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Summary: Antimicrobial resistance poses a severe threat to human health and Pseudomonas aeruginosa stands out among the pathogens responsible for this emergency. The SOS response to DNA damage is crucial in bacterial evolution, influencing resistance development and adaptability in challenging environments, especially under antibiotic exposure. Recombinase A (RecA) and the transcriptional repressor LexA are the key players that orchestrate this process, determining either the silencing or the active transcription of the genes under their control. By integrating state-of-the-art structural approaches with in vitro binding and functional assays, we elucidated the molecular events activating the SOS response in P. aeruginosa, focusing on the RecA-LexA interaction. Our findings identify the conserved determinants and strength of the interactions that allow RecA to trigger LexA autocleavage and inactivation. These results provide the groundwork for designing novel antimicrobial strategies and exploring the potential translation of Escherichia coli-derived approaches, to address the implications of P. aeruginosa infections.

PurposeThe Multicentre Acute ischemic stroke imaGIng and Clinical data (MAGIC) repository is a collaboration established in 2024 by seven stroke centres in Europe. MAGIC consolidates clinical and radiological data from acute ischemic stroke (AIS) patients who underwent endovascular therapy, intravenous thrombolysis, a combination of both, or conservative management.ParticipantsAll centres ensure accuracy and completeness of the data. Only patients who did not refuse use of their routine data collected during or after their hospital stay are included in the repository. Approvals or waivers are obtained from the responsible ethics committees before data exchange. A formal data transfer agreement (DTA) is signed by all contributing centres. The centres then share their data, and files are stored centrally on a safe server at the University Hospital Zurich. There, patient identifiers are removed and images are algorithmically de-faced. De-identified structured clinical data are connected to the imaging data by a new identifier. Data are made available to participating centres which have entered into a DTA for stroke research projects.Repository setupInitially, MAGIC is set to comprise initial and first follow-up imaging of 2,500 AIS patients. Clinical data consist of a comprehensive set of patient characteristics and routine prehospital metrics, treatment and laboratory variables.OutlookOur repository will support research by leveraging the entire range of routinely collected imaging and clinical data. This dataset reflects the current state of practice in stroke patient evaluation and management and will enable researchers to retrospectively study clinically relevant questions outside the scope of randomized controlled clinical trials. New centres are invited to join MAGIC if they meet the requirements outlined here. We aim to reach approximately 10,000 cases by 2026.

Silicate dust is found in a wide range of astrophysical environments. Nucleation and growth of silicate dust grains in circumstellar environments likely involves species with diameters ranging from

BackgroundCerebral venous thrombosis (CVT) is a rare but serious subtype of stroke. Several studies have reported an increased incidence of CVT after either COVID-19 (CoV19) infection or vaccination; however, data on clinical characteristics, the radiological profiles, and the outcomes of these patients with CVT as the only severe symptom of a CoV19 infection or vaccination compared to patients with non-CoV19-related CVT are still scarce.MethodsWe performed a retrospective monocentric study over 10 years (January 2013–December 2022) that included consecutive patients with a confirmed diagnosis of CVT based on imaging of the cerebral venous system. Patients were categorized as CoV19 CVT (either due to infection or post-vaccination) or non-CoV19 CVT and compared regarding demographics, risk factors, clinical characteristics, and imaging findings as well as outcome (at discharge, at 6 months, and last follow-up). Furthermore, sub-analyses were performed to compare CoV19-infection-related-CVT and CoV19-vaccination-related-CVT patients.ResultsOverall, 122 patients with suspected CVT were identified. After excluding patients with missing data (n = 20) or missing imaging of the cerebral venous system (n = 31), 71 patients with confirmed CVT remained for the final analyses. Of those, 11 patients had CoV19 CVT (infection n = 3, vaccination n = 8), and 60 patients had non-CoV19-CVT. There were no differences regarding median age (CoV19: 40 [IQR: 22–70] vs. non-CoV19: 41 [IQR:27–64]) or percentage of female sex among both groups. A lower rate of CVT risk factors was observed in the CoV19 group but without significant differences. No patient with CoV19 CVT displayed impaired consciousness on presentation, and only 30% had focal neurological deficits compared to 51.7% in the control group. The rate of CVT-related intracranial hemorrhage and venous infarcts were 27.3% and 9.1%, respectively, in the CoV19 group and 30% and 16.7%, respectively, in the non-CoV19 group. The mortality rate at discharge was 9.1% in the CoV19-CVT group vs. 3.3% in the non-CoV19-CVT group, without differences in functional outcomes during the follow-up period. Sub-analyses comparing CoV19-infection-related CVT vs. CoV19-vaccination-related CVT patients revealed no significant differences in clinical, imaging, or treatment characteristics.ConclusionIn this monocentric study, there was no signal for a worse severity of CoV19 CVT compared to non-CoV19 CVT regarding clinical characteristics, imaging profile, or outcomes in patients with CVT only. Larger observational data with sophisticated workups of CVT patients are needed to confirm our results.

Abstract A central characteristic of Bayesian statistics is the ability to consistently incorporate prior knowledge into various modeling processes. In this paper, we focus on translating domain expert knowledge into corresponding prior distributions over model parameters, a process known as prior elicitation. Expert knowledge can manifest itself in diverse formats, including information about raw data, summary statistics, or model parameters. A major challenge for existing elicitation methods is how to effectively utilize all of these different formats in order to formulate prior distributions that align with the expert’s expectations, regardless of the model structure. To address these challenges, we develop a simulation-based elicitation method that can learn the hyperparameters of potentially any parametric prior distribution from a wide spectrum of expert knowledge using stochastic gradient descent. We validate the effectiveness and robustness of our elicitation method in four representative simulation studies covering linear models, generalized linear models, and hierarchical models. Our results support the claim that our method is largely independent of the underlying model structure and adaptable to various elicitation techniques, including quantile-based, moment-based, and histogram-based methods.

Most of Switzerland is inhabited by the nominotypical subspecies of the barred grass snake (Natrix helvetica helvetica), which is characterized by mitochondrial DNA lineage E. Only in the northeast of the country, the common grass snake (N. natrix) occurs and hybridizes with N. h. helvetica in a narrow contact zone. However, we discovered that in southern and western Switzerland barred grass snakes representing another mtDNA lineage (lineage C) are widely distributed. Lineage C is typical for Alpine populations of the southern subspecies N. h. sicula. Our microsatellite analyses of the Swiss samples revealed differences between the two subspecies and also a substructure with two clusters in each subspecies. Furthermore, we discovered a contact and hybrid zone of N. h. helvetica and N. h. sicula along the northern shore of Lake Geneva and also confirm that interbreeding with alien common grass snakes (N. n. moreotica, mtDNA lineage 7) occurs there. This finding is of concern for nature conservation and measures should be taken to prevent further genetic pollution. Using morphometrics, we found no differences between the two subspecies of N. helvetica, while N. natrix was slightly distinct from N. helvetica.

The decreasing well-being among doctoral candidates, coupled with a high prevalence of distress problems, is a topic of increasing concern in the field of higher education and research policy. The present study aimed to replicate, implement, and evaluate the effectiveness of The Third Half, a multi-component psychoeducational program in doctoral students. To address the limitations of the pilot study, we conducted a non-randomized controlled study using a repeated measures pre-post design with a total of 97 participants (Mage = 32.5; SD = 8.23), of whom 26 participated in the experimental group. Results showed that Third Half program participants reported significant decreases in indicators of negative affect (F = 4.01; p = .04) and anxiety (F = 4.95; p = .02) compared to the general control group; in the matched sample analysis (n = 20) significant decreases were found in indicators of negative affect (F = 4.72; p = .03), anxiety (F = 4.09; p

Abstract Microglia are critically involved in post‐stroke inflammation affecting neurological outcomes. Lipid droplet (LD) accumulation in microglia results in a dysfunctional and pro‐inflammatory state in the aged brain and worsens the outcome of neuroinflammatory and neurodegenerative diseases. However, the role of LD‐rich microglia (LDRM) under stroke conditions is unknown. Using in vitro and in vivo stroke models, herein accumulation patterns of microglial LD and their corresponding microglial inflammatory signaling cascades are studied. Interactions between temporal and spatial dynamics of lipid profiles and microglial phenotypes in different post‐stroke brain regions are found. Hence, microglia display enhanced levels of LD accumulation and elevated perilipin 2 (PLIN2) expression patterns when exposed to hypoxia or stroke. Such LDRM exhibit high levels of TNF‐α, IL‐6, and IL‐1β as well as a pro‐inflammatory phenotype and differentially expressed lipid metabolism‐related genes. These post‐ischemic alterations result in distinct lipid profiles with spatial and temporal dynamics, especially with regard to cholesteryl ester and triacylglycerol levels, further exacerbating post‐ischemic inflammation. The present study sheds new light on the dynamic changes of brain lipid profiles and aggregation patterns of LD in microglia exposed to ischemia, demonstrating a mutual mechanism between microglial phenotype and function, which contributes to progression of brain injury.

Abstract Using ferric chloride (FeCl3) to induce experimental superior sagittal sinus (SSS) thrombosis might interfere with magnetic resonance imaging (MRI)-assisted visualization and evaluation of the thrombus, the brain parenchyma, and the quality of the occlusion. The aim of this study was to investigate whether aluminum chloride (AlCl3)-induced thrombosis of the SSS has comparable properties to those of FeCl3 without causing artifacts in MRI. SSS thrombosis was induced in 14 male Wistar rats by exposure of the SSS and subsequent topical application of a filter paper strip soaked in AlCl3 (n = 7) or FeCl3 (n = 7) over a period of 15 min. The animals with AlCl3-induced SSS thrombosis showed a constant and complete occlusion with in histological analysis large thrombi. Blood flow measurements indicated a significant reduction on the first and seventh postoperative day compared to preoperative measurements. MRI enabled visualization and subsequent evaluation of the thrombus and the surrounding parenchyma. In comparison, FeCl3-induced SSS thrombosis could not be evaluated by MRI due to artifacts caused by the paramagnetic properties and increased susceptibility of FeCl3. The occluded sinus and the surrounding area appeared hypointense. The quality of SSS occlusion by AlCl3 was comparable to that of FeCl3. AlCl3 therefore represents a significant alternative substance in experimental SSS thrombosis ideally suited for studies using MRI.

Abstract Background Retinal artery occlusions lead to sudden, painless vision loss, affecting millions globally. Despite their significance, treatment strategies remain unestablished, contrasting with acute ischemic stroke (AIS), where IVT has proven efficacy. Similar to AIS, retinal artery occlusions demand urgent evaluation and treatment, reflecting the principle "time is retina". Even for patients with transient monocular vision loss, also known as amaurosis fugax (AF), pertinent guidelines meanwhile recommend immediate emergency assessment in a specialized facility. However, data on the clinical benefit and comparability with persistent occlusions are missing. This study aimed to compare the results of a comprehensive stroke-workup among patients with persistent retinal artery occlusions (RAO), including both central retinal (CRAO) and branch retinal artery occlusion (BRAO) and those with AF. Methods Conducted at the University Hospital Giessen, Germany, this exploratory cross-sectional study enrolled patients with transient or permanent unilateral vision loss of non-arteritic origin. The primary outcome were differences between the two groups RAO and AF with regard to cardiovascular risk profiles and comorbidities, vascular and pharmacological interventions and clinical neurological and ophthalmological outcomes. Secondary outcome was a sub-group analysis of patients receiving IVT. Results Out of 166 patients assessed, 76 with RAO and 40 with AF met the inclusion criteria. Both groups exhibited comparable age, gender distribution, and cardiovascular risk profiles. Notably, RAO patients did not show significantly more severe vascular comorbidities than AF patients. However, AF patients received vascular interventions more frequently. Pharmacological intervention rates were similar across groups. RAO patients had slightly worse neurological outcomes, and IVT did not yield favorable ophthalmological outcomes within any observed patients. Conclusion The study found similar vascular burden and risk factors in patients with RAO and AF, with implications for clinical workflows. IVT for RAO may only be effective in very early treatment windows. This emphasizes the need for public awareness and collaborative protocols between ophthalmologists and neurologists to improve outcomes.

Background: Postoperative cognitive decline (POCD) after cardiosurgical interventions are well described through objective psychometric tests. However, a patient’s subjective perception is essential to clinical assessment and quality of life. This study systematically evaluated patient-reported POCD between subjects undergoing coronary artery bypass grafting and heart valve replacement. Methods: This study was a multicentre, prospective questionnaire survey conducted at the cardiac surgery departments at the Kerckhoff Clinic in Bad Nauheim and the University Hospital in Giessen, Germany. We included patients undergoing elective coronary artery bypass grafting (CABG), aortic valve replacement (AVR), mitral valve replacement or reconstruction (MVR), and combined surgery (CABG + valve replacement [VR]) with extracorporeal circulation. The Hospital Anxiety and Depression Scale, the Cognitive Failures Questionnaire (CFQ) for Self-assessment (CFQ-S), and the external assessment (CFQ-foreign [F]) were completed preoperatively, as well as at 3 and 12 months postoperatively. Results: A total of 491 patients were available for analyses (CABG = 182, AVR = 134, MVR = 93, CABG + VR = 82). POCD and postoperative depression increase (PODI) were observed for each surgical procedure. (At the 3-month follow-up: CFQ-S [CABG = 7.1%, AVR = 3.7%, MVR = 9.7%, CABG + VR = 9.8%]; CFQ-F [CABG = 9.9%, AVR = 9.7%, MVR = 9.7%, CABG + VR = 15.9%]; PODI [CABG = 7.7%, AVR = 9.7%, MVR = 6.5%, CABG + VR = 8.5%]. At the 12-month follow-up: CFQ-S [CABG = 6.6%, AVR = 7.5%, MVR = 15.1%, CABG + VR = 7.3%]; CFQ-F [CABG = 7.1%, AVR = 14.9%, MVR = 10.8%, CABG + VR = 9.8%]; PODI [CABG = 10.4%, AVR = 11.2%, MVR = 6.5%, CABG + VR = 4.9%]). No significant between-group effects were observed for the CFQ-S, CFQ-F, or the Hospital Anxiety and Depression Scale. Conclusions: For clinicians, paying attention to patients' self-reported experiences of reduced cognitive function and symptoms of depression following cardiac surgery is important. Such reporting is an indication that interventions such as cognitive training or psychotherapy should be considered. Résumé: Contexte: Le déclin cognitif postopératoire (DCPO) à la suite d’interventions de chirurgie cardiaque est bien décrit par des évaluations psychométriques objectives. Cependant, la perception subjective du patient est essentielle à l’évaluation clinique et à la qualité de vie. Cette étude visait à évaluer de façon systématique le DCPO déclaré par le patient chez des sujets ayant subi un pontage aortocoronarien ou une chirurgie valvulaire. Méthodologie: Cette étude prospective multicentrique par questionnaire a été menée aux services de chirurgie cardiaque de la clinique Kerckhoff de Bad Nauheim et de l’hôpital universitaire de Giessen, en Allemagne. Elle a porté sur des patients ayant subi un pontage aortocoronarien (PAC), un remplacement valvulaire aortique (RVA), un remplacement ou une reconstruction de la valvule mitrale (RVM) ou une chirurgie combinée (PAC et remplacement valvulaire [RV]) avec circulation extracorporelle, en situation non urgente. L’échelle d’évaluation de l’anxiété et de la dépression à l’hôpital (HADS), le questionnaire d’auto-évaluation des déficits cognitifs (CFQ-S) et le questionnaire d’évaluation externe des déficits cognitifs (CFQ-F) ont été remplis avant l’intervention chirurgicale, ainsi que 3 et 12 mois après la chirurgie. Résultats: Au total, les résultats de 491 patients étaient disponibles aux fins d’analyses (PAC = 182, RVA = 134, RVM = 93, PAC et RV = 82). Des cas de DCPO et une augmentation postopératoire des symptômes de dépression (APOD) ont été observés après chacune des interventions chirurgicales. (Lors du suivi après 3 mois : DCPO selon le CFQ-S [PAC = 7,1 %, RVA = 3,7 %, RVM = 9,7 %, PAC + RV = 9,8 %]; DCPO selon le CFQ-F [PAC = 9,9 %, RVA = 9,7 %, RVM = 9,7 %, PAC + RV = 15,9 %]; APOD [PAC = 7,7 %, RVA = 9,7 %, RVM = 6,5 %, PAC + RV = 8,5 %]. Lors du suivi après 12 mois : DCPO selon le CFQ-S [PAC = 6,6 %, RVA = 7,5 %, RVM = 15,1 %, PAC + RV = 7,3 %]; DCPO selon le CFQ-F [PAC= 7,1 %, RVA = 14,9 %, RVM = 10,8 %, PAC+ RV = 9,8 %]; APOD [PAC = 10,4 %, RVA = 11,2 %, RVM = 6,5 %, PAC + RV = 4,9 %]). Aucun effet intergroupe significatif n’a été observé relativement aux questionnaires CFQ-S et CFQ-F ou à l’échelle HADS. Conclusions: Il est important que les cliniciens portent attention aux déclarations des patients en ce qui concerne la diminution des fonctions cognitives et les symptômes de dépression à la suite d’une chirurgie cardiaque. De telles déclarations sont une indication que des interventions comme l’entraînement cognitif ou la psychothérapie doivent être envisagées.

Phenolic benzotriazole UV stabilizers (BUV) are commonly used additives in synthetic polymeric products, which constantly leak into the environment. They are persistent and bioaccumulative, and have been detected not only in fish, birds, and sea mammals, but also in humans, including breast milk samples. Several authorities including the European Chemical Agency already consider some BUVs as Substances of Very High Concern in need of further information, e.g. mechanistical studies and biomonitoring. In this study, we are addressing this need by investigating the effect of several BUVs on the activity of the human epidermal growth factor receptor (EGFR), an important regulator of cellular processes that has recently been identified as a cell-surface receptor for environmental organic chemicals. By combining in silico docking, mutant analyses, receptor binding and internalization assays, we demonstrate that BUVs, particularly the chlorinated variants, bind to the extracellular domain of EGFR and thereby prevent the binding of growth factors. Accordingly, BUVs can inhibit EGFR downstream events, such as ERK1/2 phosphorylation and DNA synthesis, in human keratinocytes. Our data establish EGFR as a plasma membrane receptor for BUVs, offering novel mechanistic insights into the biological effects induced by these widespread and persistent chemicals. The findings of this study may not only improve hazard assessment for BUVs, but also contribute to the development of novel EGFR-targeting drugs.

Abstract Electronic immunosensors are indispensable tools for diagnostics, particularly in scenarios demanding immediate results. Conventionally, these sensors rely on the chemical immobilization of antibodies onto electrodes. However, globular proteins tend to adsorb and unfold on these surfaces. Therefore, self‐assembled monolayers (SAMs) of thiolated alkyl molecules are commonly used for indirect gold–antibody coupling. Here, a limitation associated with SAMs is revealed, wherein they curtail the longevity of protein sensors, particularly when integrated into the state‐of‐the‐art transducer of organic bioelectronics—the organic electrochemical transistor. The SpyDirect method is introduced, generating an ultrahigh‐density array of oriented nanobody receptors stably linked to the gold electrode without any SAMs. It is accomplished by directly coupling cysteine‐terminated and orientation‐optimized spyTag peptides, onto which nanobody‐spyCatcher fusion proteins are autocatalytically attached, yielding a dense and uniform biorecognition layer. The structure‐guided design optimizes the conformation and packing of flexibly tethered nanobodies. This biolayer enhances shelf‐life and reduces background noise in various complex media. SpyDirect functionalization is faster and easier than SAM‐based methods and does not necessitate organic solvents, rendering the sensors eco‐friendly, accessible, and amenable to scalability. SpyDirect represents a broadly applicable biofunctionalization method for enhancing the cost‐effectiveness, sustainability, and longevity of electronic biosensors, all without compromising sensitivity.

Targeted protein degradation (TPD) allows cells to maintain a functional proteome and to rapidly adapt to changing conditions. Methods that repurpose TPD for the deactivation of specific proteins have demonstrated significant potential in therapeutic and research applications. Most of these methods are based on proteolysis targeting chimaeras (PROTACs) which link the protein target to an E3 ubiquitin ligase, resulting in the ubiquitin-based degradation of the target protein. In this study, we introduce a method for ubiquitin-independent TPD based on nanobody-conjugated plant ubiquitin regulatory X domain-containing (PUX) adaptor proteins. We show that the PUX-based NAnobody Degraders (P-NADs) can unfold a target protein through the Arabidopsis and human orthologues of the CDC48 unfoldase without the need for ubiquitination or initiating motifs. We demonstrate that P-NAD plasmids can be transfected into a human cell line, where the produced P-NADs use the endogenous CDC48 machinery for ubiquitin-independent TPD of a 143 kDa multidomain protein. Thus, P-NADs pave the road for ubiquitin-independent therapeutic TPD approaches. In addition, the modular P-NAD design combined with in vitro and cellular assays provide a versatile platform for elucidating functional aspects of CDC48-based TPD in plants and animals.

Objective Digital health interventions for behaviour change are usually complex interventions, and intervention developers should ‘articulate programme theory’, that is, they should offer detailed descriptions of individual intervention components and their proposed mechanisms of action. However, such detailed descriptions often remain lacking. The objective of this work was to provide a conceptual case study with an applied example of ‘articulating programme theory’ for a newly developed digital health intervention. Methods Intervention Mapping methodology was applied to arrive at a detailed description of programme theory for a newly developed digital health intervention that aims to support cardiac rehabilitation patients in establishing heart-healthy physical activity habits. Based on a Predisposing, Reinforcing, and Enabling Constructs in Educational Diagnosis and Evaluation (PRECEDE) logic model of the problem, a logic model of change was developed. The proposed mechanisms of action were visualised in an acyclic behaviour change diagram. Results Programme theory for this digital health intervention includes 4 sub-behaviours of the main target behaviour (i.e. habitual heart-healthy physical activity), 8 personal determinants and 12 change objectives (i.e. changes needed at the determinant level to achieve the sub-behaviours). These are linked to 12 distinct features of the digital health intervention and 12 underlying behaviour change methods. Conclusions This case study offers a worked example of articulating programme theory for a digital health intervention using Intervention Mapping. Intervention developers and researchers may draw on this example to replicate the method, or to reflect on most suitable approaches for their own behaviour change interventions.

Für die Aus- und Weiterbildung im Pflegebereich stehen zahlreiche Erklärvideos auf der weit verbreiteten Videostreaming-Plattform YouTube zur Verfügung. Allerdings werden die Videos weitgehend unkontrolliert veröffentlicht und sie zeichnen sich durch ein hohes Mass an Heterogenität aus. Lehrende und Lernende stehen vielfach vor der Frage, welches Video aus der umfangreichen Ergebnisliste einer Suche am besten geeignet ist. Im Mittelpunkt dieser Studie steht die qualitative Gestaltung von Erklärvideos, da auch fachlich korrekte Lehr-Lerninhalte angemessen präsentiert werden müssen, um die Wahrscheinlichkeit eines Lernerfolgs zu erhöhen. Zur qualitativen Bewertung von jeweils drei Erklärvideos zu den grundlegenden Pflegethemen Infusionsvorbereitung und 30-Grad-Positionierung wird ein disziplinübergreifendes Analyseraster verwendet, das pädagogisch-didaktische, (lern-)psychologische und filmanalytische Merkmale berücksichtigt. Die Ergebnisse der empirischen Untersuchung zeigen eine durchwachsene Qualität von Erklärvideos für den Pflegebereich. Die evaluierten Erklärvideos berücksichtigen jeweils unterschiedlich umfangreich die Qualitätskriterien und erfüllen kaum (medien-)pädagogisch-didaktische Qualitätskriterien. Die Autoren arbeiten heraus, wann die Erklärvideos dennoch für unterschiedliche Zielgruppen geeignet sind und wie (lern-)psychologische und filmgestalterische Kriterien ineinandergreifen.

Abstract Background Endovascular thrombectomy (EVT) is highly effective in acute stroke patients with intracranial large vessel occlusion (LVO), however, presence of concomitant cervical occlusion of the internal carotid artery (ICA) may limit the endovascular access. This study describes feasibility and efficacy of a surgical carotid access (cutdown) to perform interdisciplinary recanalization therapy including carotid endarterectomy (CEA) followed by EVT for recanalization of intracranial LVO in stroke patients with tandem occlusions. Methods We identified stroke patients with tandem occlusions who underwent a combined surgical-endovascular approach over a 5-year period. Surgical cutdown was provided by a cardiovascular surgery team at the angio-suite followed by EVT performed by the neuroradiological team. Demographics, stroke characteristics, treatments including antithrombotic management, procedure times, and clinical follow-up were assessed. Results Four patients with acute stroke because of tandem occlusions received CEA followed by EVT (two patients after frustrating femoral catheterization, two as first-line approach). Successful recanalization (TICI ≥ 2b) via endovascular thrombectomy was achieved in all patients at a median of 28 min after successful surgical CEA. Intraprocedural complication was observed in one case (25%; i.e. ICA dissection). Conclusions This small study provides evidence that a combined interdisciplinary approach of CEA followed by EVT in the angio-suite in acute stroke patients with tandem occlusions is a feasible procedure in patients otherwise not accessible to endovascular recanalizing therapy and, therefore, high likelihood of developing large hemispheric infarction. Prospective data are warranted to identify patients who benefit from this combined approach as first-line therapy.

Abstract The COVID-19 pandemic, caused by SARS-CoV-2, has emphasized the necessity for scalable diagnostic workflows using locally produced reagents and basic laboratory equipment with minimal dependence on global supply chains. We introduce an open-source automated platform for high-throughput RNA extraction and pathogen diagnosis, which uses reagents almost entirely produced in-house. This platform integrates our methods for self-manufacturing magnetic nanoparticles and qRT-PCR reagents-both of which have received regulatory approval for clinical use–with an in-house, open-source robotic extraction protocol. It also incorporates our "Nanopore Sequencing of Isothermal Rapid Viral Amplification for Near Real-time Analysis" (NIRVANA) technology, designed for tracking SARS-CoV-2 mutations and variants. The platform exhibits high reproducibility and consistency without cross-contamination, and its limit of detection, sensitivity, and specificity are comparable to commercial assays. Automated NIRVANA effectively identifies circulating SARS-CoV-2 variants. Our in-house, cost-effective reagents, automated diagnostic workflows, and portable genomic surveillance strategies provide a scalable and rapid solution for COVID-19 diagnosis and variant tracking, essential for current and future pandemic responses.

Abstract Co-electrolysis of carbon oxides and nitrogen oxides promise to simultaneously help restore the balance of the C and N cycles while producing valuable chemicals such as urea. However, co-electrolysis processes are still largely inefficient and numerous knowledge voids persist. Here, we provide a solid thermodynamic basis for modelling urea production via co-electrolysis. First, we determine the energetics of aqueous urea produced under electrochemical conditions based on experimental data, which enables an accurate assessment of equilibrium potentials and overpotentials. Next, we use density functional theory (DFT) calculations to model various co-electrolysis reactions producing urea. The calculated reaction free energies deviate significantly from experimental values for well-known GGA, meta-GGA and hybrid functionals. These deviations stem from errors in the DFT-calculated energies of molecular reactants and products. In particular, the error for urea is approximately -0.25 ± 0.10 eV. Finally, we show that all these errors introduce large inconsistencies in the calculated free-energy diagrams of urea production via co-electrolysis, such that gas-phase corrections are strongly advised.

Abstract Although there is evidence for the generosity of high-status individuals, there seems to be a strong perception that the elites are selfish and contribute little to others’ welfare, and even less so than poorer people. We argue that this perception may derive from a gap between normative and empirical expectations regarding the behavior of the elites. Using large-scale survey experiments, we show that high-status individuals are held to higher ethical standards in both the US and China, and that there is a strong income gradient in normatively expected generosity. We also present evidence for a gap between people’s normative expectations of how the rich should behave, and their empirical expectations of how they actually do: empirical expectations are generally lower than both normative expectations and actual giving.

Abstract Wiedemann‐Rautenstrauch Syndrome (WRS; MIM 264090) is an extremely rare and highly heterogeneous syndrome that is inherited in a recessive fashion. The patients have hallmark features such as prenatal and postnatal growth retardation, short stature, a progeroid appearance, hypotonia, facial dysmorphology, hypomyelination leukodystrophy, and mental impairment. Biallelic disease‐causing variants in the RNA polymerase III subunit A (POLR3A) have been associated with WRS. Here, we report the first identified cases of WRS syndrome with novel phenotypes in three consanguineous families (two Omani and one Saudi) characterized by biallelic variants in POLR3A. Using whole‐exome sequencing, we identified one novel homozygous missense variant (NM_007055: c.2456C>T; p. Pro819Leu) in two Omani families and one novel homozygous variant (c.1895G>T; p Cys632Phe) in Saudi family that segregates with the disease in the POLR3A gene. In silico homology modeling of wild‐type and mutated proteins revealed a substantial change in the structure and stability of both proteins, demonstrating a possible effect on function. By identifying the homozygous variants in the exon 14 and 18 of the POLR3A gene, our findings will contribute to a better understanding of the phenotype‐genotype relationship and molecular etiology of WRS syndrome.

Abstract Structure determination of amorphous materials remains challenging, owing to the disorder inherent to these materials. Nuclear magnetic resonance (NMR) powder crystallography is a powerful method to determine the structure of molecular solids, but disorder leads to a high degree of overlap between measured signals, and prevents the unambiguous identification of a single modeled periodic structure as representative of the whole material. Here, we determine the atomic-level ensemble structure of the amorphous form of the drug AZD4625 by combining solid-state NMR experiments with molecular dynamics (MD) simulations and machine-learned chemical shifts. By considering the combined shifts of all 1H and 13C atomic sites in the molecule, we determine the structure of the amorphous form by identifying an ensemble of local molecular environments that are in agreement with experiment. We then extract and analyze preferred conformations and intermolecular interactions in the amorphous sample in terms of the stabilization of the amorphous form of the drug.

Abstract Mathematical models of cognition are often memoryless and ignore potential fluctuations of their parameters. However, human cognition is inherently dynamic. Thus, we propose to augment mechanistic cognitive models with a temporal dimension and estimate the resulting dynamics from a superstatistics perspective. Such a model entails a hierarchy between a low-level observation model and a high-level transition model. The observation model describes the local behavior of a system, and the transition model specifies how the parameters of the observation model evolve over time. To overcome the estimation challenges resulting from the complexity of superstatistical models, we develop and validate a simulation-based deep learning method for Bayesian inference, which can recover both time-varying and time-invariant parameters. We first benchmark our method against two existing frameworks capable of estimating time-varying parameters. We then apply our method to fit a dynamic version of the diffusion decision model to long time series of human response times data. Our results show that the deep learning approach is very efficient in capturing the temporal dynamics of the model. Furthermore, we show that the erroneous assumption of static or homogeneous parameters will hide important temporal information.

Abstract Receptor tyrosine kinases (RTKs) are typically activated through a precise sequence of intracellular phosphorylation events starting with a tyrosine residue on the activation loop (A-loop) of the kinase domain (KD). From this point the mono-phosphorylated enzyme is active, but subject to stringent regulatory mechanisms which can vary dramatically across the different RTKs. In the absence of extracellular stimulation, fibroblast growth factor receptor 2 (FGFR2) exists in the mono-phosphorylated state in which catalytic activity is regulated to allow rapid response upon ligand binding, whilst restricting ligand-independent activation. Failure of this regulation is responsible for pathologic outcomes including cancer. Here we reveal the molecular mechanistic detail of KD control based on combinatorial interactions of the juxtamembrane (JM) and the C-terminal tail (CT) regions of the receptor. JM stabilizes the asymmetric dimeric KD required for substrate phosphorylation, whilst CT binding opposes dimerization, and down-regulates activity. Direct binding between JM and CT delays the recruitment of downstream effector proteins adding a further control step as the receptor proceeds to full activation. Our findings underscore the diversity in mechanisms of RTK oligomerisation and activation.

[This corrects the article DOI: 10.1371/journal.pone.0249277.].

BackgroundPatients with atrial fibrillation (AF) have a high risk for recurrent clinical events after an ischemic stroke. Direct oral anticoagulants (DOAC) are prescribed for secondary prevention. Adherence to DOAC is crucial mainly because of their short elimination half-life. Non-adherence to DOAC can negatively impact patients' outcomes. The relationship between (non-)adherence and recurrent clinical events is unknown in AF patients after initial stroke. We investigated adherence to DOAC in stroke survivors with AF who were included in the MAAESTRO study at the University Hospital Basel, Switzerland, between 2008 and 2022.MethodsThis study is a secondary analysis of data from MAAESTRO with a matched nested case-control design and 1:2 ratio. DOAC intake was measured with a small electronic device (Time4MedTM). We defined two arbitrary intervals of 17 days and 95 days as the longest time spans with electronic monitoring data per patient to maximize the number of participants with adequate amount of observation time available for analysis. Taking and timing adherence were calculated retrospectively i.e., prior to the recurrent event for cases. Trendline analysis of adherence over 95 days was calculated. Linear regression analysis was performed after adjusting for the co-variables age and daily pill burden. Sensitivity analysis was performed with controls for intervals in the reverse direction (prospectively).ResultsWe analyzed 11 cases and 22 matched controls (mean age: 75.9 ± 9.2 years vs. 73.1 ± 8.4 years; n.s.) with similar stroke characteristics (NIHSS, mRS, MoCA) and 36.4% women in each group. Mean adherence values were high and similar between cases and controls (95 days taking: 87.0 ± 18.9% (cases) vs. 90.8 ± 9.8% (controls), n.s.; similar values for timing adherence). Six hemorrhagic and five ischemic events had occurred. Compared to controls, a significantly higher 95 days taking adherence was observed for hemorrhagic events (96.0 ± 5.0% (cases) vs. 88.1 ± 11.5% (controls); pConclusionBecause recurrent ischemic events after an AF-related stroke were associated with low adherence to DOAC 96%.Trial registrationClinicalTrials.gov NCT03344146.

Myasthenic crises (MC) are potentially life-threatening acute exacerbations of myasthenia gravis (MG) characterized by profound muscle weakness, bulbar symptoms, and potential for respiratory failure. Intravenous immunoglobulins (IVIG) and plasma exchange (PLEX) are conventional treatments for myasthenic exacerbations. Recently, new therapeutic options for generalized acetylcholine-receptor antibody positive (AchR+) MG were approved as an add-on therapy. They mainly consist of complement C5 inhibitors such as eculizumab and ravulizumab and neonatal Fc receptor antagonists such as efgartigimod with the approval of more options pending, e.g., zilucoplan and rozanolixizumab. More therapeutic options are in the pipeline. Although the data show a quick and reliable treatment response, these medications have not been studied for the therapy of myasthenic crisis. We present the case of a 57-year-old male with his first episode of generalized myasthenia gravis (MG) and positive acetylcholine-receptor antibodies (AchR+) who was transferred to our neurological intensive care unit with worsening generalized weakness, dysphagia, and respiratory distress. The crisis was triggered by pneumonia due to dysphagia. He was diagnosed with myasthenic crisis and treated with intravenous pyridostigmine, plasmapheresis (PLEX), and continued prednisone. Initial improvement was followed by deterioration, requiring readmission and additional PLEX. After a further decline, efgartigimod was administered, leading to significant improvement within 48 hours, as evidenced by reduced MG-ADL and QMG scores. The patient continued to improve and was stable enough for transfer to a rehabilitation facility. This case illustrates the potential of efgartigimod as a novel treatment for refractory myasthenic crises.

IntroductionDirect oral anticoagulants (DOACs) have become widely used in clinical practice for preventing thromboembolic events. Point-of-care testing methods, particularly those based on urine samples, offer a promising approach for rapid and accurate assessment of DOAC presence. This pilot study aims to evaluate the utility of a urine-based DOAC dipstick test as a point-of-care tool for identifying DOAB presence in acute ischemic stroke (AIS) or transient ischemic attack (TIA) patients.Patients and methodsThis prospective pilot study included patients with AIS/TIA eligible for DOAC-measurement. After exclusion of 3 patients, 23 patients with DOAC-intake (DOAC group; factor-Xa-inhibitors; n = 23) and 21 patients without DOAC-intake (control-group) remained for analyses. The urine-based DOAC dipstick test and parallel blood-based specific DOAC-level assessment were performed in all patients. Time-intervals of sampling urine/blood sampling and result of DOAC-test were recorded to analyze a potential time benefit based on dipstick evaluation.ResultsThe urine-based DOAC dipstick test demonstrated high sensitivity (100%) and specificity (100%), correctly identifying all patients with anticoagulatory activity due to DOAC intake (i.e., anti-Xalevel ≥30 ng/mL). Moreover, the visual readout of the test provided semiquantitative information on drug-specific anti-Xa levels, showing a sensitivity of 83% and specificity of 93% to detect anti-Xa levels ≥120 ng/mL. The dipstick test exhibited a median time-benefit of 2:25 h compared to standard blood-based DOAC-level testing.DiscussionThe results of this pilot study underline the efficacy of urine-based point-of-care testing as a rapid and reliable method for assessing DOAC presence in patients with acute ischemic stroke.ConclusionThe value of this tool for clinical decision-making in stroke management needs to be established in future trials.Clinical Trial Registration: Clinicaltrails.org identifier [NCT06037200].

Background and Purpose This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD). Methods This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015–2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0–2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching. Results Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10–19] vs. 4 [2–7], P

Abstract Introduction There is growing evidence to support the use of co‐design in developing interventions across many disciplines. This scoping review aims to examine how co‐design methodology has been used in the development of cardiovascular disease (CVD) secondary prevention interventions within health and community settings. Methods We searched four academic databases for studies that used the co‐design approach to develop their intervention. Studies were included if consumers (adults with CVD) and key stakeholders (e.g. clinicians, service providers) were involved in the co‐design process. The review focused on methodology rather than traditional study outcomes; therefore, co‐design processes and activities were extracted and evaluated against a selected co‐design framework. Results Twenty‐two studies were included in this review. Studies were implemented across various settings with consumers and stakeholder groups most frequently consisting of patients and healthcare professionals, respectively. Most studies specifically stated that they used a ‘co‐design’ approach (n = 10); others used terms such as participatory action research (n = 3), user‐centred design (n = 3) and community‐based participatory research (n = 2). Although there was variability in terminology, co‐design processes, and participants, all studies adhered to the key principles of consumer engagement. Predominant co‐design activities included semistructured interviews, focus groups, co‐design/development workshops and advisory group meetings. Intervention effectiveness was assessed in eight studies showing mixed results. Conclusions This review provides an overview of how the co‐design approach has previously been used in the development of CVD secondary prevention interventions. These findings provide methodological considerations that can guide researchers and healthcare services when implementing co‐design to develop feasible and acceptable interventions that can improve outcomes for CVD populations. Patient or Public Contribution No patients, service users, caregivers, people with lived experience or members of the public were involved in this scoping review. This review article was written by academics who have undertaken a significant amount of co‐design work with consumers and stakeholders.

Abstract Compound heterozygous mutations in SHQ1 have been associated with a rare and severe neurological disorder characterized by global developmental delay (GDD), cerebellar degeneration coupled with seizures, and early-onset dystonia. Currently, only five affected individuals have been documented in the literature. Here, we report three children from two unrelated families harboring a homozygous variant in the gene but with a milder phenotype than previously described. The patients had GDD and seizures. Magnetic resonance imaging analyses revealed diffuse white matter hypomyelination. Sanger sequencing confirmed the whole-exome sequencing results and revealed full segregation of the missense variant (SHQ1:c.833 T > C; p.I278T) in both families. We performed a comprehensive in silico analysis using different prediction classifiers and structural modeling of the variant. Our findings demonstrate that this novel homozygous variant in SHQ1 is likely to be pathogenic and leads to the clinical features observed in our patients.

Microcephaly is often caused by an impairment of the generation of neurons in the brain, a process referred to as neurogenesis. While most neurogenesis in mammals occurs during brain development, it thought to continue to take place through adulthood in selected regions of the mammalian brain, notably the hippocampus. However, the generality of neurogenesis in the adult brain has been controversial. While studies in mice and rats have provided compelling evidence for neurogenesis occurring in the adult rodent hippocampus, the lack of applicability in humans of key methods to demonstrate neurogenesis has led to an intense debate about the existence and, in particular, the magnitude of neurogenesis in the adult human brain. Here, we demonstrate the applicability of a powerful method to address this debate, that is, the in vivo labeling of adult human patients with 15N-thymidine, a non-hazardous form of thymidine, an approach without any clinical harm or ethical concerns. 15N-thymidine incorporation into newly synthesized DNA of specific cells was quantified at the single-cell level with subcellular resolution by Multiple-isotype imaging mass spectrometry (MIMS) of brain tissue resected for medical reasons. Two adult human patients, a glioblastoma patient and a patient with drug-refractory right temporal lobe epilepsy, were infused for 24 h with 15N-thymidine. Detection of 15N-positive leukocyte nuclei in blood samples from these patients confirmed previous findings by others and demonstrated the appropriateness of this approach to search for the generation of new cells in the adult human brain. 15N-positive neural cells were easily identified in the glioblastoma tissue sample, and the range of the 15N signal suggested that cells that underwent S-phase fully or partially during the 24 h in vivo labeling period, as well as cells generated therefrom, were detected. In contrast, within the hippocampus tissue resected from the epilepsy patient, none of the 2,000 dentate gyrus neurons analyzed was positive for 15N-thymidine uptake, consistent with the notion that the rate of neurogenesis in the adult human hippocampus is rather low. Of note, the likelihood of detecting neurogenesis was reduced because of (i) the low number of cells analyzed, (ii) the fact that hippocampal tissue was explored that may have had reduced neurogenesis due to epilepsy, and (iii) the labeling period of 24 h which may have been too short to capture quiescent neural stem cells. Yet, overall, our approach to enrich NeuN-labeled neuronal nuclei by FACS prior to MIMS analysis provides a promising strategy to quantify even low rates of neurogenesis in the adult human hippocampus after in vivo15N-thymidine infusion. From a general point of view and regarding future perspectives, the in vivo labeling of humans with 15N-thymidine followed by MIMS analysis of brain tissue constitutes a novel approach to study mitotically active cells and their progeny in the brain, and thus allows a broad spectrum of studies of brain physiology and pathology, including microcephaly.

The fungus Ophiodimyces ophiodiicola is the etiologic agent of snake fungal disease. Recent findings date US occurrence at least as far back as 1945. We analyzed 22 free-ranging snakes with gross lesions consistent with snake fungal disease from museum collections from Europe. We found 5 positive samples, the oldest collected in 1959.

Abstract A new family of phase change material based on antimony has recently been explored for applications in near-IR tunable photonics due to its wide bandgap, manifested as broadband transparency from visible to NIR wavelengths. Here, we characterize $$\hbox {Sb}_{2} \hbox {S}_{3}$$ Sb 2 S 3 optically and demonstrate the integration of this phase change material in a silicon nitride platform using a microring resonator that can be thermally tuned using the amorphous and crystalline states of the phase change material, achieving extinction ratios of up to 18 dB in the C-band. We extract the thermo-optic coefficient of the amorphous and crystalline states of the $$\hbox {Sb}_{2}\hbox {S}_{3}$$ Sb 2 S 3 to be 3.4 x $$10^{-4}\hbox {K}^{-1}$$ 10 - 4 K - 1 and 0.1 x 10 $$^{-4}\hbox {K}^{-1}$$ - 4 K - 1 , respectively. Additionally, we detail the first observation of bi-directional shifting for permanent trimming of a non-volatile switch using continuous wave (CW) laser exposure ( $$-5.9$$ - 5.9 to 5.1 dBm) with a modulation in effective refractive index ranging from +5.23 x $$10^{-5}$$ 10 - 5 to $$-1.20$$ - 1.20 x 10 $$^{-4}$$ - 4 . This work experimentally verifies optical phase modifications and permanent trimming of $$\hbox {Sb}_{2}\hbox {S}_{3}$$ Sb 2 S 3 , enabling potential applications such as optically controlled memories and weights for neuromorphic architecture and high density switch matrix using a multi-layer PECVD based photonic integrated circuit.

Predicting structures and stabilities of solid-solid interfaces presents an ongoing and increasingly important challenge for development of new technologies. Here authors report an unconstrained and generally applicable non-periodic screening method for systematic exploration of material´s interfaces.

Objective: Most methods to detect copy number variation (CNV) have high false positive rates, especially for small CNVs and in real-life samples from clinical studies. In this study, we explored a novel scatterplot-based method to detect CNVs in microarray samples.Methods: Illumina SNP microarray data from 13,254 individuals were analyzed with scatterplots and by PennCNV. The data were analyzed without the prior exclusion of low-quality samples. For CNV scatterplot visualization, the median signal intensity of all SNPs located within a CNV region was plotted against the median signal intensity of the flanking genomic region. Since CNV causes loss or gain of signal intensities, carriers of different CNV alleles pop up in clusters. Moreover, SNPs within a deletion are not heterozygous, whereas heterozygous SNPs within a duplication show typical 1:2 signal distribution between the alleles. Scatterplot-based CNV calls were compared with standard results of PennCNV analysis. All discordant calls as well as a random selection of 100 concordant calls were individually analyzed by visual inspection after noise-reduction.Results: An algorithm for the automated scatterplot visualization of CNVs was developed and used to analyze six known CNV regions. Use of scatterplots and PennCNV yielded 1019 concordant and 108 discordant CNV calls. All concordant calls were evaluated as true CNV-findings. Among the 108 discordant calls, 7 were false positive findings by the scatterplot method, 80 were PennCNV false positives, and 21 were true CNVs detected by the scatterplot method, but missed by PennCNV (i.e., false negative findings).Conclusion: CNV visualization by scatterplots allows for a reliable and rapid detection of CNVs in large studies. This novel method may thus be used both to confirm the results of genome-wide CNV detection software and to identify known CNVs in hitherto untyped samples.

Aortic distensibility is a risk factor for multiple cardiovascular events, but the genetic etiology is not well understood. Here, the authors identify genetic variants linked to aortic distensibility, highlighting mechanistic pathways and causal relationships between distensibility and both aortic aneurysms and brain small vessel disease.

Protein tyrosine kinase 2-beta is shown to function as a sensor and effector of cellular calcium influx through self-association.

Abstract Rivers are known to act as biogeographic barriers in several strictly terrestrial taxa, while possibly serving as conduits of dispersal for freshwater-tolerant or -dependent species. However, the influence of river systems on genetic diversity depends on taxa-specific life history traits as well as other geographic factors. In amphibians, several studies have demonstrated that river systems have only minor influence on their divergence. Here, we assess the role of the paleodrainage systems of the Sunda region (with a focus on the island of Sumatra) in shaping the evolutionary history of two genera of frogs (Sumaterana and Wijayarana) whose tadpoles are highly dependent on cascading stream habitats. Our phylogenetic results show no clear association between the genetic diversification patterns of both anurans genera and the existence of paleodrainage systems. Time-calibrated phylogenies and biogeographical models suggest that these frogs colonized Sumatra and diversified on the island before the occurrence of the Pleistocene drainage systems. Both genera demonstrate phylogenetic structuring along a north–south geographic axis, the temporal dynamics of which coincide with the geological chronology of proto Sumatran and -Javan volcanic islands. Our results also highlight the chronic underestimation of Sumatran biodiversity and call for more intense sampling efforts on the island.

Abstract Background Patients with wake-up ischemic stroke are frequently excluded from thrombolytic treatment due to unknown symptom onset time and limited availability of advanced imaging modalities. The Tenecteplase in Wake-up Ischaemic Stroke Trial (TWIST) is a randomized controlled trial of intravenous tenecteplase 0.25 mg/kg and standard care versus standard care alone (no thrombolysis) in patients who wake up with acute ischemic stroke and can be treated within 4.5 h of wakening based on non-contrast CT findings. Objective To publish the detailed statistical analysis plan for TWIST prior to unblinding. Methods The TWIST statistical analysis plan is consistent with the Consolidating Standard of Reporting Trials (CONSORT) statement and provides clear and open reporting. Discussion Publication of the statistical analysis plan serves to reduce potential trial reporting bias and clearly outlines the pre-specified analyses. Trial registration ClinicalTrials.gov NCT03181360 . EudraCT Number 2014-000096-80 . WHO ICRTP registry number ISRCTN10601890 .

Abstract Background Swallowing difficulties (dysphagia) and community-acquired pneumonia are common in frail older people and maybe addressed through targeted training of the anterior neck musculature that affects the swallow. We have developed a swallowing exercise rehabilitation intervention (CTAR-SwiFt) by adapting a previously established swallowing exercise to ensure patient safety and ease of execution in the frail elderly population. The CTAR-SwiFt intervention consists of a feedback-enabled exercise ball that can be squeezed under the chin, with real-time feedback provided via a mobile application. The aim of this study is to evaluate the feasibility of assessing the effectiveness of the CTAR-SwiFt intervention in reducing dysphagia and community-acquired pneumonia, prior to a larger-scale multi-centre randomised controlled trial. Methods We will recruit 60 medically stable patients over the age of 75 years who have been admitted with a diagnosis of pneumonia to the acute frailty wards at two participating hospitals in the UK. Study participants will be randomised into one of three groups: standard care, low intensity (once daily) CTAR-SwiFt exercise or high intensity (twice daily) CTAR-SwiFt exercises. The intervention period will last for 12 weeks, the final follow-up assessment will be conducted at 24 weeks. We will assess the feasibility outcomes, including rates of participant recruitment and retention, compliance with the exercise regime and adverse incidents. Additionally, we will assess the usability and acceptability of the intervention device and the performance of different clinical outcome measures (e.g. chin tuck strength, Functional Oral Intake Scale, SWAL-QOL, EQ-5D and swallow speed). A sub-sample of study participants will complete videofluoroscopic assessments of swallowing function before and after the intervention to evaluate the physiological changes (e.g. bolus flow rates, laryngeal elevation, base-of-tongue retraction). Conclusions By improving the ability to swallow, using our chin tuck exercise intervention, in frail older patients admitted to hospital with pneumonia, it is anticipated that patients’ oral intake will improve. It is suggested that this will further impact clinical, patient and healthcare economic outcomes, i.e. reduce the need for supplemental feeding, improve patient satisfaction with oral intake and swallowing-related quality of life, decrease the occurrence of chest infections and reduce hospital admissions and related healthcare costs. Trial registration ISRCTN, ISRCTN12813363 . Registered on 20 January 2020

Background and Purpose Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce. Methods We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019). Results We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031). Conclusions Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

ThThe relative autonomy of Pädagogik (education) as an academic field has always been in jeopardy. Consequently, we take a closer look at its past, present, and future. We begin by retracing the historical development of this field of study in the German-speaking context. In the second part, we look at the current state of the discipline and spotlight current developments threatening education’s autonomy, first and foremost the steep rise and dominance of Empirische Bildungsforschung (empirical educational research). In the last part, we argue for education as an independent discipline and outline how educationalists can strengthen its autonomy and disciplinary identity.

Abstract Background The 16S mitochondrial rRNA gene is the most widely sequenced molecular marker in amphibian systematic studies, making it comparable to the universal CO1 barcode that is more commonly used in other animal groups. However, studies employ different primer combinations that target different lengths/regions of the 16S gene ranging from complete gene sequences (~ 1500 bp) to short fragments (~ 500 bp), the latter of which is the most ubiquitously used. Sequences of different lengths are often concatenated, compared, and/or jointly analyzed to infer phylogenetic relationships, estimate genetic divergence (p-distances), and justify the recognition of new species (species delimitation), making the 16S gene region, by far, the most influential molecular marker in amphibian systematics. Despite their ubiquitous and multifarious use, no studies have ever been conducted to evaluate the congruence and performance among the different fragment lengths. Results Using empirical data derived from both Sanger-based and genomic approaches, we show that full-length 16S sequences recover the most accurate phylogenetic relationships, highest branch support, lowest variation in genetic distances (pairwise p-distances), and best-scoring species delimitation partitions. In contrast, widely used short fragments produce inaccurate phylogenetic reconstructions, lower and more variable branch support, erratic genetic distances, and low-scoring species delimitation partitions, the numbers of which are vastly overestimated. The relatively poor performance of short 16S fragments is likely due to insufficient phylogenetic information content. Conclusions Taken together, our results demonstrate that short 16S fragments are unable to match the efficacy achieved by full-length sequences in terms of topological accuracy, heuristic branch support, genetic divergences, and species delimitation partitions, and thus, phylogenetic and taxonomic inferences that are predicated on short 16S fragments should be interpreted with caution. However, short 16S fragments can still be useful for species identification, rapid assessments, or definitively coupling complex life stages in natural history studies and faunal inventories. While the full 16S sequence performs best, it requires the use of several primer pairs that increases cost, time, and effort. As a compromise, our results demonstrate that practitioners should utilize medium-length primers in favor of the short-fragment primers because they have the potential to markedly improve phylogenetic inference and species delimitation without additional cost.

Abstract Background Value of a Statistical Life Year (VSLY) provides an important economic measure of an individual’s trade-off between health risks and other consumption, and is a widely used policy parameter. Measuring VSLY is complex though, especially in low-income and low-literacy communities. Methods Using a large randomized experiment (N = 3027), we study methodological aspects of stated-preference elicitation with payment cards (price lists) in an extreme poverty context. In a 2 × 2 design, we systematically vary whether buying or selling prices are measured, crossed with the range of the payment card. Results We find substantial effects of both the pricing method and the list range on elicited VSLY. Estimates of the gross domestic product per capita multiplier for VSLY range from 3.5 to 33.5 depending on the study design. Importantly, all estimates are economically and statistically significantly larger than the current World Health Organization threshold of 3.0 for cost-effectiveness analyses. Conclusions Our results inform design choice in VSLY measurements, and provide insight into the potential variability of these measurements and possibly robustness checks.

Abstract Background Plasmodium simium, a malaria parasite of non-human primates (NHP), was recently shown to cause zoonotic infections in humans in Brazil. We sequenced the P. simium genome to investigate its evolutionary history and to identify any genetic adaptions that may underlie the ability of this parasite to switch between host species. Results Phylogenetic analyses based on whole genome sequences of P. simium from humans and NHPs reveals that P. simium is monophyletic within the broader diversity of South American Plasmodium vivax, suggesting P. simium first infected NHPs as a result of a host switch of P. vivax from humans. The P. simium isolates show the closest relationship to Mexican P. vivax isolates. Analysis of erythrocyte invasion genes reveals differences between P. vivax and P. simium, including large deletions in the Duffy-binding protein 1 (DBP1) and reticulocyte-binding protein 2a genes of P. simium. Analysis of P. simium isolated from NHPs and humans revealed a deletion of 38 amino acids in DBP1 present in all human-derived isolates, whereas NHP isolates were multi-allelic. Conclusions Analysis of the P. simium genome confirmed a close phylogenetic relationship between P. simium and P. vivax, and suggests a very recent American origin for P. simium. The presence of the DBP1 deletion in all human-derived isolates tested suggests that this deletion, in combination with other genetic changes in P. simium, may facilitate the invasion of human red blood cells and may explain, at least in part, the basis of the recent zoonotic infections.

BackgroundCerebral microbleeds (CMBs) may have a differential impact on clinical outcome in stroke patients with atrial fibrillation (AF) treated with different types of oral anticoagulation (OAC).MethodsObservational single-center study on AF-stroke-patients treated with OAC. Magnetic-resonance-imaging was performed to assess CMBs. Outcome measures consisted of recurrent ischemic stroke (IS), intracranial hemorrhage (ICH), death, and their combined analysis. Functional disability was assessed by mRS. Using adjusted logistic regression and Cox proportional-hazards models, we assessed the association of the presence of CMBs and OAC type (vitamin K antagonists [VKAs] vs. direct oral anticoagulants [DOACs]) with clinical outcome.ResultsOf 310 AF-stroke patients treated with OAC [DOACs: n = 234 (75%); VKAs: n = 76 (25%)], CMBs were present in 86 (28%) patients; of these, 66 (77%) received DOACs. In both groups, CMBs were associated with an increased risk for the composite outcome: VKAs: HR 3.654 [1.614; 8.277]; p = 0.002; DOACs: HR 2.230 [1.233; 4.034]; p = 0.008. Patients with CMBs had ~50% higher absolute rates of the composite outcome compared to the overall cohort, with a comparable ratio between treatment groups [VKAs 13/20(65%) vs. DOACs 19/66(29%); p < 0.01]. The VKA-group had a 2-fold higher IS [VKAs:4 (20%) vs. DOACs:6 (9%); p = 0.35] and a 10-fold higher ICH rate [VKAs: 3 (15%) vs. DOACs: 1 (1.5%); p = 0.038]. No significant interaction was observed between type of OAC and presence of CMBs. DOAC-patients showed a significantly better functional outcome (OR 0.40 [0.17; 0.94]; p = 0.04).ConclusionsIn AF-stroke patients treated with OAC, the presence of CMBs was associated with an unfavorable composite outcome for both VKAs and DOACs, with a higher risk for recurrent IS than for ICH. Strokes were numerically higher under VKAs and increased in the presence of CMBs.Clinical trial registrationhttp://www.clinicaltrials.gov, Unique identifier: NCT03826927.