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Enhancing thromboresistance of neurovascular nickel-titanium devices with responsive heparin hydrogel coatings
No full textBackground Neurointerventional devices, particularly laser-cut thin-strut stents made of self-expanding nickel-titanium alloy, are increasingly utilized for endovascular applications in intracranial arteries and dural venous sinuses. Preventing thrombosis and stroke necessitates systemic anticoagulant and antiplatelet therapies with the risk of bleeding complications. Antithrombotic coatings present a promising solution.
Methods In this study, we investigated the potential of hydrogels composed of four-armed poly(ethylene glycol) (starPEG) and heparin, with or without coagulation-responsive heparin release, as coatings for neurovascular devices to mitigate blood clot formation. We evaluated the feasibility and efficacy of these coatings on neurovascular devices through in vitro Chandler-Loop assays and implantation experiments in the supra-aortic arteries of rabbits.
Results Stable and coagulation-responsive starPEG-heparin hydrogel coatings exhibited antithrombotic efficacy in vitro, although with a slightly reduced thromboprotection observed in vivo. Furthermore, the hydrogel coatings demonstrated robustness against shear forces encountered during deployment and elicited only marginal humoral and cellular inflammatory responses compared with the reference standards.
Conclusion Heparin hydrogel coatings offer promising benefits for enhancing the hemocompatibility of neurointerventional devices made of self-expanding nickel-titanium alloy. The variance in performance between in vitro and in vivo settings may be attributed to differences in low- and high-shear blood flow conditions inherent to these models. These models may represent the differences in venous and arterial systems. Further optimization is warranted to tailor the hydrogel coatings for improved efficacy in arterial applications
Predictors for severe persisting pain in rheumatoid arthritis are associated with pain origin and appraisal of pain
No full textObjectives To determine the proportion of patients with rheumatoid arthritis (RA) with severe persisting pain and to identify predictive factors despite treatment-controlled disease activity.
Methods This prospective multicentre study included outpatients with RA scheduled for escalation of anti-inflammatory treatment due to active disease and severe pain (Disease Activity Score 28 (DAS28)>3.2 and Visual Analogue Scale (VAS)>50). At week 24, patients were stratified into reference group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score3.2, regardless of VAS pain score) and persisting pain group (DAS28 improvement>1.2 or DAS28≤3.2 and VAS pain score≥50). The former two subgroups ended the study at week 24. The latter continued until week 48. Demographic data, DAS28-C reactive protein, VAS for pain, painDETECT Questionnaire (PD-Q) to identify neuropathic pain (NeP) and the Pain Catastrophising Scale were assessed and tested for relation to persisting pain.
Results Of 567 patients, 337 (59.4%) were classified as reference group, 102 (18.0%) as non-responders and 128 (22.6%) as patients with persisting pain. 21 (8.8%) responders, 28 (35.0%) non-responders and 27 (26.5%) persisting pain patients tested positive for NeP at week 24. Pain catastrophising (p=0.002) and number of tender joints (p=0.004) were positively associated with persisting pain at week 24. Baseline PD-Q was not related to subsequent persisting pain.
Conclusions Persisting and non-nociceptive pain occur frequently in RA. Besides the potential involvement of NeP, pain catastrophising and a higher number of tender joints coincide with persisting pain
Textbook Neoadjuvant Outcome - Novel Composite Measure of Oncological Outcomes among Gastric Cancer Patients Undergoing Multimodal Treatment
No full textThe incidence of gastric cancer (GC) is expected to increase to 1.77 million cases by 2040. To improve treatment outcomes, GC patients are increasingly treated with neoadjuvant chemotherapy (NAC) prior to curative-intent resection. Although NAC enhances locoregional control and comprehensive patient care, survival rates remain poor, and further investigations should establish outcomes assessment of current clinical pathways. Individually assessed parameters have served as benchmarks for treatment quality in the past decades. The Outcome4Medicine Consensus Conference underscores the inadequacy of isolated metrics, leading to increased recognition and adoption of composite measures. One of the most simple and comprehensive is the “All or None” method, which refers to an approach where a specific set of criteria must be fulfilled for an individual to achieve the overall measure. This narrative review aims to present the rationale for the implementation of a novel composite measure, Textbook Neoadjuvant Outcome (TNO). TNO integrates five objective and well-established components: Treatment Toxicity, Laboratory Tests, Imaging, Time to Surgery, and Nutrition. It represents a desired, multidisciplinary care and hospitalization of GC patients undergoing NAC to identify the treatment- and patient-related data required to establish high-quality oncological care further. A key strength of this narrative review is the clinical feasibility and research background supporting the implementation of the first and novel composite measure representing the “ideal” and holistic care among patients with locally advanced esophago-gastric junction (EGJ) and GC in the preoperative period after NAC. Further analysis will correlate clinical outcomes with the prognostic factors evaluated within the TNO framework
Who Gets the Credit for Success and the Blame for Failure? On the Links Between Narcissism and Self- and Group-Serving Biases
No full textPeople often attribute success to themselves and failure to others. Past research indicates that this tendency toward self-serving attributions is pronounced among individuals high in trait narcissism. The aim of this registered report was to re-visit the link between narcissism and self-serving attributions by studying attributions in a group context and by distinguishing between two major dimensions of grandiose narcissism, admiration, and rivalry. We conducted a group study, (N = 422 participants nested in 54 groups), in which participants of each group were randomly assigned to one of two teams which then engaged in an intergroup competition. In line with our hypotheses, admiration predicted the tendency to take personal credit for success. Contrary to our hypotheses, rivalry did not uniquely predict the tendency to blame others for failure. Instead, admiration uniquely predicted the tendency to attribute negative team outcomes to unfairness of the competing outgroup. Explorative analyses further revealed that both admiration and rivalry were associated with the tendency to attribute negative, rather than positive, team outcomes to chance. Taken together, the findings indicate that narcissism goes along with an increased propensity for self-serving attributions in competitive intergroup settings and that this tendency is mainly driven by the admiration dimension
A Reduction in the Readily Releasable Vesicle Pool Impairs GABAergic Inhibition in the Hippocampus after Blood–Brain Barrier Dysfunction
No full textMajor burdens for patients suffering from stroke are cognitive co-morbidities and epileptogenesis. Neural network disinhibition and deficient inhibitive pulses for fast network activities may result from impaired presynaptic release of the inhibitory neurotransmitter GABA. To test this hypothesis, a cortical photothrombotic stroke was induced in Sprague Dawley rats, and inhibitory currents were recorded seven days later in the peri-infarct blood–brain barrier disrupted (BBBd) hippocampus via patch-clamp electrophysiology in CA1 pyramidal cells (PC). Miniature inhibitory postsynaptic current (mIPSC) frequency was reduced to about half, and mIPSCs decayed faster in the BBBd hippocampus. Furthermore, the paired-pulse ratio of evoked GABA release was increased at 100 Hz, and train stimulations with 100 Hz revealed that the readily releasable pool (RRP), usually assumed to correspond to the number of tightly docked presynaptic vesicles, is reduced by about half in the BBBd hippocampus. These pathophysiologic changes are likely to contribute significantly to disturbed fast oscillatory activity, like cognition-associated gamma oscillations or sharp wave ripples and epileptogenesis in the BBBd hippocampus
Tenascin-R promotes assembly of the extracellular matrix of perineuronal nets via clustering of aggrecan
No full textCognition in patients with myelin oligodendrocyte glycoprotein antibody- associated disease: a prospective, longitudinal, multicentre study of 113 patients (CogniMOG-Study)
No full textBackground Data on cognition in patients with myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) are limited to studies with small sample sizes. Therefore, we aimed to analyse the extent, characteristics and the longitudinal course of potential cognitive deficits in patients with MOGAD.
Methods The CogniMOG-Study is a prospective, longitudinal and multicentre observational study of 113 patients with MOGAD. Individual cognitive performance was assessed using the Paced Auditory Serial Addition Task (PASAT), the Symbol Digit Modalities Test (SDMT) and the Multiple Sclerosis Inventory Cognition (MuSIC), which are standardised against normative data from healthy controls. Cognitive performance was assessed at baseline and at 1-year and 2-year follow-up assessments. Multiple linear regression was used to analyse demographic and clinical predictors of cognitive deficits identified in previous correlation analyses.
Results At baseline, the study sample of MOGAD patients showed impaired standardised performance on MuSIC semantic fluency (mean=−0.29, 95% CI (−0.47 to −0.12)) and MuSIC congruent speed (mean=−0.73, 95% CI (−1.23 to −0.23)). Around 1 in 10 patients showed deficits in two or more cognitive measures (11%). No decline in cognition was observed during the 1-year and 2-year follow-up period. Cerebral lesions were found to be negatively predictive for SDMT (B=−8.85, 95% CI (−13.57 to −4.14)) and MuSIC semantic fluency (B=−4.17, 95% CI (−6.10 to −2.25)) test performance.
Conclusions Based on these data, we conclude that MOGAD patients show reduced visuomotor processing speed and semantic fluency to the extent that the disease burden includes cerebral lesions
Distinct characteristics of unique immunoregulatory canine non-conventional TCRαβpos CD4negCD8αneg double-negative T cell subpopulations
No full textConventional CD4pos regulatory T (Treg) cells characterized by expression of the key transcription factor forkhead box P3 (FoxP3) are crucial to control immune responses, thereby maintaining homeostasis and self-tolerance. Within the substantial population of non-conventional T cell receptor (TCR)αβpos CD4negCD8αneg double-negative (dn) T cells of dogs, a novel FoxP3pos Treg-like subset was described that, similar to conventional CD4pos Treg cells, is characterized by high expression of CD25. Noteworthy, human and murine TCRαβpos regulatory dn T cells lack FoxP3. Immunosuppressive capacity of canine dn T cells was hypothesized based on expression of inhibitory molecules (interleukin (IL)-10, cytotoxic T-lymphocyte associated protein 4, CTLA4). Here, to verify their regulatory function, the dnCD25pos (enriched for FoxP3pos Treg-like cells) and the dnCD25neg fraction, were isolated by fluorescence-activated cell sorting from peripheral blood mononuclear cells (PBMC) of Beagle dogs and analyzed in an in vitro suppression assay in comparison to conventional CD4posCD25pos Treg cells (positive control) and CD4posCD25neg T cells (negative control). Canine dnCD25pos T cells suppressed the Concanavalin A-driven proliferation of responder PBMC to a similar extent as conventional CD4posCD25pos Treg cells. Albeit to a lesser extent than FoxP3-enriched dn and CD4posCD25pos populations, even dnCD25neg T cells reduced the proliferation of responder cells. This is remarkable, as dnCD25neg T cells have a FoxP3neg phenotype comparable to non-suppressive CD4posCD25neg T cells. Both, CD25pos and CD25neg dn T cells, can mediate suppression independent of cell-cell contact and do not require additional signals from CD4posCD25neg T cells to secrete inhibitory factors in contrast to CD4posCD25pos T cells. Neutralization of IL-10 completely abrogated the suppression by dnCD25pos and CD4posCD25pos Treg cells in a Transwell™ system, while it only partially reduced suppression by dnCD25neg T cells. Taken together, unique canine non-conventional dnCD25pos FoxP3pos Treg-like cells are potent suppressor cells in vitro. Moreover, inhibition of proliferation of responder T cells by the dnCD25neg fraction indicates suppressive function of a subset of dn T cells even in the absence of FoxP3. The identification of unique immunoregulatory non-conventional dn T cell subpopulations of the dog in vitro is of high relevance, given the immunotherapeutic potential of manipulating regulatory T cell responses in vivo
Improving the predictions of black carbon (BC) optical properties at various aging stages using a machine-learning-based approach
No full textIt is necessary to accurately determine the optical properties of highly absorbing black carbon (BC)
aerosols to estimate their climate impact. In the past, there has been hesitation about using realistic fractal mor-
phologies when simulating BC optical properties due to the complexity involved in the simulations and the cost
of the computations. In this work, we demonstrate that, by using a benchmark machine learning (ML) algorithm,
it is possible to make fast and highly accurate predictions of the optical properties for BC fractal aggregates.
The mean absolute errors (MAEs) for the optical efficiencies ranged between 0.002 and 0.004, whereas they
ranged between 0.003 and 0.004 for the asymmetry parameter. Unlike the computationally intensive simula-
tions of complex scattering models, the ML-based approach accurately predicts optical properties in a fraction
of a second. Physiochemical properties of BC, such as total particle size (number of primary particles (Npp),
outer volume equivalent radius (ro), mobility diameter (Dm), outer primary particle size (ao), fractal dimension
(Df), wavelength (λ), and fraction of coating (fcoating), were used as input parameters for the developed ML
algorithm. An extensive evaluation procedure was carried out in this study while training the ML algorithms.
The ML-based algorithm compared well with observations from laboratory-generated soot, demonstrating how
realistic morphologies of BC can improve their optical properties. Predictions of optical properties like single-
scattering albedo (ω) and mass absorption cross-section (MAC) were improved compared to the conventional
Mie-based predictions. The results indicate that it is possible to generate optical properties in the visible spec-
trum using BC fractal aggregates with any desired physicochemical properties within the range of the training
dataset, such as size, morphology, or organic coating. Based on these findings, climate models can improve their
radiative forcing estimates using such comprehensive parameterizations for the optical properties of BC based
on their aging stages
Assoziation genetischer Polymorphismen im TLR7-Gen mit Krankheitsstadium und Verlauf der Hepatitis-B-Virus-Infektion: Dissertation zur Erlangung des akademischen Grades Dr. med. dent. an der Medizinischen Fakultät der Universität Leipzig
No full textHintergrund: Hepatitis B ist weltweit die Hauptursache für Leberzirrhose und hepatozelluläre Karzinome, an deren Folgen jährlich etwa 820.000 Menschen sterben. Aufgrund dieser globalen Auswirkung hat sich die WHO das Ziel gesetzt, die Erkrankung der viralen Hepatitis B bis 2030 vollständig zu eliminieren. Diese Zielsetzung zeigt die Bedeutung und Relevanz für die aktuelle klinische Forschung im Hinblick auf neue Therapieverfahren bis hin zur vollständigen Ausheilung der viralen Hepatitis-B-Infektion. Es gibt bereits Ansätze, welche sich auf die gezielte Aktivierung der angeborenen Immunabwehr fokussieren. Hierbei steht vor allem der TLR7-Rezeptor im Fokus der aktuellen Forschung.
Fragestellung: In dieser Studie wurden erstmalig vier unterschiedliche (rs179008, rs864058, rs2302267, rs3853839) genetische Polymorphismen des TLR7-Gens im Hinblick auf Krankheitsstadium und Verlauf der Hepatitis-B-Virus-Infektion untersucht.
Methodik: Es konnten in dem Zeitraum von 2003 bis 2015 insgesamt 922 Patienten kaukasischer Herkunft in die Studie eingeschlossen werden: In die Testgruppe (HBV-Infektion) wurden 668 Patienten eingeschlossen. Hierbei wurden sowohl Patienten mit chronischer HBV Infektion (nachweisliche HBsAg und HBV-DNA für mehr als 6 Monate, n = 417), als auch Patienten mit spontanem HBsAg-Verlust (Abwesenheit von HBsAg, jedoch mit Antikörpern gegen das HBsAg (anti-HBs) und Hepatitis-Core-Antigen (anti-HBc), n = 251) aufgenommen.
Die Kontrollgruppe umfasste unverwandte gesunde Blutspender (alle ohne nachweisliches HBsAg und ohne anti-HBc, n = 254). Ausschlusskriterien waren eine akute HBV- sowie HCV, HDV- oder HIV-Infektion als Koinfektion.
Die zu untersuchende genomische DNA lag bereits durch Vorarbeiten der Arbeitsgruppe vor. Daraufhin erfolgte die Amplifizierung der Patienten-DNA mittels PCR. Die genaue Genotypenverteilung der vier unterschiedlichen Polymorphismen wurde mittels Schmelzkurvenanalyse analysiert. Die statistische Auswertung der epidemiologischen Assoziationen wurde mit der Software SPSS Version 27.0 ausgewertet, dabei wurden p Werte ≤ 0,05 als statistisch signifikant definiert.
Ergebnisse: Der Wildtyp (AA) des SNP rs179008 stellt einen Risikofaktor bei weiblichen Patientinnen in Bezug auf die Entwicklung einer chronischen HBV-Infektion dar. Des Weiteren konnte ein Zusammenhang zwischen dem Wildtyp (TT) des SNP rs2302267 und dem Verlauf der Hepatitis-B-Virus-Infektion festgestellt werden. Dabei zeigte sich, dass der Wildtyp (TT) des SNP rs2302267 statistisch signifikant häufiger bei Patienten mit einer chronischen Hepatitis-B auftritt. Ebenso konnte gezeigt werden, dass der Wildtyp (GG) des SNP rs864058 mit dem Auftreten einer Leberzirrhose assoziiert ist.
Schlussfolgerung: Es konnten neue Auswirkungen zusätzlicher TLR7-Varianten auf das Fortschreiten der Hepatitis-B-Virus-Infektion festgestellt werden. Die Resultate unterstreichen die Bedeutung des Geschlechts, die genetische Veranlagung für die individualisierte Medizin, sowie die Entwicklung neuer auf TLR7-gerichteter Therapieansätze