within EP5, an emergent MRSA lineage spreading among the European horse population (EP5-Leq) diverged approximately 1996 from the pig lineage (EP5-Lpg), and also contains human-related strains. EP5-Leq is characterized by staphylococcal cassette chromosome mec (SCCmec) IVa and spa type t011 (CC398-IVa-t011), and EP5-Lpg by CC398-SCCmecVc-t011. The lineage-specific antibiotic resistance and virulence gene patterns are mostly mediated by the acquisition of mobile genetic elements like SCCmec, S. aureus Genomic Islands (SaGIs), prophages and transposons. Different combinations of virulence factors are present on S. aureus pathogenicity islands (SaPIs), and novel antimicrobial resistance gene containing elements are associated with certain lineages expanding in Europe. This WGS-based analysis reveals the actual evolutionary trajectory and epidemiological trend of the international MRSA CC398 population considering host, temporal, geographical and molecular factors. It provides a baseline for global WGS-based One-Health studies of adaptive evolution of MRSA CC398 as well as for local outbreak investigations.

Abstract Microplastic particles have been discovered in virtually all ecosystems worldwide, yet they may only represent the surface of a much larger issue. Nanoplastics, with dimensions well below 1 µm, pose an even greater environmental concern. Due to their size, they can infiltrate and disrupt individual cells within organisms, potentially exacerbating ecological impacts. Moreover, their minute dimensions present several hurdles for removal, setting them apart from microplastics. Here, we describe a process to remove colloidally stable nanoplastics from wastewater, which synergistically combines electrophoretic deposition and the formation of particle-stabilized foam. This approach capitalizes on localized changes in particle hydrophilicity induced by pH fluctuations resulting from water electrolysis at the electrode surface. By leveraging these pH shifts to enhance particle attachment to nascent bubbles proximal to the electrode, separation of colloidal particles from aqueous dispersions is achieved. Using poly(methyl methacrylate) (PMMA) colloidal particles as a model, we gain insights into the separation mechanisms, which are subsequently applied to alternative model systems with varying surface properties and materials, as well as to real-world industrial wastewaters from dispersion paints and PMMA fabrication processes. Our investigations demonstrate removal efficiencies surpassing 90%.

We examine the impact of water (160 ± 41 ppm of reference) on the anode, cathode, separator and electrolyte in two aging scenarios: calendric aging (60 °C, 80 days, charged state), resulting in a triggered current interrupt device (CID), and cycling 1680 times (charge/discharge with 1C, 2.75–4.2 V, 20 ± 2 °C), resulting in 24.5% residual capacity. We applied computer tomography (CT), scanning electron microscopy (SEM), energy dispersive spectroscopy (EDS) and secondary ion mass spectrometry (SIMS) to understand the capacity loss. The aged NMC/LCO–graphite cells were compared to a reference cell in pristine state. Both aging scenarios showed (a) thick depositions on the anode and cathode consisting mainly of oxygen, fluorine and phosphorous, (b) reduced separator pore sizes, (c) the deposition of Mn, Co and Ni on top of the anode and (d) the decomposition of the conductive salt LiPF6 accompanied by HF formation and a loss of active lithium. Calendric aging consumes the water content and additionally leads to (e) the decomposition of the organic solvent followed by CO2 gas formation. Cyclic aging increases the water content and additionally results in (f) the consumption of the additive fluoroethylene carbonate (FEC). These findings show how water affects aging phenomena and results in a capacity decrease in the cell.

Abstract Objective We studied the impact of depressive symptoms on adverse effects (AEs) in people with epilepsy (PWE) on antiseizure medication (ASM) therapy. An effect of depression on the AE burden has already been reported. We studied the correlation of various depressive symptoms with specific AEs to assess which AEs are especially prone to being confounded by particular depressive symptoms. Methods PWE filled in a variety of questionnaires including the “Neurological Disorder Depression Inventory for Epilepsy” (NDDI‐E), “Emotional Thermometers 4” (ET4) and “Liverpool Adverse Events Profile” (LAEP). Depression was defined by a NDDI‐E score > 13. Depressive symptoms consisted of NDDI‐E and ET4 items. Discriminant analysis identified those AEs (=LAEP items) that were most highly influenced by depression. Logistic regression analysis yielded correlations of different depressive symptoms with specific AEs. Results We included 432 PWE. The strongest discriminators for depression were the LAEP items “Depression”, “Nervousness/agitation,” and “Tiredness”. Out of all depressive symptoms “Everything I do is a struggle” most strongly correlated with total LAEP score (odds ratio [OR] = 3.1) and correlated with all but one LAEP item. Other depressive symptoms correlated to varying degrees with total LAEP and item scores. The number of ASMs, lack of seizure remission, and female gender correlated with high LAEP scores. Significance To the best of our knowledge, we are the first to show that various depressive symptoms correlate with specific LAEP items. This information can be helpful for quick evaluation of whether the reporting of different LAEP items may be confounded by particular depressive symptoms. This is relevant because changes in therapy may differ depending on if AEs are confounded by depressive symptoms. Simply reporting a particular depressive symptom may give a clue to whether specific AEs are confounded by depression. Our findings confirm the importance of screening for depression in all PWE. Plain Language Summary In this study we measured depressive disorder and side effects caused by medication used to treat epilepsy with self‐reported questionnaires in a cohort of people with epilepsy. We found depressive disorder to influence the perception of side effects that are caused by drugs used to treat epilepsy. This knowledge can help to identify if the reporting of side effects is influenced by depression. Treating depression may help to reduce side effects and may thus increase the tolerability of anti‐epileptic medication. People who tolerate their medication are more likely to take it and are thus less likely to develop epileptic seizure.

Abstract Background Earlier studies have estimated the impact of increased body mass index (BMI) on healthcare costs. Various methods have been used to avoid potential biases and inconsistencies. Each of these methods measure different local effects and have different strengths and weaknesses. Methods In the current study we estimate the impact of increased BMI on healthcare costs using nine common methods from the literature: multivariable regression analyses (ordinary least squares, generalized linear models, and two-part models), and instrumental variable models (using previously measured BMI, offspring BMI, and three different weighted genetic risk scores as instruments for BMI). We stratified by sex, investigated the implications of confounder adjustment, and modelled both linear and non-linear associations. Results There was a positive effect of increased BMI in both males and females in each approach. The cost of elevated BMI was higher in models that, to a greater extent, account for endogenous relations. Conclusion The study provides solid evidence that there is an association between BMI and healthcare costs, and demonstrates the importance of triangulation.

BackgroundIn organ donation from deceased donors, the interaction between the donor’s relatives and intensive care personnel is an important factor. The organ donation (OD) process is complex, and patients’ relatives play a vital role. Intensive care professionals need knowledge about how relatives perceive and experience the process to create a caring environment and support them throughout. Therefore, this collaborative project aims to explore both relatives’ and intensive care personnel’s perspectives of care in deceased organ donation in Scandinavia. ObjectiveThis study aims to (1) investigate donor relatives’ satisfaction and ICU personnel’s perception of their own professional competence and (2) explore donor relatives’ and ICU personnel’s experiences in the OD process to design for care and support in OD. MethodsThis protocol outlines a Scandinavian (Norway, Sweden, and Denmark) project, including 4 work packages. Work package 1 started in 2023 with the translation and validation of the Family Satisfaction in the Intensive Care Unit questionnaire into a Danish version and the translation of the Professional Competence in Organ Donation Questionnaire into a Swedish and Danish version. A cross-sectional survey measuring Scandinavian relatives’ perception of support in and satisfaction with the organ donation process and a cross-sectional survey measuring Scandinavian intensive care personnel’s competence in organ donation are the foundation for work package 2 (2024). The data from both surveys will be analyzed using descriptive and comparative analysis. The results will inform the interview guides in qualitative studies (work packages 3 and 4). Participants in the quantitative study will be invited to participate in in-depth interviews. In work package 3, in-depth interviews will be conducted to illuminate relatives’ experiences in the organ donation process. The interviews will be analyzed using thematic analysis, according to Braun and Clarke. In work package 4 (2025-2026), 1 qualitative design study will be conducted to illuminate ICU personnel’s experiences. Furthermore, the results from work packages 2 and 3 will inform the development of specific programs for care, support, and communication in the organ donation process. ResultsThe project was funded by the Norwegian Organ Donor Foundation in 2022 and Scandiatransplant in 2023. The Norwegian Nurses Organisation supports the project by funding a PhD student. The PhD student was employed by the University in Agder in May 2024. ConclusionsThis project will provide new knowledge that will assist us in designing and establishing programs for care, support, and donor relatives’ involvement in OD processes. International Registered Report Identifier (IRRID)PRR1-10.2196/55643

Hereditary spastic paraplegias (HSPs) are a diverse set of neurological disorders characterized by progressive spasticity and weakness in the lower limbs caused by damage to the axons of the corticospinal tract. More than 88 genetic mutations have been associated with HSP, yet the mechanisms underlying these disorders are not well understood. We replicated the pathophysiology of one form of HSP known as spastic paraplegia 15 (SPG15) in zebrafish. This disorder is caused in humans by mutations in the ZFYVE26 gene, which codes for a protein called SPASTIZIN. We show that, in zebrafish, the significant reduction of Spastizin caused degeneration of large motor neurons. Motor neuron degeneration is associated with axon demyelination in the spinal cord and impaired locomotion in the spastizin mutants. Our findings reveal that the reduction in Spastizin compromises axonal integrity and affects the myelin sheath, ultimately recapitulating the pathophysiology of HSPs.

IntroductionPatients with Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS) experience cognitive problems with attention, information processing speed, working memory, learning efficiency, and executive function. Commonly, patients report worsening of cognitive symptoms over time after physical and/or cognitive challenges. To determine, monitor, and manage longitudinal decrements in cognitive function after such exposures, it is important to be able to screen for cognitive dysfunction and changes over time in clinic and also remotely at home. The primary objectives of this paper were: (1) to determine whether a brief computerized cognitive screening battery will detect differences in cognitive function between ME/CFS and Healthy Controls (HC), (2) to monitor the impact of a full-day study visit on cognitive function over time, and (3) to evaluate the impact of exercise testing on cognitive dysfunction.MethodsThis cognitive sub-study was conducted between 2013 and 2019 across seven U.S. ME/CFS clinics as part of the Multi-Site Clinical Assessment of ME/CFS (MCAM) study. The analysis included 426 participants (261 ME/CFS and 165 HC), who completed cognitive assessments including a computerized CogState Brief Screening Battery (CBSB) administered across five timepoints (T0-T4) at the start of and following a full day in-clinic visit that included exercise testing for a subset of participants (182 ME/CFS and 160 HC). Exercise testing consisted of ramped cycle ergometry to volitional exhaustion. The primary outcomes are performance accuracy and latency (performance speed) on the computerized CBSB administered online in clinic (T0 and T1) and at home (T2-T4).ResultsNo difference was found in performance accuracy between ME/CFS and HCs whereas information processing speed was significantly slower for ME/CFS at most timepoints with Cohen’s d effect sizes ranging from 0.3–0.5 (p < 0.01). The cognitive decline over time on all CBSB tasks was similar for patients with ME/CFS independent of whether exercise testing was included in the clinic visit.ConclusionThe challenges of a clinic visit (including cognitive testing) can lead to further cognitive deficits. A single short session of intense exercise does not further reduce speed of performance on any CBSB tasks.

Objective Lipomatous hypertrophy of the interatrial septum (LHIS) is a distinct section of epicardial adipose tissue. However, its association with COPD is poorly documented. Methods Patients undergoing coronary computed tomography angiography (CTA) for clinical indications were recruited retrospectively and screened for LHIS and COPD. LHIS density and the coronary artery disease profile were quantified by CTA: stenosis severity (coronary artery disease radiological reporting system (CADRADS)), coronary artery calcium (CAC) and high-risk plaque (HRP). COPD patients with LHIS were matched for age and sex, the major cardiovascular risk factors (CVRFs), and compared to controls. Results The prevalence of LHIS in all 5466 patients was 5.9%. 151 (72.6%) of 208 patients with COPD had LHIS. LHIS density in COPD patients was higher (−10.93 HU versus −21.1 HU; p30 kg·m−2) patients (20.4 versus 13.6 HU; p=0.02). BMI was inversely correlated with LHIS density (BetaR −0.031; 95% CI: −0.054– −0.008; p=0.007). LHIS density was associated with COPD, but not with BMI on multivariate models. CAC and coronary stenosis severity (CADRADS and >50% stenosis) were not different (p=0.106, p=0.156 and p=0.350, respectively). HRPs were observed more frequently in COPD patients with severe Global Initiative for Chronic Obstructive Lung Disease (GOLD) stages ≥2 (32.3% versus 20.1%; p=0.044), but not when adding mild GOLD stages. Conclusions The prevalence of LHIS in COPD patients is high (72.6%), and the adipose tissue density is higher, indicating a higher brown fat component. In obese, patients LHIS density is lower and declines along with BMI. Coronary stenosis severity and calcium were not different; however HRPs were more frequent in severe COPD.

Background: Cardiovascular risk (CV)-stratification in females is challenging, and current models miss a high proportion at-risk. Breast arterial calcifications (BAC) are independent prognosticators, but their interaction with the coronary artery disease profile by computed tomography (CT) is controverse, and the role of BAC 0 unclear. Objective: to investigate the interaction of BAC with coronary CT outcomes (CAC score, coronary stenosis severity and high-risk plaque (HRP). Methods: Consecutive patients referred to mammography (MG) and coronary CTA for clinical indications within 1 year were included. Three different age groups were compared (65 years). Results: 443 patients were included. There were significant age differences for the prevalence of BAC 0 (p300 AU (p=0.0023) and obstructive disease (>50% stenosis)(p=0.0048) but not for high-risk-plaque (HRP)(p=0.4905). High CAC (>300 AU) was present in only 0.82% of females with BAC 0 in less than 55 year, but significantly more often in those above 65 years (p=0.0004;OR=16.58:95% CI: 2.829-361.7) and 55 years with 12.1% and 8.4%. Obstructive coronary disease (>50% stenosis) in BAC 0 was present in 18.2%; with age-dependent differences (10.7% vs 14.7% vs 29.9%) (p=0.0003). The correlation between BAC, CAC and CADRADS was weak (r=0.246 and r=0.243, p300AU in females

Besides being an essential structural component of plasma membranes and the precursor of many functional compounds and signaling molecules, cholesterol was also proposed to play a role in the etiology and/or manifestation of Parkinson’s disease (PD). However, so far systematic investigations on the role of cholesterol and its metabolites present in the brain for the etiology of PD are missing. Here, we investigate for the first time the association of PD with SNPs in the genes of four cytochromes P450 (P450), CYP46A1, CYP39A1, CYP27A1 and CYP7B1, which are critical for the degradation of cholesterol in the brain. Analyzing 1,349 individuals from the PPMI data base, we found 24 SNPs in these four genes, which are significantly over- or under-represented in patients suffering from idiopathic PD (IPD). Studying each of the 362 IPD patients individually, we found that most patients (45%) showed only one associated SNP in one of the four P450 genes, while 31% displayed two associated SNPs and 18% three associated SNPs. The occurrence of some associated SNPs is in the same order of magnitude as SNPs in the GBA (beta-glucocerebrosidase) and thus might reflect a genetic predisposition for PD. As all 24 SNPs were located in introns and 3′ untranslated regions, we evaluated the prospective regulatory impact of the surrounding genomic regions by using transcriptome and epigenome data from the Foundational Data Initiative for Parkinson Disease (FOUNDIN-PD). FOUNDIN-PD provides gene expression, open chromatin and DNA methylation data in a cohort of 89 induced pluripotent stem cell (iPSC) lines differentiated to dopaminergic (DA) neurons derived from people in the PPMI study. Indeed, two of the 24 SNPs, one in CYP7B1 (rs118111353) and the other one in CYP27A1 (rs74446825), were localized within a region of open chromatin in differentiated neurons. Interestingly, all iPSC lines with open chromatin in rs118111353 showed the reference allele. As all four P450, CYP46A1, CYP39A1, CYP27A1 and CYP7B1, are expressed in dopaminergic neurons, we discuss further functional studies to connect SNPs in regulatory regions with gene expression levels. Finally, potential possibilities for personalized therapeutic treatment of patients with SNPs in the four investigated P450 are discussed.

BackgroundThe benefit of chronic total occlusion (CTO)-percutaneous coronary intervention (PCI) is controversial because of a lack of high-quality evidence. We aim to evaluate the impact of CTO-PCI on symptoms, quality of life and mortality.MethodsWe conducted a retrospective single center study of patients with CTO-PCI in a tertiary center in Austria. The study outcomes were Canadian Cardiovascular Society (CCS) angina score, quality of life measured by Seattle Angina Questionnaire (SAQ), and death at median follow up for patients with successful vs. failed CTO-PCI.ResultsA total of 300 patients underwent CTO-PCI for coronary artery disease, of which 252 (84%) were technically successful with median follow up of 3.4 years. There were no significant differences in in-hospital or all-cause mortality, major adverse cardiovascular event, or stent-related complications between the groups of failed and successful CTO-PCI. Among patients with successful CTO-PCI there was a significant improvement in CCS score, which was not found for the group with failed CTO-PCI. Successful reopening was associated with significant benefits of the SAQ domains of angina with stressful activity [3.7 ± 0.9 vs. 3.1 ± 0.5, p = 0.004, use of nitrates (4.7 ± 0.5 vs. 3.0 ± 1.0) p = 0.005] and satisfaction from angina relief (4.4 ± 1.1 vs. 3.6 ± 1.4 p

The global antimicrobial resistance crisis has been the driver of several international strategies on antimicrobial stewardship. For their implementation at the field level, the veterinary sector encounters several specific challenges and in particular: (i) a shortage of experts in key disciplines related to antimicrobial stewardship, (ii) a lack of evidence-based antimicrobial treatment guidelines, and (iii) inferior diagnostic tests available compared to human medicine. The present white paper describes how the COST Action ENOVAT (the European Network for Optimization of Veterinary Antimicrobial Treatment, CA18217), comprising 332 persons from 51 countries, worked towards solutions to these challenges. Initially, surveys were conducted to explore the present state in Europe in terms of existing antimicrobial use guidelines and microbiology practices performed. Concurrently, various research activities were launched to optimize diagnostics, including development of epidemiological cut-offs, clinical breakpoints and matrix-assisted laser desorption ionization time of flight mass spectrometry interpretive criteria. Also, guidelines drafting groups working towards evidence-based antimicrobial treatment guidelines for six conditions in food-producing and companion animals were established. The processes and outcomes, also in terms of capacity building, are summarized in this white paper where emphasis is placed on sustainability of the activities. Although several ENOVAT initiatives and spin-off projects will continue beyond the Action, we recommend that a new European veterinary research agenda is launched focusing on research and funding leading to long-term impacts on veterinary antimicrobial use.

The use of near-infrared spectroscopy (NIRS) in sports science has become increasingly important in the past few years (Perrey et al., 2024). One application is to determine thresholds from different NIRS parameters like oxygenated (O2Hb) or deoxygenated (HHb) hemoglobin to distinguish between hard and severe-intensity exercise (Caen et al., 2018). Such applications are frequently validated by comparison to established threshold determination concepts. However, it is not yet known which of the two parameters is more closely related to classical concepts. Therefore, the aim of this project was do analyze which NIRS parameter (oxygenated [O2Hb] or deoxygenated [HHb] hemoglobin) better reflects systemic behavior determined from ventilation (VE). Thirteen physically active participants (4 females, 9 males; mean age: 26.3 ± 4.4 years, height: 176.0 ± 10.3 cm, weight: 71.9 ± 9.3 kg) were included in the study. VE and NIRS data from a major locomotor muscle (vastus lateralis) during a step-incremental single leg cycle ergometer test were recorded. We used a custom MATLAB script to fit piecewise linear continuous functions by regression to estimate NIRS and VE thresholds. We used two distinct segments for NIRS data and three distinct segments for VE data. NIRS thresholds were defined as the point of intersection of the two segments in O2Hb and HHb signals, respectively. The ventilatory threshold was defined as the second increase in VE. We used a resampling strategy to reduce the impact of outliers or peculiar data distributions on threshold estimates. Thresholds from O2Hb and HHb in the active leg and VE were observed at 78.24%, 76.37%, and 84.15% of the maximum power achieved. Both O2Hb (r = 0.85, p < 0.001) and HHb (r = 0.75, p = 0.0051) thresholds were significantly correlated, but mean values were significantly different (p < 0.05) from the respiratory compensation point (RCP) mean value. Correlations between O2Hb and HHb values from the passive leg and the RCP values were in the same range (r = 0.88, p < 0.001 and r = 0.79, p = 0.0023, respectively). The results indicate that, based on the correlations, O2Hb is slightly closer related to the second ventilatory threshold compared to HHb. The present study shows that thresholds from both NIRS parameters are closely related to the second ventilatory threshold which indicates a physiological relationship. However, thresholds cannot be used interchangeably as NIRS parameters derived from the working muscle appear earlier than systemic thresholds that demonstrate a delay in kinetics between the working muscle and the system. References Caen, K., Vermeire, K., Bourgois, J. G., & Boone, J. (2018). Exercise thresholds on trial: Are they really equivalent? Medicine & Science in Sports & Exercise, 50(6), 1277-1284. https://doi.org/10.1249/mss.0000000000001547 Perrey, S., Quaresima, V., & Ferrari, M. (2024). Muscle oximetry in sports science: An updated systematic review. Sports Medicine, 54, 975-996. https://doi.org/10.1007/s40279-023-01987-x

Die Welt der Wissenschaft befindet sich seit einiger Zeit im Umbruch. Waren bisher wissenschaftliche Arbeiten und Forschungsergebnisse entweder nur eingeschränkt oder in einem Fachjournal zu veröffentlichen und der Zugang dazu in weiterer Folge einer kleinen Community, vielleicht sogar zu (hohen) Kosten möglich, so steht nun die Öffnung wissenschaftlicher Arbeiten am politischen Programm. Diese Entwicklung hat – wie immer – zwei Seiten, sowohl für Studierende und Forschende, für Universitäten und Fachhochschulen, als auch für die Gesellschaft insgesamt. In diesem Artikel werden zuerst einige Aspekte des Urheberrechts und der Veröffentlichungspflicht dargestellt, danach wird auf die Themen Open Access (OA) im Allgemeinen sowie der mögliche Einsatz von Creative Commons (CC)-Lizenzen eingegangen. Ein besonderes Augenmerk bei den folgenden Ausführungen wird auf die Gegebenheiten der Fachhochschule JOANNEUM (FHJ) gelegt.

Abstract Background Existing knowledge on healthcare use and costs in the last months of life is often limited to one patient group (i.e., cancer patients) and one level of healthcare (i.e., secondary care). Consequently, decision-makers lack knowledge in order to make informed decisions about the allocation of healthcare resources for all patients. Our aim is to elaborate the understanding of resource use and costs in the last six months of life by describing healthcare use and costs for all causes of death and by all levels of formal care. Method Using five national registers, we gained access to patient-level data for all individuals who died in Norway between 2009 and 2013. We described healthcare use and costs for all levels of formal care—namely primary, secondary, and home- and community-based care —in the last six months of life, both in total and differentiated across three time periods (6-4 months, 3-2 months, and 1-month before death). Our analysis covers all causes of death categorized in ten ICD-10 categories. Results During their last six months of life, individuals used an average of healthcare resources equivalent to €46,000, ranging from €32,000 (Injuries) to €64,000 (Diseases of the nervous system and sense organs). In terms of care level, 63% of healthcare resources were used in home- and community-based care (i.e., in-home nursing, practical assistance, or nursing home care), 35% in secondary care (mostly hospital care), and 2% in primary care (i.e., general practitioners). The amount and level of care varied by cause of death and by time to death. The proportion of home- and community-based care which individuals received during their last six months of life varied from 38% for cancer patients to 92% for individuals dying with mental diseases. The shorter the time to death, the more resources were needed: nearly 40% of all end-of-life healthcare costs were expended in the last month of life across all causes of death. The composition of care also differed depending on age. Individuals aged 80 years and older used more home- and community-based care (77%) than individuals dying at younger ages (40%) and less secondary care (old: 21% versus young: 57%). Conclusions Our analysis provides valuable evidence on how much healthcare individuals receive in their last six months of life and the associated costs, broken down by level of care and cause of death. Healthcare use and costs varied considerably by cause of death, but were generally higher the closer a person was to death. Our findings enable decision-makers to make more informed resource-allocation decisions and healthcare planners to better anticipate future healthcare needs.

Abstract CSMD1 (Cub and Sushi Multiple Domains 1) is a well-recognized regulator of the complement cascade, an important component of the innate immune response. CSMD1 is highly expressed in the central nervous system (CNS) where emergent functions of the complement pathway modulate neural development and synaptic activity. While a genetic risk factor for neuropsychiatric disorders, the role of CSMD1 in neurodevelopmental disorders is unclear. Through international variant sharing, we identified inherited biallelic CSMD1 variants in eight individuals from six families of diverse ancestry who present with global developmental delay, intellectual disability, microcephaly, and polymicrogyria. We modeled CSMD1 loss-of-function (LOF) pathogenesis in early-stage forebrain organoids differentiated from CSMD1 knockout human embryonic stem cells (hESCs). We show that CSMD1 is necessary for neuroepithelial cytoarchitecture and synchronous differentiation. In summary, we identified a critical role for CSMD1 in brain development and biallelic CSMD1 variants as the molecular basis of a previously undefined neurodevelopmental disorder.

Abstract Introduction Cluster headache is a severe and debilitating neurological condition characterized by intense, excruciating pain with a significant impact on patients' wellbeing. Although different treatment options are available, many patients continue to experience inadequate relief. Therefore, experimental strategies are increasingly studied. One of the more promising approaches is the use of ketamine. We present the currently available evidence and our own data. Methods In this mixed-methods paper, we first summarize the available evidence of ketamine for treatment of cluster headache based on a systematic review of literature in MEDLINE, EMBASE and the Cochrane library of systematic reviews. As the level of evidence is quite limited, we report our own cohort study with ten patients treated with ketamine infusions for cluster headache. They were followed up to investigate the patients’ experience of treatment success and quality of life. Results The search and review of literature identified four reports with a total of 68 patients. All were uncontrolled case series. The current literature suggests that ketamine might decrease cluster headache. However, as the applied regimes and reported outcomes are highly heterogeneous, further analysis was futile. Our own data show high patient satisfaction with ketamine treatment. Conclusion Despite the limited evidence, ketamine might be considered a potential therapeutic approach for cluster headache. Therefore, further research including randomized controlled trials should be encouraged.

Abstract Background With approximately 500 people affected in Austria, epidermolysis bullosa (EB) is a rare genetic skin disease reducing the quality of life of those affected and their relatives. The intensive efforts of the patient organisation DEBRA Austria during the last decades have led to a unique situation of those affected and their relatives, with increased support and broader knowledge about the disease in the general population. The aim of the study is to evaluate the current situation of patients and their relatives living in Austria, with a focus on burdens and helpful practices. Results The mixed-methods study consisted of two parts: a qualitative interview study to identify psychosocial aspects of EB in those affected and their relatives, and a subsequent online survey to further assess those aspects in a larger sample, resulting in a total of n=78 Austrian participants. The impact of EB on the quality of life of EB patients and their relatives in Austria is related to the current health status, psychological burden, mobility, visibility, financial situation as well as job prospects. Personal and social resources and external support have a significant influence on the individual situation. Conclusions The outcome is mapped to concrete implications regarding targeted support for EB patients and their relatives on an individual level and their needs in regard to the Austrian health care system.

Abstract We present the calculation of the contribtuions from the chromomagnetic and four-top-quark-operators within Standard Model Effective Field Theory (SMEFT) to Higgs boson pair production in gluon fusion, combined with QCD corrections that are at NLO with full m t -dependence for the leading operators. We study the effects of these operators on the total cross section and the invariant mass distribution of the Higgs-boson pair, at $$\sqrt{s}$$ = 13.6 TeV. These subleading operators are implemented in the generator ggHH_SMEFT, in the same Powheg-Box-V2 framework as the leading operators, such that their effects can be easily studied in a unified setup.

Abstract We present numerical results for the two-loop virtual amplitude entering the NNLO corrections to Higgs boson production in association with a top quark pair at the LHC, focusing, as a proof of concept of our method, on the part of the quark-initiated channel containing loops of massless or massive quarks. Results for the UV renormalised and IR subtracted two-loop amplitude for each colour structure are given at selected phase-space points and visualised in terms of surfaces as a function of two-dimensional slices of the full phase space.

Abstract Essential tremor (ET) is a prevalent neurological disorder with a largely unknown underlying biology. In this genome-wide association study meta-analysis, comprising 16,480 ET cases and 1,936,173 controls from seven datasets, we identify 12 sequence variants at 11 loci. Evaluating mRNA expression, splicing, plasma protein levels, and coding effects, we highlight seven putative causal genes at these loci, including CA3 and CPLX1. CA3 encodes Carbonic Anhydrase III and carbonic anhydrase inhibitors have been shown to decrease tremors. CPLX1, encoding Complexin-1, regulates neurotransmitter release. Through gene-set enrichment analysis, we identify a significant association with specific cell types, including dopaminergic and GABAergic neurons, as well as biological processes like Rho GTPase signaling. Genetic correlation analyses reveals a positive association between ET and Parkinson’s disease, depression, and anxiety-related phenotypes. This research uncovers risk loci, enhancing our knowledge of the complex genetics of this common but poorly understood disorder, and highlights CA3 and CPLX1 as potential therapeutic targets.

Abstract Background Stress impacts healthy behaviours and may influence life and health-related quality of life (HRQOL). A stressful event occurred when the COVID-19 pandemic hit in March 2020. The present study aims to explore possible gender differences in stress, psychosocial factors (self-efficacy, self-esteem, loneliness), pain, HL, and HRQOL in parents of adolescents one year into the COVID-19 pandemic, and to explore possible associations between gender, demographic and psychosocial factors, pain, HL, and HRQOL. Methods Parents of adolescents aged 16–17 took part in the study from January to February 2021, when the COVID-19 pandemic was ongoing. Data on socio-demographics, stress, self-efficacy, self-esteem, pain, HL, loneliness, and HRQOL were collected. HRQOL was assessed using RAND-36. Results Among the 320 parents from the general population, the mean age was 47.6 (standard deviation (SD) = 4.6) years, 81% were mothers, 79% were married or cohabiting, 81% had a university degree, and the majority worked full time (78%) or part time (13%). The average pain score was low, 0.48 (95% CI [0.43–0.54]). However, 50% of the parents reported persistent pain and more mothers reported persistent pain compared to fathers (53% vs. 37%). The parents’ mean (SD) score for RAND-36 was 52.1 (95% CI [51.2–53.0]) for the physical component summary (PCS) score and 51.0 (95% CI [50.0–52.1]) for the mental component summary (MCS) score. Mothers reported significantly lower scores for all the eight RAND-36 domains and the PCS and MCS scores. Adjusting for gender, age, living condition, education, pain, HL, self-efficacy and loneliness, we revealed no associations between stress and RAND-36-PCS. University education of four years or more was positively associated (B = 3.29, 95% CI: [0.78–5.80]) with RAND-36-PCS, while persistent pain was negatively associated (B = -7.13, CI: [-9.20– -5.06]). We identified a strong negative association between RAND-36-MCS and stress (B = -43.11, CI: [-48.83– -37.38]) and a positive association with older age (B = 0.21, CI: [ 0.04, 0.39)]. Conclusion One year into the COVID-19 pandemic, we identified a strong negative association between stress and mental HRQOL, while pain was strongly negatively associated with physical HRQOL.

Abstract Background Human pluripotent stem cells (hPSCs) have an enormous therapeutic potential, but large quantities of cells will need to be supplied by reliable, economically viable production processes. The suspension culture (three-dimensional; 3D) of hPSCs in stirred tank bioreactors (STBRs) has enormous potential for fuelling these cell demands. In this study, the efficient long-term matrix-free suspension culture of hPSC aggregates is shown. Methods and results STBR-controlled, chemical aggregate dissociation and optimized passage duration of 3 or 4 days promotes exponential hPSC proliferation, process efficiency and upscaling by a seed train approach. Intermediate high-density cryopreservation of suspension-derived hPSCs followed by direct STBR inoculation enabled complete omission of matrix-dependent 2D (two-dimensional) culture. Optimized 3D cultivation over 8 passages (32 days) cumulatively yielded ≈4.7 × 1015 cells, while maintaining hPSCs’ pluripotency, differentiation potential and karyotype stability. Gene expression profiling reveals novel insights into the adaption of hPSCs to continuous 3D culture compared to conventional 2D controls. Conclusions Together, an entirely matrix-free, highly efficient, flexible and automation-friendly hPSC expansion strategy is demonstrated, facilitating the development of good manufacturing practice-compliant closed-system manufacturing in large scale.

Abstract Background The use of open-ended questions supplementing static questionnaires with closed questions may facilitate the recognition of symptoms and toxicities. The open-ended ‘Write In three Symptoms/Problems (WISP)’ instrument permits patients to report additional symptoms/problems not covered by selected EORTC questionnaires. We evaluated the acceptability and usefulness of WISP with cancer patients receiving active and palliative care/treatment in Austria, Chile, France, Jordan, the Netherlands, Norway, Spain and the United Kingdom. Methods We conducted a literature search on validated instruments for cancer patients including open-ended questions and analyzing their responses. WISP was translated into eight languages and pilot tested. WISP translations were pre-tested together with EORTC QLQ-C30, QLQ-C15-PAL and relevant modules, followed by patient interviews to evaluate their understanding about WISP. Proportions were used to summarize patient responses obtained from interviews and WISP. Results From the seven instruments identified in the literature, only the free text collected from the PRO-CTAE has been analyzed previously. In our study, 161 cancer patients participated in the pre-testing and interviews (50% in active treatment). Qualitative interviews showed high acceptability of WISP. Among the 295 symptoms/problems reported using WISP, skin problems, sore mouth and bleeding were more prevalent in patients in active treatment, whereas numbness/tingling, dry mouth and existential problems were more prevalent in patients in palliative care/treatment. Conclusions The EORTC WISP instrument was found to be acceptable and useful for symptom assessment in cancer patients. WISP improves the identification of symptoms/problems not assessed by cancer-generic questionnaires and therefore, we recommend its use alongside the EORTC questionnaires.

Abstract Pulmonary metastasectomy (PM) is consensually performed in a parenchyma-sparing manner to preserve functionally healthy lung tissue. However, this may increase the risk of local recurrence at the surgical margin. Laser assisted pulmonary metastasectomy (LPM) is a relatively recent innovation that is especially useful to resect multiple metastatic pulmonary nodules. In this study we investigated the rate of local recurrence after LPM and evaluated the influence of various clinical and pathological factors on local recurrence. Retrospectively, a total of 280 metastatic nodules with different histopathological entities were studied LPM from 2010 till 2018. All nodules were resected via diode-pumped neodymium: yttrium–aluminum-garnet (Nd:YAG) 1,318 nm laser maintaining a safety margin of 5 mm. Patients included were observed on average for 44 ± 17 months postoperatively. Local recurrence at the surgical margin following LPM was found in 9 nodules out of 280 nodules (3.21%). Local recurrence at the surgical margin occurred after 20 ± 8.5 months post operation. Incomplete resection (p =

Abstract The Berlin Fat Mouse Inbred line (BFMI) is a model for obesity and metabolic syndrome. The sublines BFMI861-S1 and BFMI861-S2 differ in weight despite high genetic similarity and a shared obesity-related locus. This study focused on identifying additional body weight quantitative trait loci (QTLs) by analyzing weekly weight measurements in a male population of the advanced intercross line BFMI861-S1 x BFMI861-S2. QTL analysis, utilizing 200 selectively genotyped mice (GigaMUGA) and 197 males genotyped for top SNPs, revealed a genome-wide significant QTL on Chr 15 (68.46 to 81.40 Mb) for body weight between weeks 9 to 20. Notably, this QTL disappeared (weeks 21 to 23) and reappeared (weeks 24 and 25) coinciding with a diet change. Additionally, a significant body weight QTL on Chr 16 (3.89 to 22.79 Mb) was identified from weeks 6 to 25. Candidate genes, including Gpt, Cbx6, Apol6, Apol8, Sun2 (Chr 15) and Trap1, Rrn3, Mapk1 (Chr 16), were prioritized. This study unveiled two additional body weight QTLs, one of which is novel and responsive to diet changes. These findings illuminate genomic regions influencing weight in BFMI and emphasize the utility of time series data in uncovering novel genetic factors.

Abstract Background The geographic distribution and host-parasite interaction networks of Sarcocystis spp. in small mammals in eastern Asia remain incompletely known. Methods Experimental infections, morphological and molecular characterizations were used for discrimination of a new Sarcocystis species isolated from colubrid snakes and small mammals collected in Thailand, Borneo and China. Results We identified a new species, Sarcocystis muricoelognathis sp. nov., that features a relatively wide geographic distribution and infects both commensal and forest-inhabiting intermediate hosts. Sarcocystis sporocysts collected from rat snakes (Coelognathus radiatus, C. flavolineatus) in Thailand induced development of sarcocysts in experimental SD rats showing a type 10a cyst wall ultrastructure that was identical with those found in Rattus norvegicus from China and the forest rat Maxomys whiteheadi in Borneo. Its cystozoites had equal sizes in all intermediate hosts and locations, while sporocysts and cystozoites were distinct from other Sarcocystis species. Partial 28S rRNA sequences of S. muricoelognathis from M. whiteheadi were largely identical to those from R. norvegicus in China but distinct from newly sequenced Sarcocystis zuoi. The phylogeny of the nuclear 18S rRNA gene placed S. muricoelognathis within the so-called S. zuoi complex, including Sarcocystis attenuati, S. kani, S. scandentiborneensis and S. zuoi, while the latter clustered with the new species. However, the phylogeny of the ITS1-region confirmed the distinction between S. muricoelognathis and S. zuoi. Moreover, all three gene trees suggested that an isolate previously addressed as S. zuoi from Thailand (KU341120) is conspecific with S. muricoelognathis. Partial mitochondrial cox1 sequences of S. muricoelognathis were almost identical with those from other members of the group suggesting a shared, recent ancestry. Additionally, we isolated two partial 28S rRNA Sarcocystis sequences from Low’s squirrel Sundasciurus lowii that clustered with those of S. scandentiborneensis from treeshews. Conclusions Our results provide strong evidence of broad geographic distributions of rodent-associated Sarcocystis and host shifts between commensal and forest small mammal species, even if the known host associations remain likely only snapshots of the true associations. Graphical Abstract

The global antimicrobial resistance crisis has been the driver of several international strategies on antimicrobial stewardship. For their implementation on field level, the veterinary sector encounters several specific challenges and in particular: (i) a shortage of experts in key disciplines related to antimicrobial stewardship, (ii) a lack of evidence-based antimicrobial treatment guidelines, and (iii) inferior diagnostic tests available compared to human medicine. The present white paper describes how the COST Action ENOVAT (the European Network for Optimization of Veterinary Antimicrobial Treatment, CA18217), comprising 332 persons from 51 countries, worked towards solutions to these challenges. Initially, surveys were conducted to explore the present state in Europe in terms of existing antimicrobial use guidelines and microbiology practices performed. Concurrently, various research activities were launched to optimize diagnostics, including development of epidemiological cut-offs, clinical breakpoints and matrix-assisted laser desorption ionization time of flight mass spectrometry interpretive criteria. Also, guidelines drafting groups working towards evidence-based antimicrobial treatment guidelines for six conditions in food-producing and companion animals were established. The processes and outcomes, also in terms of capacity building, are summarized in this white paper where emphasis is placed on sustainability of the activities. Although several ENOVAT initiatives and spin-off projects will continue beyond the Action, we recommend that a new European veterinary research agenda is launched focusing on research and funding leading to long-term impacts on veterinary antimicrobial use.

Abstract Fresh coastal groundwater is a valuable water resource of global significance, but its quality is threatened by saltwater intrusion. Excessive groundwater abstraction, sea‐level rise (SLR), land subsidence and other climate‐related factors are expected to accelerate this process in the future. The objective of this study is to (a) quantify the impact of projected climate change and (b) explore the role of individual hydrogeological boundaries on groundwater salinization of low‐lying coastal groundwater systems until 2100 CE. We employ numerical density‐dependent groundwater flow and salt transport modeling for this purpose, using Northwestern Germany as a case. Separate model variants are constructed and forced with climate data, that is, projected SLR and groundwater recharge, as well as likely ranges of other hydrogeological boundaries, including land subsidence, abstraction rates and drain levels. We find that autonomous salinization in the marsh areas, resulting from non‐equilibrium of the present‐day groundwater salinity distribution with current boundary conditions, is responsible for >50% of the salinization increase until 2100 CE. Sea‐level rise, land subsidence and drain levels are the other major factors controlling salinization. We further show that salinization of the water resources is a potential threat to coastal water users, including water suppliers and the agrarian sector, as well as coastal ecosystems. Regional‐scale uplifting of drain levels is identified as an efficient measure to mitigate salinization of deep and shallow groundwater in the future. The presented modeling approach highlights the consequences of climate change and anthropogenic impacts for coastal salinization, supporting the timely development of mitigation strategies.

Background: Bisphenol A (BPA; or 4,4′-isopropylidenediphenol) is an endocrine disrupting chemical. It was widely used in a variety of plastic-based manufactured products for several years. The European Food Safety Authority (EFSA) recently reduced the Tolerable Daily Intake (TDI) for BPA by 20,000 times due to concerns about immune-toxicity. Objective: We used human biomonitoring (HBM) data to investigate the general level of BPA exposure from 2007 to 2014 of European women aged 18–73 years (n = 4,226) and its determinants. Methods: Fifteen studies from 12 countries (Austria, Belgium, Denmark, France, Germany, Greece, Israel, Luxembourg, Slovenia, Spain, Sweden, and the United Kingdom) were included in the BPA Study protocol developed within the European Joint Programme HBM4EU. Seventy variables related to the BPA exposure were collected through a rigorous post-harmonization process. Linear mixed regression models were used to investigate the determinants of total urine BPA in the combined population. Results: Total BPA was quantified in 85–100 % of women in 14 out of 15 contributing studies. Only the Austrian PBAT study (Western Europe), which had a limit of quantification 2.5 to 25-fold higher than the other studies (LOQ=2.5 µg/L), found total BPA in less than 5 % of the urine samples analyzed. The geometric mean (GM) of total urine BPA ranged from 0.77 to 2.47 µg/L among the contributing studies. The lowest GM of total BPA was observed in France (Western Europe) from the ELFE subset (GM=0.77 µg/L (0.98 µg/g creatinine), n = 1741), and the highest levels were found in Belgium (Western Europe) and Greece (Southern Europe), from DEMOCOPHES (GM=2.47 µg/L (2.26 µg/g creatinine), n = 129) and HELIX-RHEA (GM=2.47 µg/L (2.44 µg/g creatinine), n = 194) subsets, respectively. One hundred percent of women in 14 out of 15 data collections in this study exceeded the health-based human biomonitoring guidance value for the general population (HBM-GVGenPop) of 0.0115 µg total BPA/L urine derived from the updated EFSA’s BPA TDI. Variables related to the measurement of total urine BPA and those related to the main socio-demographic characteristics (age, height, weight, education, smoking status) were collected in almost all studies, while several variables related to BPA exposure factors were not gathered in most of the original studies (consumption of beverages contained in plastic bottles, consumption of canned food or beverages, consumption of food in contact with plastic packaging, use of plastic film or plastic containers for food, having a plastic floor covering in the house, use of thermal paper…). No clear determinants of total urine BPA concentrations among European women were found. A broader range of data planned for collection in the original questionnaires of the contributing studies would have resulted in a more thorough investigation of the determinants of BPA exposure in European women. Conclusion: This study highlights the urgent need for action to further reduce exposure to BPA to protect the population, as is already the case in the European Union. The study also underscores the importance of pre-harmonizing HBM design and data for producing comparable data and interpretable results at a European-wide level, and to increase HBM uptake by regulatory agencies.

Am 28. September 2023 fand in der Aula am Campus der Universität Wien die „Tagung wissenschaftliche Abschlussarbeiten und Hochschulschriften-Repositorien“, kurz tawiab2023, statt. Diese stand im Zeichen der Schwerpunkte Urheberrecht, Plagiatsprüfung, Ablieferung von Dissertationen an die Österreichische Nationalbibliothek, Barrierefreiheit und Vergabe von DOIs.