Background Several commercially available software packages exist for the analysis of three-dimensional cine phase-contrast cardiovascular magnetic resonance (CMR) with three-directional velocity encoding (four-dimensional (4D) flow CMR). Only sparse data are available on the impact of these different software solutions on quantitative results. We compared two different commercially available and widely used software packages and their impact on the forward flow volume (FFV), peak velocity (PV), and maximum wall shear stress (WSS) per plane.Materials and methods 4D flow CMR datasets acquired by 3 Tesla magnetic resonance imaging of 10 healthy volunteers, 13 aortic stenosis patients, and 7 aortic valve replacement patients were retrospectively analyzed for FFV, PV, and WSS using two software packages in six analysis planes along the thoracic aorta. Absolute (AD) and relative differences (RD), intraclass correlation coefficients (ICC), Bland-Altman analysis, and Spearman's correlation analysis were calculated.Results For the FFV and PV in healthy volunteers, there was good to excellent agreement between both software packages [FFV: ICC = 0.93-0.97, AD: 0.1 +/- 5.4 ml (-2.3 +/- 2.4 ml), RD: -0.3 +/- 8% (-5.7 +/- 6.0%); PV: ICC = 0.81-0.99, AD: -0.02 +/- 0.02 ml (-0.1 +/- 0.1 ml), RD: -1.6 +/- 2.1% (-9.3 +/- 6.1%)]. In patients, the FFV showed good to excellent agreement [ICC: 0.75-0.91, AD: -1.8 +/- 6.5 ml (-8.3 +/- 9.9 ml), RD: -2.2 +/- 9.2% (-13.8 +/- 17.4%)]. In the ascending aorta, PV showed only poor to moderate agreement in patients (plane 2 ICC: 0.33, plane 3 ICC: 0.72), whereas the rest of the thoracic aorta revealed good to excellent agreement [ICC: 0.95-0.98, AD: -0.03 +/- 0.07 (-0.1 +/- 0.1 m/s), RD: -3.5 +/- 7.9% (-7.8 +/- 9.9%)]. WSS analysis showed no to poor agreement between both software packages. Global correlation analyses revealed good to very good correlation between FFV and PV and only poor correlation for WSS.Conclusions There was good to very good agreement for the FFV and PV except for the ascending aorta in patients when comparing PV and no agreement for WSS. Standardization is therefore necessary.

A 6-year-old female spayed Podenco-crossbreed dog was presented with an unusual type of focal impaired awareness seizures, including sensory ataxia and postictal rest. Magnetic resonance imaging examination revealed pre- and post-contrast agent T1-weighted bilateral symmetric hyperintensities in the lentiform nuclei and globus pallidus. Repeated cerebrospinal fluid sampling showed lymphocytic pleocytosis. Cerebrospinal fluid immunoglobulin G autoantibodies to myelin basic protein (MBP) were detected by immunofluorescence examination with strong binding to myelinated fiber tracts. The absence of binding to MBP-depleted mouse brains confirmed MBP as an antigenic target. Although the patient had minor seizure episodes every 2 months, and the owners avoided seizure triggers, they refused medical treatment before presenting to the veterinarian. To the best of our knowledge, this is the first description of MBP autoantibody-positive encephalitis in a dog.

During inflammation, human neutrophils engage beta 2-integrins to migrate from the blood circulation to inflammatory sites with high cytokine but low oxygen concentrations. We tested the hypothesis that the inhibition of prolyl hydroxylase domain-containing enzymes (PHDs), cytokines, and beta 2-integrins cooperates in HIF pathway activation in neutrophils. Using either the PHD inhibitor roxadustat (ROX) (pseudohypoxia) or normobaric hypoxia to stabilize HIF, we observed HIF1 alpha protein accumulation in adherent neutrophils. Several inflammatory mediators did not induce HIF1 alpha protein but provided additive or even synergistic signals (e.g., GM-CSF) under pseudohypoxic and hypoxic conditions. Importantly, and in contrast to adherent neutrophils, HIF1 alpha protein expression was not detected in strictly suspended neutrophils despite PHD enzyme inhibition and the presence of inflammatory mediators. Blocking beta 2-integrins in adherent and activating beta 2-integrins in suspension neutrophils established the indispensability of beta 2-integrins for increasing HIF1 alpha protein. Using GM-CSF as an example, increased HIF1 alpha mRNA transcription via JAK2-STAT3 was necessary but not sufficient for HIF1 alpha protein upregulation. Importantly, we found that beta 2-integrins led to HIF1 alpha mRNA translation through the phosphorylation of the essential translation initiation factors eIF4E and 4EBP1. Finally, pseudohypoxic and hypoxic conditions inducing HIF1 alpha consistently delayed apoptosis in adherent neutrophils on fibronectin under low serum concentrations. Pharmacological HIF1 alpha inhibition reversed delayed apoptosis, supporting the importance of this pathway for neutrophil survival under conditions mimicking extravascular sites. We describe a novel beta 2-integrin-controlled mechanism of HIF1 alpha stabilization in human neutrophils. Conceivably, this mechanism restricts HIF1 alpha activation in response to hypoxia and pharmacological PHD enzyme inhibitors to neutrophils migrating toward inflammatory sites.

Thyroid hormone receptor alpha (THR alpha) is a nuclear hormone receptor that binds triiodothyronine (T3) and acts as an important transcription factor in development, metabolism, and reproduction. In mammals, THR alpha has two major splicing isoforms, THR alpha 1 and THR alpha 2. The better-characterized isoform, THR alpha 1, is a transcriptional stimulator of genes involved in cell metabolism and growth. The less-well-characterized isoform, THR alpha 2, lacks the ligand-binding domain (LBD) and is thought to act as an inhibitor of THR alpha 1 activity. The ratio of THR alpha 1 to THR alpha 2 splicing isoforms is therefore critical for transcriptional regulation in different tissues and during development. However, the expression patterns of both isoforms have not been studied in healthy human tissues or in the developing brain. Given the lack of commercially available isoform-specific antibodies, we addressed this question by analyzing four bulk RNA-sequencing datasets and two scRNA-sequencing datasets to determine the RNA expression levels of human THRA1 and THRA2 transcripts in healthy adult tissues and in the developing brain. We demonstrate how 10X Chromium scRNA-seq datasets can be used to perform splicing-sensitive analyses of isoforms that differ at the 3 '-end. In all datasets, we found a strong predominance of THRA2 transcripts at all examined stages of human brain development and in the central nervous system of healthy human adults.

Animal manure is applied in agriculture to improve soil fertility and crop yield. Nonetheless, manure can also carry Escherichia coli (E. coli), including antibiotic-resistant strains. Therefore, it may pose a risk for environmental contamination. This review includes 50 studies which were identified from the search terms related to the transmission of E. coli through manure. The review outlines the potential routes of E. coli transmission from manure to soil, water and crops and which factors most critically determine persistence and contamination. The persistence of E. coli in soil is highly variable, ranging from <30 days for composted manures to more than 200 days in cooler conditions. These differences depend on the type of manure used, the environmental conditions and the treatment employed. While crops can be contaminated directly through application of manure, contaminated irrigation water may be a more important pathway. The foremost cause of surface water contamination seems to be rainfall runoff, whereas groundwater contamination is rather uncommon, mainly happening in areas with specific soil conditions. Composting and adherence to pre-harvest intervals are very effective mitigation strategies that can greatly reduce contamination risks. Overall, this review identifies research gaps on water contamination pathways and the persistence of resistant strains. Moreover, it sets up the basis for the development of robust risk assessments and evidence-informed approaches to address the contamination risks that are linked to animal manure.

Background Remote patient management may improve prognosis in heart failure. Daily review of transmitted data for early recognition of patients at risk requires substantial resources that represent a major barrier to wide implementation. An automated analysis of incoming data for detection of risk for imminent events would allow focusing on patients requiring prompt medical intervention. Methods We analysed data of the Telemedical Interventional Management in Heart Failure II (TIM-HF2) randomized trial that were collected during quarterly in-patient visits and daily transmissions from non-invasive monitoring devices. By application of machine learning, we developed and internally validated a risk score for heart failure hospitalisation within seven days following data transmission as estimate of short-term patient risk for adverse heart failure events. Score performance was assessed by the area under the receiver-operating characteristic (ROCAUC) and compared with a conventional algorithm, a heuristic rule set originally applied in the randomized trial. Results The machine learning model significantly outperformed the conventional algorithm (ROCAUC 0.855 vs. 0.727, p < 0.001). On average, the machine learning risk score increased continuously in the three weeks preceding heart failure hospitalisations, indicating potential for early detection of risk. In a simulated one-year scenario, daily review of only the one third of patients with the highest machine learning risk score would have led to detection of 95% of HF hospitalisations occurring within the following seven days. Conclusions A machine learning model allowed automated analysis of incoming remote monitoring data and reliable identification of patients at risk of heart failure hospitalisation requiring immediate medical intervention. This approach may significantly reduce the need for manual data review.

Gaussian states of bosonic quantum systems enjoy numerous technological applications and are ubiquitous in nature. Their significance lies in their simplicity, which in turn rests on the fact that they are uniquely determined by two experimentally accessible quantities, their first and second moments. But what if these moments are only known approximately, as is inevitable in any realistic experiment? What is the resulting error on the Gaussian state itself, as measured by the most operationally meaningful metric for distinguishing quantum states, namely, the trace distance? In this work, we fully resolve this question by demonstrating that if the first and second moments are known up to an error ε, the trace distance error on the state also scales as ε, and this functional dependence is optimal. To prove this, we establish tight bounds on the trace distance between two Gaussian states in terms of the norm distance of their first and second moments. As an application, we improve existing bounds on the sample complexity of tomography of Gaussian states.

Background: The use of mammalian target of rapamycin inhibitors (mTORis) in kidney transplantation increases the risk of donor-specific human leukocyte antigen (HLA) antibody formation and rejection. Here, we investigated the long-term consequences of early mTORi treatment compared to calcineurin inhibitor (CNI) treatment. Methods: In this retrospective single-center analysis, key outcome parameters were compared between patients participating in randomized controlled immunosuppression trials between 1998 and 2011, with complete follow-up until 2018. The outcomes of eligible patients on a CNI-based regimen (n = 384) were compared with those of patients randomized to a CNI-free mTORi-based regimen (n = 81) and 76 patients randomized to a combination of CNI and mTORi treatments. All data were analyzed according to the intention-to-treat (ITT) principle. Results: Deviation from randomized immunosuppression for clinical reasons occurred significantly more often and much earlier in both mTORi-containing regimens than in the CNI treatment. Overall patient survival, graft survival, and death-censored graft survival did not differ between the treatment groups. Donor-specific HLA antibody formation and BPARs were significantly more common in both mTORi regimens than in the CNI-based immunosuppression. Conclusions: The tolerability and efficacy of the mTORi treatment in kidney graft recipients are inferior to those of CNI-based immunosuppression, while the long-term patient and graft survival rates were similar.

Achiral molecules can be made temporarily chiral by excitation with electric fields, in the sense that an average over molecular orientations displays a net chiral signal [D. S. Tikhonov et al., Sci. Adv. 8, eade0311 (2022)]. Here, we go beyond the assumption of molecular orientations to remain fixed during the excitation process. Treating both rotations and vibrations quantum mechanically, we identify conditions for the creation of chiral vibrational wave packets, with net chiral signals, in ensembles of achiral molecules which are initially randomly oriented. Based on the analysis of symmetry and controllability, we derive excitation schemes for the creation of chiral wave packets using a combination of (a) microwave and IR pulses and (b) a static field and a sequence of IR pulses. These protocols leverage quantum rotational dynamics for pump-probe spectroscopy of chiral vibrational dynamics, extending the latter to regions of the electromagnetic spectrum other than the UV.

Squeezing is a nonclassical feature of quantum states that is a useful resource, for example, in quantum sensing of mechanical forces. Here, we show how to use optimal control theory to maximize squeezing in an optomechanical setup with two external drives and determine how fast the mechanical mode can be squeezed. For the autonomous drives considered here, we find the inverse cavity decay to lower-bound the protocol duration. At and above this limit, we identify a family of protocols leveraging a two-stage control strategy, where the mechanical mode is cooled before it is squeezed. Identification of the control strategy allows for two important insights: to determine the factors that limit squeezing and to simplify the time dependence of the external drives, making our protocol readily applicable in experiments.

Seit die Philosophie sich aus dem umfassenden Fundament der Metaphysik entlassen hatte, fächerte sie sich, ähnlich den Wissenschaften, in fachliche Segmente auf: Epistemologie, Ontologie, Geschichtsphilosophie, politische Philosophie, Naturphilosophie, Existenzphilosophie, praktische Philosophie, Ethik, Wissenschaftstheorie etc. Für das Wirtschaftliche im Philosophischen etablierte sich ab etwa Ende des 19. Jahrhunderts der Name ‘Wirtschaftsphilosophie’. Aus der Wirtschaftsphilosophie wurde aber bislang keine eigene philosophische Teildisziplin, vielmehr wurde sie auf unbestimmte Weise dem weiten Bereich der Praktischen Philosophie zugeschlagen. Wirtschaftsphilosophie ist aber vielmehr ein Reflexionsraum, der alle fachlich ausdifferenzierten Segmente des Philosophischen durchzieht. Das zeigt sich vor allem daran, auf welch verschiedene Art Wirtschaftsphilosophie heute betrieben wird: beispielsweise als epistemologische Befragung der vorherrschenden Semantik der Ökonomik, als Hinterfragen der Rationalitätsphilosophie der modern economics, als gabenökonomische Spurenanalyse einer Reziprozitätsphilosophie im Ökonomischen, als geschichtsphilosophische Rekonstruktion des Kapitalismus und seiner Industrialisierungswirkungen, als Rhetorik des Ökonomischen und ihrer narrativen Ausprägungen, als medienphilosophische Rekonstruktion der Finanzökonomie, als ethische Analyse von Normengeltung im Ökonomischen, als Philosophie der Dynamik der Ordnungsvorstellungen in der Geschichte, als politische Philosophie der politischen Ökonomie u.a. Es bildet sich kein Standardmodell heraus, sondern 2 ein bewegliches Feld philosophischer Reflektion des Ökonomischen, zum Teil “in rücksichtsloser Überschreitung” (Rorty) etablierter Begriffssysteme, um Neubeschreibungen und neue Interpretationen zu leisten. Die Philosophie hat immer schon das wirtschaftliche Handeln des Menschen thematisiert. Einschlägige Ansätze finden sich von Platon und Aristoteles über Thomas von Aquin, John Locke, Wolff, Rousseau, Fichte, Hegel, Marx und Nietzsche bis zu Bataille, Baudrillard, Derrida, Rawls, Sen und anderen. Diese Ansätze bildeten sich aber nicht zu einer spezifischen Wirtschaftsphilosophie aus, sondern blieben Reflexionen des Ökonomischen im Kontext der je eigenen Positionen und Ansätze. Heute zeigt sich: Die Philosophie, soweit sie das Wirtschaften reflektiert, denkt über die Wirtschaft als Sphäre nach, polyvalent, in all ihren Dimensionen, die das Effiziente weit übersteigen. Sie kann die Wirtschaft in ihrer Spannung zwischen Überfluss, Freiheit und Notwendigkeit reflektieren, ohne Dogmen, Mythen oder Ideologien aufzusitzen. Dieses intellektuelle Potenzial wird jedoch nicht genutzt, wenn man die Wirtschaftsphilosophie auf praktische Philosophie bzw. auf Wirtschaftsethik einschränkt. Angemessen wäre es heute, Wirtschaftsphilosophie als ein disziplinenübergreifendes Projekt anzusehen, innerhalb dessen die Reflexion erkenntnistheoretischer und methodologischer Aspekte und deren praktische Konsequenzen sowohl für die ökonomische Theoriebildung als auch das wirtschaftliche Handeln im Vordergrund stehen. Eine solche Ausfaltung des wirtschaftsphilosophischen Reflexionspotentials umfasst ein Spektrum von philosophischen Ansätzen über ökonomische Grundlagenfragen, Theorien und Praktiken, wodurch kein einheitliches Feld entsteht, sondern sich verschiedene Methoden, Narrationen, Systeme und Diskurse bilden. Ziel wirtschaftsphilosophischer Konsolidierung sollte es daher nicht sein, eine ähnliche fachliche Konsistenz wie die Wirtschaftswissenschaften erlangen zu wollen (ein Ideal, das derzeit auch innerhalb der Ökonomik herausgefordert wird), sondern einen Reflexionsraum zu schaffen, der die verschiedenen ökonomischen Theorien und Praktiken spiegeln kann (vor allem in Bezug auf ihre kontextuelle und kulturelle Einbettung). Vor diesem Hintergrund fasst das Positionspapier die wichtigsten Ergebnisse des Workshops zusammen, beschreibt die Potentiale und Probleme der Wirtschaftsphilosophie und macht Vorschläge für die Positionierung der Wirtschaftsphilosophie in Forschung, Lehre und Öffentlichkeit.

VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic) syndrome is a recently recognized systemic autoinflammatory disease caused by somatic mutations in hematopoietic progenitor cells. This case series of four patients with VEXAS syndrome and comorbid myelodysplastic syndrome (MDS) aims to describe clinical, imaging, and hematologic disease presentations as well as response to therapy. Four patients with VEXAS syndrome and MDS are described. A detailed analysis of imaging features, hemato-oncological presentation including bone marrow microscopy and clinical-rheumatological disease features and treatment outcomes is given. All patients were male; ages ranged between 64 and 81 years; all were diagnosed with MDS. CT imaging was available for three patients, all of whom exhibited pulmonary infiltrates of varying severity, resembling COVID-19 or hypersensitivity pneumonitis without traces of scarring. Bone marrow microscopy showed maturation-disordered erythropoiesis and pathognomonic vacuolation. Somatic mutation in the UBA1 codon 41 were found in all patients by next-generation sequencing. Therapy regimes included glucocorticoids, JAK1/2-inhibitors, nucleoside analogues, as well as IL-1 and IL-6 receptor antagonists. No fatalities occurred (observation period from symptom onset: 18-68 months). Given the potential underreporting of VEXAS syndrome, we highly recommend contemporary screening for UBA1 mutations in patients presenting with ambiguous signs of systemic autoinflammatory symptoms which persist over 18 months despite treatment. The emergence of cytopenia, especially macrocytic hyperchromic anemia, should prompt early testing for UBA1 mutations. Notably conspicuous, pulmonary alterations in CT imaging of patients with therapy-resistant systemic autoinflammatory symptoms should be discussed in interdisciplinary medical teams (Rheumatology, Hematology, Radiology and further specialist departments) to facilitate timely diagnosis during the clinical course of the disease.

Background Considering the expected increase in the elderly population and the growing emphasis on aging-related biomedical research, the demand for aged laboratory animals has surged, challenging established husbandry practices. Our objective was to establish a cost-effective method for environmental enrichment, utilizing the liver as a representative organ to assess potential metabolic changes in response to differing enrichment levels.

Methods We conducted a six-month study involving 24 male Sprague Dawley rats, randomly assigned to four environmental enrichment groups. Two groups were housed in standard cages, while the others were placed in modified rabbit cages. Half of the groups received weekly playtime in an activity focused rat housing unit. We evaluated hormone levels, playtime behavior, and subjective handling experience. Additionally, liver tissue proteomic analysis was performed.

Results Initial corticosterone levels and those after 3 and 6 months showed no significant differences. Yet, testosterone levels were lower in the control group by the end of the study (p = 0.007). We observed 1871 distinct proteins in liver tissue, with 77% being common across groups. In gene ontology analysis, no specific pathways were overexpressed. In semiquantitative analysis, we observed differences in proteins associated in lipid metabolism such as Apolipoprotein A-I and Acyl-CoA 6-desaturase, which were lower in the control group (p = 0.024 and p = 0.009). Rats in the intervention groups with weekly playtime displayed the least amount of reported distress during inspection or upon room entry and were less prone to accepting treats. Removing animals from their enclosure was most effortless for those in the large cage group. Over time, there was a decrease in conflicts among rats that interacted only twice weekly during playpen time.

Discussion In summary, refining husbandry practices for aging rats is both simple and budget-friendly, with no apparent adverse effects on stress levels, animal development, or relevant metabolic changes in the liver.

The aim of our study was to evaluate the potential role of Artificial Intelligence tools like ChatGPT in patient education. To do this, we assessed both the quality and readability of information provided by ChatGPT 3.5 and 4 in relation to Anterior Cruciate Ligament (ACL) injury and treatment. ChatGPT 3.5 and 4 were used to answer common patient queries relating to ACL injuries and treatment. The quality of the information was assessed using the DISCERN criteria. Readability was assessed with the use of seven readability formulae: the Flesch-Kincaid Reading Grade Level, the Flesch Reading Ease Score, the Raygor Estimate, the SMOG, the Fry, the FORCAST, and the Gunning Fog. The mean reading grade level (RGL) was compared with the recommended 8th-grade reading level, the mean RGL among adults in America. The perceived quality and mean RGL of answers given by both ChatGPT 3.5 and 4 was also compared. Both ChatGPT 3.5 and 4 yielded DISCERN scores suggesting "good" quality of information, with ChatGPT 4 slightly outperforming 3.5. However, readability levels for both versions significantly exceeded the average 8th-grade reading level for American patients. ChatGPT 3.5 had a mean RGL of 18.08, while the mean RGL of ChatGPT 4 was 17.9, exceeding the average American reading grade level by 10.08 grade levels and 9.09 grade levels, respectively. While ChatGPT can provide both reliable and good quality information on ACL injuries and treatment options, the readability of the content may limit its utility. Additionally, the consistent lack of source citation represents a significant area of concern for patients and clinicians alike. If AI is to play a role in patient education, it must reliably produce information which is accurate, easily comprehensible, and clearly sourced.

Although endangerment towards others is a criterion for an involuntary admission in many countries, research on risk assessment of endangerment among involuntarily admitted individuals is limited. In this retrospective case-control study, we calculated scores for a German-translated version of the Violence Risk Screening-10 (V-RISK-10) and the Broset Violence Checklist (BVC) in a sample of 111 people undergoing an involuntary admission in Reinickendorf, Berlin. Outcomes were violence, coercive measures, and readmission. In line with our hypotheses, the BVC demonstrated stronger predictive validities for short-term, and V-RISK-10 for long-term events. There was an incremental validity for both instruments for restraint 24 hours after admission and any violence until discharge. These findings support the evidence that structured risk assessment instruments may be useful for individuals undergoing an involuntary admission. Ethical considerations about screening procedures are discussed.

Fluorescently labelled compounds are often employed to study the paracellular properties of epithelia. For flux measurements, these compounds are added to the donor compartment and samples collected from the acceptor compartment at regular intervals. However, this method fails to detect rapid changes in permeability. For continuous transepithelial flux measurements in an Ussing chamber setting, a device was developed, consisting of a flow-through chamber with an attached LED, optical filter, and photodiode, all encased in a light-impermeable container. The photodiode output was amplified and recorded. Calibration with defined fluorescein concentration (range of 1 nM to 150 nM) resulted in a linear output. As proof of principle, flux measurements were performed on various cell lines. The results confirmed a linear dependence of the flux on the fluorescein concentration in the donor compartment. Flux depended on paracellular barrier function (expression of specific tight junction proteins, and EGTA application to induce barrier loss), whereas activation of transcellular chloride secretion had no effect on fluorescein flux. Manipulation of the lateral space by osmotic changes in the perfusion solution also affected transepithelial fluorescein flux. In summary, this device allows a continuous recording of transepithelial flux of fluorescent compounds in parallel with the electrical parameters recorded by the Ussing chamber.