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Das Bundesministerium für Bildung und Forschung (BMBF) hat die Karrierephase nach der Promotion bis zur Berufung auf eine Lebenszeitprofessur in der Vergangenheit wiederholt umgestaltet. Der Beitrag widmet sich dem derzeitigen Implementationsprozess der Tenure-Track-Professur von der politischen Intention von Bund und Ländern bis zur institutionellen Verankerung an den Universitäten. Anhand einer explorativen Fallstudie werden Hypothesen darüber gewonnen, wie Universitäten diese neue Personalkategorie in ihre institutionalisierten Strukturen eingliedern. Dazu wurden die Profilpapiere für die Berufung von Tenure-Track-Professor*innen analysiert und Expert*inneninterviews mit Dekan*innen zur Gestaltung der neuen Personalkategorie an ihren Fakultäten geführt. Der Beitrag zeigt, dass die Tenure-Track-Professur vornehmlich in aktuellen Forschungsgebieten und abseits des profilbildenden Kerns der Fächer implementiert wird. Eine Folge könnte sein, dass die Tenure-Track-Professur für Randständiges in den Forschungs- und Lehrprofilen reserviert wird. Damit scheint ihre Etablierung als gleichwertiger Karriereweg auf die Lebenszeitprofessur zweifelhaft.

Background: Patients with symptomatic internal carotid artery (ICA) stenosis are at high risk of recurrent ischemic stroke and require early interventional treatment and antiplatelet therapy. Increased bleeding rates might counterbalance the periprocedural efficacy of intensified platelet inhibition. We aim to investigate, whether Revacept, a competitive antagonist of glycoprotein VI, adjunct to standard antiplatelet therapy reduces the occurrence of ischemic lesions in patients with symptomatic ICA stenosis. Methods: International, multicenter (16 sites), 3-arm, randomized (1:1:1), double-blind, and placebo-controlled study with parallel groups, including patients with symptomatic ICA stenosis. A single infusion over 20 minutes of either placebo, 40 mg or 120 mg Revacept in addition to guideline-conform antiplatelet therapy was evaluated with regard to the exploratory efficacy end point: Number of new ischemic lesions on diffusion-weighted magnetic resonance imaging after treatment initiation. Main clinical outcome was the combined safety and efficacy end point including any stroke or death, transient ischemic attack, myocardial infarction, coronary intervention, and bleeding complications during follow-up. Results: Out of 160 randomized patients, 158 patients (68±10.1 years, 24% female) received study medication (51 patients placebo, 54 patients 40 mg Revacept and 53 patients 120 mg Revacept) and were followed for 11.2±2.3 months. A total of 1.16 (95% CI, 0.88–1.53)/1.05 (95% CI, 0.78–1.42; P =0.629)/0.63 (95% CI, 0.43–0.93) new diffusion-weighted magnetic resonance imaging lesions per patient were detected in the placebo/40 mg/120 mg Revacept groups, without statistical evidence of a difference. A reduction of the combined safety and efficacy end point during the study period was observed in patients who received 120 mg (HR, 0.46 [95% CI, 0.21–0.99]; P =0.047), but not 40 mg Revacept compared with placebo (HR, 0.72 [95% CI, 0.37–1.42]; P =0.343). Conclusions: Revacept 120 mg reduced the combined safety and efficacy end point in patients with symptomatic ICA stenosis. Registration: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT01645306.

ZusammenfassungHintergrund und Ziel der Arbeit: Bei der Kariesprophylaxe spielt eine wirksame und sichere Fluoridanwendung eine wichtige Rolle. Fluoride machen den Zahnschmelz widerstandsfähiger und schützen vor Karies. Dieser Beitrag gibt einen Überblick über die Fluoridanwendung aus unterschiedlichen Quellen zur Kariesprophylaxe bei Kindern und Jugendlichen in Deutschland.Methoden: Datengrundlage sind die in KiGGS Welle 2 (2014-2017) durchgeführten Ernährungsstudien KiESEL für 0,5- bis 5-Jährige und EsKiMo II für 6- bis 17-Jährige. Die Daten geben Auskunft über die Verwendung von Fluoridsupplementen, fluoridhaltiger Zahnpasta und fluoridiertem Salz. Ausgewiesen werden Prävalenzen und Ergebnisse multivariater binär-logistischer Regressionen. Es werden Unterschiede nach soziodemografischen Merkmalen berichtet.Ergebnisse: Von den 0,5- bis 5-Jährigen hatten 14,6 % ein Fluoridsupplement erhalten. In allen betrachteten Altersgruppen verwendeten über 90 % der Kinder und Jugendlichen üblicherweise fluoridhaltige Zahnpasta, mit Ausnahme der 0,5- bis 2-Jährigen (63,4 %). In etwa der Hälfte der Haushalte (51,3 %) der 0,5- bis 5-Jährigen wurden Mahlzeiten für das Kind überwiegend mit fluoridiertem Salz zubereitet. Bei den 6- bis 17-Jährigen war dies nur bei etwa einem Drittel (29,8 %) der Fall.Diskussion: Die Verwendung fluoridhaltiger Zahnpasta hat im Vergleich zur KiGGS-Basiserhebung (2003 - 2006) zugenommen. Sie ist bei den 0,5- bis 2-Jährigen gering, was sich teilweise durch die Empfehlungen zur Zeit der Datenerhebung erklären lässt, aber auch damit, dass bei einem Teil dieser Kinder (noch) keine Zahnpasta verwendet wurde. Fluoridiertes Salz wird insbesondere bei Kindern ab 6 Jahren noch zu selten zur Mahlzeitenzubereitung genutzt. Dies spricht für eine verstärkte Kommunikation der Empfehlungen zur Kariesprophylaxe und zur Förderung einer zahngesunden Ernährung.

A pre pre-release to obtain a valid DOI from Zenodo to be used in the publication for which this supporting repository was created.

PG16 is a broadly neutralizing antibody that binds to the gp120 subunit of the HIV-1 Env protein. The major interaction site is formed by the unusually long complementarity determining region (CDR) H3. The CDRH3 residue Tyr100H is known to represent a tyrosine sulfation site; however, this modification is not present in the experimental complex structure of PG16 with full-length HIV-1 Env. To investigate the role of sulfation for this complex, we modeled the sulfation of Tyr100H and compared the dynamics and energetics of the modified and unmodified complex by atomistic molecular dynamics simulations. Our results show that sulfation does not affect the overall conformation of CDRH3, but still enhances gp120 interactions both at the site of mutation and for the neighboring residues. This stabilization affects not only protein-protein contacts, but also the interactions between PG16 and the gp120 glycan shield. Further, we also investigated whether PG16-CDRH3 is a suitable template for the development of peptide mimetics. For a peptide spanning residues 93-105 of PG16 we obtained an experimental EC50 value of 3nM for the binding of gp120 to the peptide. This affinity can be enhanced by almost one order of magnitude by artificial disulfide bonding between residues 99 and 100F. In contrast, any truncation results in significantly lower affinity, suggesting that the entire peptide segment is involved in gp120 recognition. Their high affinity makes PG16-derived peptides useful building blocks for further optimization to obtain a potent inhibitor that efficiently blocks HIV-1 infection.

This is the version of the repository sent out for review, along with the accompanying pyglotaran v0.7.0 release paper. What's Changed ✨ Add case studies by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/1 🚇 Add pipeline to create PDFs from notebooks by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/3 ♻️ Refactor with project API by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/4 ✨ Create guides for r1-r4 with pyglotaran by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/6 ✨ Pre process raw data by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/7 👌 Use LaTeX equations in a markdown cell instead of an image by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/8 👌Improve 4TT case study notebook by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/9 🩹 Fix rc part3 case study after changing to pyglotaran guides by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/11 👌 Rename 'kinetic' parameters group to 'rates' for consistency and clarity by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/10 📚 Updated README with basics getting started instructions 👌 by @jsnel in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/12 📚🩹 Fix conda env creation instructions by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/13 ⬆️ Adapt to the release of pyglotaran v0.7.0 and pyglotaran-extras v0.7.0 by @jsnel in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/14 👌 Improve zenodo config by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/2 🧹 Remove deprecated figure_only argument in pyglotaran-extras plot functions by @s-weigand in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/15 New Contributors @s-weigand made their first contribution in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/1 @jsnel made their first contribution in https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/pull/12 Full Changelog: https://github.com/glotaran/pyglotaran-release-paper-supplementary-information/compare/obtain-doi...ready-for-review

PDF file - 45K, Associations between cumulative HPV load and SCC, stratified by skin type and time since transplantation (for OTR). In each case the reference category is HPV negative combined with the lowest load tertile.

Background: Beta-human papillomavirus (betaPV) may play a role in the development of cutaneous squamous cell carcinoma (SCC). However betaPV is highly prevalent, and it may only be people with a higher viral load who have increased risk of SCCs. We therefore examined the association between betaPV load and SCCs.Methods: We recruited 448 immunocompetent cases with SCCs and 464 controls from Italy and Australia and 497 immunosuppressed organ transplant recipients (OTR; 179 cases and 318 controls) from Europe. We used reverse hybridization to genotype 25 betaPV types in eyebrow hair follicles and determined the viral load for eight selected types using quantitative PCR. We used logistic regression to assess associations between type-specific and cumulative viral load and SCCs.Results: Australian and OTR participants in the highest cumulative load tertile were at significantly higher risk of SCCs than those in the lowest tertile. Those with more than four betaPV types in the high load tertile were at approximately three-fold increased risk of SCCs. In Australia, HPV23 and 36 loads were significantly associated with SCCs, with borderline associations for HPV5 and 38. In OTR, HPV8 and 38 loads were significantly associated and HPV20 and 36 were borderline. We found little evidence for an association between load and SCCs in Italy.Conclusions: High viral load may be associated with risk of cutaneous SCCs, with total load seemingly more important than the load of any specific type.Impact: Our findings lend weight to the hypothesis that HPV plays a role in skin carcinogenesis. Cancer Epidemiol Biomarkers Prev; 22(4); 719–27. ©2013 AACR.

Hepatic encephalopathy (HE) is a frequent and debilitating complication of liver disease and is oftentimes associated with hyperammonaemia. However, hyperammonaemia may occur in underlying conditions other than acute or chronic liver failure and clinical awareness is needed in order to be recognized and treated properly. A 24-year-old woman presented herself to our emergency department with acute confusion and altered mental state due to severe hyperammonaemia. The patient was diagnosed in the age of 14 with ornithine transcarbamylase (OTC) deficiency and was incompliant regarding her diet and suggested medication to treat this disorder. She was treated with sodium benzoate 250 mg/kg i.v., sodium phenylbutyrate/sodium phenylacetate 250 mg/kg i.v., L-arginine 250 mg/kg i.v., and received continuous hemofiltration. Under simultaneous medical treatment and haemodialysis, ammonia levels dropped to normal within 24 h and symptomatic encephalopathy ceased completely. OTC deficiency is rare in adults, and the majority of patients are diagnosed in childhood. It can lead to death if not diagnosed and treated properly. Our case underlines the importance of considering causes of HE other than liver cirrhosis.

Background: Cell-free DNA (cfDNA) and endogenous deoxyribonuclease activity are opposing mediators and might influence the inflammatory response following acute ischemic stroke. In this cohort study, we investigated the relation between these markers, circulating inflammatory mediators and clinical course including occurrence of stroke-associated infections (SAI) in patients with acute stroke. Methods: Ninety-two patients with stroke due to large vessel occlusion undergoing mechanical thrombectomy were prospectively recruited at Hannover Medical School from March 2018 to August 2019. Deoxyribonuclease activity, cfDNA, damage-associated molecular patterns, and circulating cytokines were measured in venous blood collected immediately before mechanical thrombectomy and 7 days later. Reperfusion status was categorized (sufficient/insufficient). Clinical outcome was evaluated using the modified Rankin Scale after 90 days, where a score of 3 to 6 was considered unfavorable. To validate findings regarding SAI, another stroke cohort (n=92) was considered with blood taken within 24 hours after stroke onset. Results: Patients with unfavorable clinical outcome had higher cfDNA concentrations. After adjustment for confounders (Essen Stroke Risk Score, National Institutes of Health Stroke Scale, and sex), 7-day cfDNA was independently associated with clinical outcome and especially mortality (adjusted odds ratio: 3.485 [95% CI, 1.001–12.134] and adjusted odds ratio: 9.585 [95% CI, 2.006–45.790]). No association was found between reperfusion status and cfDNA or deoxyribonuclease activity. While cfDNA concentrations correlated positively, deoxyribonuclease activity inversely correlated with distinct biomarkers. Baseline deoxyribonuclease activity was lower in patients who developed SAI compared with patients without SAI. This association was confirmed after adjustment for confounding factors (adjusted odds ratio: 0.447 [95% CI, 0.237–0.844]). In cohort 2, differences of deoxyribonuclease activity between patients with and without SAI tended to be higher with higher stroke severity. Conclusions: The interplay of endogenous deoxyribonuclease activity and cfDNA in acute stroke entails interesting novel diagnostic and potential therapeutic approaches. We confirm an independent association of cfDNA with a detrimental clinical course after stroke due to large vessel occlusion. This study provides first evidence for lower endogenous deoxyribonuclease activity as risk factor for SAI after severe stroke.

BackgroundThe identification of the underlying mechanism in ischemic stroke has important implications for secondary prevention. A disintegrin and metalloprotease with a thrombospondin type 1 motif, member 13 (ADAMTS-13) has antithrombotic properties and was repeatedly implicated in the pathophysiology of stroke. In this study, we, therefore, aimed to investigate whether ADAMTS-13 is associated with stroke etiology and the burden of vascular risk factors.MethodsWe determined ADAMTS-13 activity in two prospectively recruited stroke cohorts in the long-term course after the event. Cohort 1 (n = 88) consisted of patients who suffered a stroke due to embolic stroke of undetermined source (ESUS), cardioembolic stroke due to atrial fibrillation (AF), large-artery atherosclerosis, or small vessel disease. In cohort 2, patients with cryptogenic stroke and patent foramen ovale (PFO) scheduled for PFO closure (n = 38) were enrolled. As measures of vascular risk factor burden, the CHA2DS2VASC score, the Essen Stroke Risk Score (ESRS), and the Risk of Paradoxical Embolism (RoPE) score were calculated, as appropriate.ResultsADAMTS-13 activity was lower in patients with AF-related stroke compared to patients with ESUS (p = 0.0227), which was, however, due to confounding by vascular risk factors. ADAMTS-13 activity inversely correlated with the ESRS (r = −0.452, p < 0.001) and CHA2DS2VASC (r = −0.375, p < 0.001) in cohort 1. In accordance with these findings, we found a positive correlation between ADAMTS-13 activity and the RoPE score in cohort 2 (r = 0.413, p = 0.010).ConclusionADAMTS-13 activity is inversely correlated with the number of vascular risk factors across different stroke etiologies. Further study is warranted to establish ADAMTS-13 as a mediator of cerebrovascular risk.

Supplemental material, sj-docx-1-eso-10.1177_23969873231182492 for Diagnostic value of carotid intima-media thickness and clinical risk scores in determining etiology of ischemic stroke by Esther MW Sievering, Anika Grosshennig, Martina Kottas, Johanna Ernst, Rieke Ringlstetter, Armin Koch, Karin Weissenborn and Gerrit M Grosse in European Stroke Journal

Supplemental material, sj-docx-1-wso-10.1177_17474930231184366 for Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study by Gerrit M Grosse, Anika Hüsing, Andreas Stang, Nils Kuklik, Marcus Brinkmann, Darius Nabavi, Paul Sparenberg, Karin Weissenborn, Klaus Gröschel, Georg Royl, Sven Poli, Dominik Michalski, Christoph C Eschenfelder, Christian Weimar and Hans-Christoph Diener in International Journal of Stroke

Supplemental material, sj-docx-1-wso-10.1177_17474930231184366 for Early or late initiation of dabigatran versus vitamin-K-antagonists in acute ischemic stroke or TIA: The PRODAST study by Gerrit M Grosse, Anika Hüsing, Andreas Stang, Nils Kuklik, Marcus Brinkmann, Darius Nabavi, Paul Sparenberg, Karin Weissenborn, Klaus Gröschel, Georg Royl, Sven Poli, Dominik Michalski, Christoph C Eschenfelder, Christian Weimar and Hans-Christoph Diener in International Journal of Stroke

Background and aims Neuropsychiatric symptoms in hepatitis C (HCV) patients resemble those of patients with autoimmune hepatitis (AIH) or primary biliary cholangitis (PBC), whilst the mechanisms behind them are unknown. Here we looked for cerebral metabolic and/or microstructural alterations in patients with HCV, AIH or PBC as possible causes behind these symptoms. Methods Patients with HCV infection (n = 17), AIH (n = 14) or PBC (n = 11) and age-adjusted healthy controls (n = 18) underwent brain magnetic resonance imaging (MRI), magnetic resonance spectroscopy (MRS) and psychometric assessment of memory and attention. Brain relative proton density (PD) and T2 relaxation time (T2) were determined in 17 regions of interest (ROIs), as were the concentrations of N-acetyl-aspartate, choline, creatine, myo-inositol and glutamine + glutamate in frontal- (fWM) and parietal white matter (pWM). One-way analysis of variance and Kruskal-Wallis tests were used for group comparison. Correlations between altered neuropsychological findings and MRI/MRS observations were estimated with the Spearman ρ test. Results HCV, AIH and PBC patients revealed similar alterations in brain PD and metabolites compared to controls: significantly decreased PD in 7/17 ROIs in the HCV group, 16/17 ROIs in the PBC group and 14/17 ROIs in the AIH group, significantly increased N-acetyl-aspartate in fWM in all patients, significantly increased choline in the PBC group in both fWM and pWM, in the AIH group only in pWM and with a trend in the HCV group in pWM. Correlation analysis did not reveal significant associations between MRI/MRS alterations and neuropsychological dysfunction. Conclusion The findings suggest similar pathophysiological mechanisms behind neuropsychiatric symptoms associated with HCV infection, AIH and PBC.

In der Vergangenheit gab es in Deutschland unterschiedliche Empfehlungen zur Kariespravention durch Fluoridanwendung im Sauglings- und fruhen Kindesalter (0 bis 6 Jahre). Parallel existierende, unterschiedliche Empfehlungen fuhren jedoch zur Verunsicherung von Beratungskraften und Eltern/Betreuungspersonen, zu geringer Akzeptanz und zu unzureichender Umsetzung der Empfehlungen. Vertreterinnen und Vertreter der relevanten Fachgesellschaften und -gruppen bewerteten in einem vom Netzwerk Gesund ins Leben koordinierten Prozess die wissenschaftliche Evidenz, unter Berucksichtigung von Umsetzbarkeit und Erreichbarkeit auch von Familien mit erhohtem Kariesrisiko. In einem mehrstufigen Prozess wurden gemeinsame Empfehlungen formuliert. Von der Geburt bis zum Zahndurchbruch sollen Sauglinge ein Supplement mit 400–500 I.E. Vitamin D und 0,25 mg Fluorid erhalten. Nach dem Zahndurchbruch wird das Kind behutsam und allmahlich an das Zahneputzen herangefuhrt. Dabei soll entweder die Weiterfuhrung der systemischen Fluoridanwendung (0,25 mg Fluorid und 400–500 I.E. Vitamin D) oder die Fluoridanwendung durch Zahnpasta mit 1000 ppm Fluorid (bis zu 2‑mal taglich, jeweils bis zu 0,125 g, Reiskorngrose) gewahlt werden; das Vitamin-D-Supplement wird bis zum zweiten erlebten Fruhsommer weitergefuhrt. Ab 12 Monaten wird das 2‑mal tagliche Zahneputzen mit einer fluoridhaltigen Zahnpasta (1000 ppm Fluorid) fur alle Kinder empfohlen, zunachst mit einer geringen Zahnpastamenge (jeweils bis zu 0,125 g, Reiskorngrose), ab 24 Monaten mit einer groseren Menge (jeweils bis zu 0,25 g, Erbsengrose). Um eine zu hohe Fluoridaufnahme zu vermeiden, ist eine korrekte Dosierung der Zahnpasta unerlasslich. Die Aufklarung und Beratung zur Kariespravention und zur korrekten Umsetzung der Empfehlungen sollen im Rahmen der padiatrischen und zahnarztlichen Fruherkennungsuntersuchungen sowie im Rahmen der zahnmedizinischen Gruppenprophylaxe nach § 21 SGB V erfolgen.

BackgroundFibroblast activation protein α (FAP), a membrane glycoprotein with dipeptidyl-peptidase and collagenase properties, is expressed in atherosclerotic plaques and remodeling of the extracellular matrix based on fibrosis. Fibrosis is a main contributor of atrial cardiomyopathies. In acute MI, circulating FAP is associated with outcome. Here, we investigated the correlation of circulating FAP to echocardiographic parameters of atrial remodeling and neurological impairment in acute ischemic stroke.MethodsCirculating FAP plasma concentrations were determined by ELISA in 47 patients with acute stroke and 22 control patients without stroke. Echocardiography was performed in all participants. Laboratory analysis, National Institutes of Health Stroke Scale (NIHSS) scoring and prolonged Holter-ECG-monitoring were performed in all stroke patients.ResultsPatients with acute stroke had lower circulating FAP concentrations than the control cohort (92 ± 24 vs. 106 ± 22 ng/mL, P < 0.001). There was no difference between the circulating FAP concentration comparing stroke due to atrial fibrillation, embolic stroke of undetermined source (ESUS) or atherosclerotic origin. Septal atrial conduction time (sPA-TDI) and left atrial (LA) volume index to tissue Doppler velocity (LAVI/a‘) representing echocardiographic parameters of LA remodeling did not correlate with FAP concentrations (sPA-TDI: r = 0.123, p = 0.31; LAVI/a‘: r = 0.183, p = 0.132). Stroke severity as assessed by NIHSS inversely correlated with circulating FAP (r = −0.318, p = 0.04). FAP concentration had a fair accuracy for identifying stroke in the receiver operating characteristic (ROC) analysis (AUC = 0.710, 95% CI: 0.577–0.843). A FAP concentration of 101 ng/mL discriminated between presence and absence of stroke with a sensitivity of 72% and a specificity of 77%. Lower circulating FAP concentration was associated with cardio-cerebro-vascular events within 12 months after admission.ConclusionsOur study is the first to associate FAP with echocardiographic parameters of LA-remodeling and function. FAP did not correlate with sPA-TDI and LAVI/a‘. However, FAP was associated with stroke, neurological impairment, and cardio-cerebral events within 12 months. Therefore, FAP might enable individualized risk stratification in ischemic stroke.

(1) Background: Neurological complications such as acute ischemic stroke or postoperative delirium are frequent after cardiac surgery or percutaneous valve replacement. This study aimed to identify corresponding risk factors. (2) Methods: 297 patients with percutaneous valve replacement or cardiac surgery were postoperatively screened for neurological complications such as delirium, stroke, seizures and hallucinations twice daily for three days. Pre- and perioperative risk factors were evaluated in a multivariate model. (3) Results: Neurological complications occurred in 43.8% (n = 130) as composed of delirium (43.43%, n = 129), stroke (2.7%, n = 8), seizures (1.35%, n = 4) and real hallucinations (3.36%, n = 10). Multiple logistic regression revealed an association of neurological complications with lower Montreal Cognitive Assessment scores (Exp(B) 2.042; 95% CI, 1.183–3.525, p = 0.010), older age (Exp(B) 1.071; 95% CI, 1.036–1.107, p < 0.001), red blood cell transfusions until postoperative day 3 (Exp(B) 1.157; 95% CI, 1.030–1.300, p = 0.014), history of heart failure (Exp(B) 1.985; 95% CI, 1.130–3.487, p = 0.017) and increased CRP levels (Exp(B) 1.004; 95% CI, 1.000–1.008, p = 0.037). (4) Conclusions: Postoperative delirium remains a frequent complication after cardiac surgery, while stroke and seizures occur rarely. A preoperative risk profile including older age, history of heart failure and cognitive impairment was identified for a complicated postoperative course. However, the impact of an intense inflammatory response must not be neglected.

Background Iodine is an essential trace element, which is important for human metabolism, growth and mental development. Iodine deficiency may still occur in Europe and the use of iodised salt is an effective measure to enhance iodine intake. Knowledge and awareness about the importance of iodine in nutrition and health can have a positive impact on the use of iodised salt. Therefore, the aim of this study was to assess the knowledge about and use of iodised salt among university students in two European countries. Method Data from two countries (Germany and Greece) were extracted from a multi-centre cross-sectional survey, conducted among non-nutrition science/non-medical students from October 2018 to April 2019. Results Among the 359 participants in Germany (35% females, median age: 22 years) and the 403 participants in Greece (51% females, median age: 21 years), 41% and 37%, respectively, reported use of iodised salt at home. Users and non-users did not differ by age, gender and Body Mass Index or general interest in nutrition in both cohorts. However, those who had a better knowledge about iodine and (iodised) salt or had previously attended nutrition classes were more likely to report iodised salt usage. Conclusion The results suggest that strengthening the imparting of nutritional information and additional education of young adults are needed and may improve knowledge about and usage of iodised salt.

Microscopic fuel fragments, so-called “hot particles”, were released during the 1986 accident at the Chornobyl nuclear powerplant and continue to contaminate the exclusion zone in northern Ukraine. Isotopic analysis can provide vital information about sample origin, history and contamination of the environment, though it has been underutilized due to the destructive nature of most mass spectrometric techniques, and inability to remove isobaric interference. Recent developments have diversified the range of elements that can be investigated through resonance ionization mass spectrometry (RIMS), notably in the fission products. The purpose of this study is to demonstrate the application of multi-element analysis on hot particles as relates to their burnup, particle formation in the accident, and weathering. The particles were analysed with two RIMS instruments: resonant-laser secondary neutral mass spectrometry (rL-SNMS) at the Institute for Radiation Protection and Radioecology (IRS) in Hannover, Germany, and laser ionization of neutrals (LION) at Lawrence Livermore National Laboratory (LLNL) in Livermore, USA. Comparable results across instruments show a range of burnup dependent isotope ratios for U and Pu and Cs, characteristic of RBMK-type reactors. Results for Rb, Ba and Sr show the influence of the environment, retention of Cs in the particles and time passed since fuel discharge.

Background and Purpose Preexisting autoantibodies against N-methyl-D-aspartate-receptor subunit NR1 (NMDAR1-AB) in acute ischemic stroke patients with previously intact blood-brain-barrier were associated with smaller evolution of lesion size. Effects of chronic exposure to NMDAR1-AB long after stroke, however, have remained unclear. We investigated in a prospective follow-up study whether long-term neuropsychiatric outcome after stroke differs depending on NMDAR1-AB status. Methods Blood samples for NMDAR1-AB analysis were collected within 24 h after ischemic stroke from n = 114 patients. Outcome was assessed 1–3 years later using NIHSS, modified Rankin-scale, Barthel-Index, RBANS (Repeatable Battery for the Assessment of Neuropsychological Status) subcategories (immediate/delayed memory, attention, visuoconstruction), anamnesis evaluating neuropsychiatric symptoms (e.g. hallucinations, psychomotor slowing, reduced alertness, depressiveness, fatigue) and questionnaires (Beck's Depression Inventory-BDI, Fatigue Impact Scale-FIS). Scores were generated to cover RBANS plus neuropsychiatric symptoms (Score A; n = 96) or only neuropsychiatric symptoms (Score B; n = 114, including patients unable to conduct RBANS). Depression/fatigue were measured in patients, capable to perform questionnaires (n = 86). Results NMDAR1-AB (IgM, IgA, IgG) were detected in n = 27 patients (23.7%). NMDAR1-AB seropositive patients showed inferior results in Score A (p = 0.006), Score B (p = 0.004), BDI (p = 0.013) and FIS (p = 0.018), compared to seronegative patients. Multiple regression analysis including covariates age, NIHSS at day 7 post-stroke, and days from stroke to follow-up, showed NMDAR1-AB seropositivity associated with worse outcome in Scores A (b: 1.517, 95%CI: 0.505–2.529, p = 0.004) and B (b: 0.803, 95%CI: 0.233–1.373; p = 0.006). Also FIS was unfavorably associated with NMDAR1-AB seropositivity (binary logistic regression: OR: 3.904, 95%CI: 1.200–12.695; p = 0.024). Conclusions Even though the numbers of included patients are low, our data apparently indicate that NMDAR1-AB seropositivity at the time point of acute ischemic stroke is associated with neuropsychiatric symptoms including cognitive dysfunction and fatigue years after stroke. Preclinical proof of a causal relation provided, targeted immunosuppression may be a future prophylactic option to be clinically evaluated.

Mechanical thrombectomy (MT) is a highly efficient treatment in patients with acute ischemic stroke due to large vessel occlusion (LVO). However, in a relevant proportion of LVO, no sufficient recanalization can be achieved. The composition of cerebral thrombi is highly heterogeneous and may constitute a relevant factor for insufficient reperfusion. We hypothesized that circulating cytokines and growth factors involved in thromboinflammation and platelet activation may be associated with reperfusion status and thrombus composition in patients undergoing MT. An according biomarker panel was measured in plasma specimens taken prior to MT and at a 7-day follow-up. The reperfusion status was categorized into sufficient or insufficient. The composition of retrieved thrombi was histologically analyzed. Differences of baseline biomarker concentrations between insufficient and sufficient reperfusions were highest for interferon (IFN)-γ, epidermal growth factor, platelet-derived growth factor (PDGF)-AB/BB, and IFN-γ-induced protein 10 (IP-10/CXCL10). After applying correction for multiple comparisons and logistic regression analysis adjusting for stroke etiology, intravenous thrombolysis, and vascular risk factors, PDGF-AB/BB was identified as an independent predictor of reperfusion status (odds ratio: 0.403; 95% confidence interval: 0.199–0.819). Histological analysis revealed that the majority of thrombi had a mixed composition. In conclusion, this study provides the first evidence that cytokines and growth factors are potential effectors in patients undergoing MT for the treatment of acute ischemic stroke.

We recently identified Galectin-1 (Gal-1), a β-galactoside-binding lectin, as a novel immune regulator in neuroblastoma (NB). Here, we characterized the tolerogenic function of Gal-1 within the CD8+ T cell compartment and further evaluated its relevance as an antigen for effective DNA vaccination against NB in a mouse model. NB cells with Gal-1 knockdown (NXS-2L) exhibited significantly reduced tumor growth compared to NXS-2 NB cells. Administration of anti-CD8 antibodies prevented this antitumor effect, with primary tumor growth comparable to that from Gal-1 (G1)-sufficient NB cells. Peptide epitope screening with online databases and in silico docking experiments predicted the sequences "FDQADLTI" (#1), "GDFKIKCV" (#2), and "AHGDANTI" (#3) to have superior H2-KK binding affinities and "KFPNRLNM" (#4), "DGDFKIKCV" (#5), and "LGKDSNNL" (#6) to have superior H2-DD binding affinities. Minigenes encoding G1-KK (#1-#2-#3), G1-DD (#4-#5-#6) and the triplet with the highest affinity, G1-H (#1-#2-#4), were generated and cloned into a ubiquitin-containing plasmid (pU). Mice receiving pU-G1-KK or pU-G-1H presented a reduction in the s.c. tumor volume and weight of up to 80% compared to control mice; this reduction was associated with increased cytotoxicity of isolated splenocytes from vaccinated animals. Vaccination with pUG1-DD showed a lower capability to suppress primary tumor progression. In conclusion, Gal-1 expression by NB negatively regulates CD8+ T cells. Vaccination with DNA plasmids encoding Gal-1 epitopes overcomes immune escape, enhances CD8+ T cell-dependent immunity and displays effective antitumor activity against NB.

Fungal peroxygenases (UPOs) have emerged as oxyfunctionalization catalysts of tremendous interest in recent years. However, their widespread use in the field of biocatalysis is still hampered by their challenging heterologous production, substantially limiting the panel of accessible enzymes for investigation and enzyme engineering. Building upon previous work on UPO production in yeast, we have developed a combined promoter and signal peptide shuffling system for episomal high throughput UPO production in the industrially relevant, methylotrophic yeast Pichia pastoris. Eleven endogenous and orthologous promoters were shuffled with a diverse set of 17 signal peptides. Three previously described UPOs were selected as first test set, leading to the identification of beneficial promoter/signal peptide combinations for protein production. We applied the system then successfully to produce two novel UPOs: MfeUPO from Myceliophthora fergusii and MhiUPO from Myceliophthora hinnulea. To demonstrate the feasibility of the developed system to other enzyme classes, it was applied for the industrially relevant lipase CalB and the laccase Mrl2. In total, approximately 3200 transformants of eight diverse enzymes were screened and the best promoter/signal peptide combinations studied at various cofeeding, derepression, and induction conditions. High volumetric production titers were achieved by subsequent creation of stable integration lines and harnessing orthologous promoters from Hansenula polymorpha. In most cases promising yields were also achieved without the addition of methanol under derepressed conditions. To foster the use of the episomal high throughput promoter/signal peptide Pichia pastoris system, we made all plasmids available through Addgene.

Music has been a part of human development since before speech evolved and is an effective form of communication and expression across the world. In particular, the connection between music and emotions seem to be very strong but not very much understood. Recent studies in the past few decades have just begun to delve into the concrete associations between music and emotion. There have been debates about whether there is a significant difference between the way we identify emotions in music through different listener features (based on the circumstances and the identity of the listener). Our paper aimed to investigate whether there would be a difference in recognizing emotions within classical music depending on different listener features such as age, sex, familiarity with classical music, personality, mental health, and culture (within the Korean-American community). Our results show that there are not many significant differences between any of the categories, implying that although subjective experience makes musical experience unique, the intentions of the composer are intact and may be identified throughout all the categories.

In patients with left ventricular assist devices (LVADs), ischemic and hemorrhagic stroke are dreaded complications. Predictive markers for these events are lacking. This study aimed to investigate the prevalence and predictive value of microembolic signals (MES) for stroke, detected by Transcranial Doppler sonography (TCD) in patients with HeartMate 3 (HM 3) or HeartWare (HW).A thirty-minute bilateral TCD monitoring of the middle cerebral artery (MCA) was performed in 62 outpatients with LVAD (HM 3 N = 31, HW N = 31) and 31 healthy controls. Prevalence and quantity of MES were investigated regarding clinical and laboratory parameters. Cerebrovascular events (CVE) were recorded on follow-up at 90 and 180 days.MES were detected in six patients with HM 3, three patients with HW, and three controls. Within the LVAD groups, patients on monotherapy with vitamin-K-antagonist (VKA) without antiplatelet therapy were at risk for a higher count of MES (negative binomial regression: VKA: 1; VKA + ASA: Exp(B) = 0.005, 95%CI 0.001-0.044; VKA + clopidogrel: Exp(B) = 0.012, 95%CI 0.002-0.056). There was no association between the presence of MES and CVE or death on follow-up (p 0.05).For the first time, the prevalence of MES was prospectively investigated in a notable outpatient cohort of patients with HM 3 and HW. Despite optimized properties of the latest LVAD, MES remain detectable depending on antithrombotic therapy. No association between MES and CVE could be detected.

Background Pharmacist-led medication review and medication management programs (MMP) are well-known strategies to improve medication safety and effectiveness. If performed interprofessionally, outcomes might even improve. However, little is known about task sharing in interprofessional MMP, in which general practitioners (GPs) and community pharmacists (CPs) collaboratively perform medication reviews and continuously follow-up on patients with designated medical and pharmaceutical tasks, respectively. In 2016, ARMIN (Arzneimittelinitiative Sachsen-Thüringen) an interprofessional MMP was launched in two German federal states, Saxony and Thuringia. The aim of this study was to understand how GPs and CPs share tasks in MMP when reviewing the patients’ medication. Methods This was a cross-sectional postal survey among GPs and CPs who participated in the MMP. Participants were asked who completed which MMP tasks, e.g., checking drug-drug interactions, dosing, and side effects. In total, 15 MMP tasks were surveyed using a 5-point Likert scale ranging from “I complete this task alone” to “GP/CP completes this task alone”. The study was conducted between 11/2020 and 04/2021. Data was analyzed using descriptive statistics. Results In total, 114/165 (69.1%) GPs and 166/243 (68.3%) CPs returned a questionnaire. The majority of GPs and CPs reported (i) checking clinical parameters and medication overuse and underuse to be completed by GPs, (ii) checking storage conditions of drugs and initial compilation of the patient’s medication including brown bag review being mostly performed by CPs, and (iii) checking side-effects, non-adherence, and continuous updating of the medication list were carried out jointly. The responses differed most for problems with self-medication and adding and removing over-the-counter medicines from the medication list. In addition, the responses revealed that some MMP tasks were not sufficiently performed by either GPs or CPs. Conclusions Both GPs’ and CPs’ expertise are needed to perform MMP as comprehensively as possible. Future studies should explore how GPs and CPs can complement each other in MMP most efficiently.

IntroductionUnderstanding prognosis, especially long-term outcome, in advanced nonsmall cell lung cancer (NSCLC) is crucial to inform patients, guide treatment and plan supportive and palliative care.MethodsPrognostic factors influencing overall survival (OS) and progression-free survival (PFS) in 2082 patients with wild-type (WT)-NSCLC (629 M1a, 249 M1b, 1204 M1c) are reported. Patients were included in the prospective German CRISP registry recruiting in >150 centres. Analysis for pre-therapeutic factors was based on results from Cox proportional hazard models.ResultsCurrent M-descriptors of the Union for International Cancer Control-8 staging system were validated: M1a and M1b patients had significantly longer median time to events compared to M1c (OS/PFS 16.4/7.2 months, 17.8/6.7 months and 10.9/5.4 months, respectively). OS and PFS were influenced by number and location of metastatic organ systems. M1c and four or more metastatic organs involved had shorter OS and PFS than M1c with one to three organs (OS hazard ratio (HR) 1.69, pConclusionIn this large observational dataset, we further defined factors for outcome in WT-NSCLC, including increased number of involved metastatic organ systems and liver metastases, as those with overall poorer prognosis and reduced survival chance.

Zusammenfassung Hintergrund Laut S3-Leitlinie „Allergieprävention“ (Update 2021) soll bei nicht (voll) gestillten Säuglingen mit erhöhtem Allergierisiko geprüft werden, ob eine Säuglingsnahrung mit nachgewiesener allergiepräventiver Wirksamkeit verfügbar ist. Einige Hersteller bewerben ihre Produkte entsprechend. Ziel der Arbeit Der Artikel gibt einen Überblick über die wissenschaftliche Evidenz und internationale Empfehlungen zum Einsatz von hydrolysierter Säuglingsnahrung (sog. hypoallergene [HA-]Nahrung) zur Prävention von atopischen Erkrankungen. Materialien und Methoden In medizinischen Datenbanken wurde eine Literaturrecherche (Zeitraum: 2016–2021) zum Nutzen von hydrolysierten Säuglingsnahrungen für die Allergieprävention bei Risikokindern und zu entsprechenden internationalen Leitlinien durchgeführt. Auf dieser Basis wurden die aktuelle Empfehlung der deutschen S3-Leitlinie sowie die Produkte auf dem deutschen Markt eingeordnet. Ergebnisse Es gibt keine hinreichenden Belege für einen generellen allergiepräventiven Nutzen von Säuglingsnahrungen mit Proteinhydrolysat bei Säuglingen mit erhöhtem Allergierisiko. Die GINI-Interventionsstudie deutet darauf hin, dass eine der eingesetzten Hydrolysatnahrungen zur Prävention atopischer Dermatitis bei Risikokindern wirksam gewesen sein könnte. Die Ergebnisse können aber, auch angesichts methodischer Schwächen, nicht als alleinige Basis für eine allgemeine Empfehlung zur Verwendung von HA-Nahrung herangezogen werden. Internationale Fachgesellschaften sprechen sich seit einigen Jahren eher gegen eine solche Empfehlung aus. Diskussion Für die derzeit in Deutschland vermarkteten Säuglingsnahrungen auf Basis von partiell hydrolysiertem Protein fehlen Wirksamkeitsbelege. Sie können daher nicht zur Allergieprävention empfohlen werden.

A bioinspired emulsification strategy resulted in substantially increased enzymatic activities in the degradation of synthetic polyisoprene with the latex clearing protein LcpK30, even with cis : trans ratios of 56 : 27.

Carbene transfer biocatalysis has evolved from basic science to an area with vast potential for the development of new industrial processes. In this study, we show that YfeX, naturally a peroxidase, has great potential for the development of new carbene transferases, due to its high intrinsic reactivity, especially for the N-H insertion reaction of aromatic and aliphatic primary and secondary amines. YfeX shows high stability against organic solvents (methanol and DMSO), greatly improving turnover of hydrophobic substrates. Interestingly, in styrene cyclopropanation, WT YfeX naturally shows high enantioselectivity, generating the trans product with 87 % selectivity for the (R,R) enantiomer. WT YfeX also catalyzes the Si-H insertion efficiently. Steric effects in the active site were further explored using the R232A variant. Quantum Mechanics/Molecular Mechanics (QM/MM) calculations reveal details on the mechanism of Si-H insertion. YfeX, and potentially other peroxidases, are exciting new targets for the development of improved carbene transferases.

Objectives Intravenous application of contrast media is part of a wide spectrum of diagnostic procedures for better imaging quality. Clinical avoidance of contrast-enhanced imaging is an ever-present quandary in patients with impaired kidney function. The objective of this study was to estimate the risk for acute kidney injury (AKI), dialysis and mortality among patients undergoing contrast-enhanced CT compared to propensity score–matched controls (i.e. contrast-unenhanced CT). Selected cohort studies featured high-risk patients with advanced kidney disease and critical illness. Methods This review was designed to conform to the Preferred Reporting Items in Systematic Reviews and Meta-Analysis (PRISMA) guidelines. PubMed was searched from August 2021 to November 2021 for all-language articles without date restriction. A random-effects model (DerSimonian and Laird method) was used for meta-analysis. Results Twenty-one articles were included, comprising data of 169,455 patients. The overall risk of AKI was similar in the contrast-enhanced and unenhanced groups (OR: 0.97 [95% CI: 0.85; 1.11], p = 0.64), regardless of baseline renal function and underlying disease. Substantial heterogeneity was detected (I2 = 90%, p ≤ 0.0001). Multivariable logistic regression identified hypertension (p = 0.03) and estimated glomerular filtration rate (eGFR) ≤ 30 mL/min/1.73 m2 (p = 0.0001) as factors associated with greater risk of post-contrast AKI. Conclusions Based on propensity score–matched pairs obtained from 21 cohort studies, we found no evidence for increased risk for AKI, dialysis or mortality after contrast-enhanced CT among patients with eGFR ≥ 45 mL/min/1.73 m2. In congruence with the emerging evidence in the literature, caution should be exercised in patients with hypertension and eGFR ≤ 30 mL/min/1.73 m2. Key Points • The application of contrast media for medical imaging is not associated with higher odds for AKI, induction of renal replacement therapy, or mortality. Many comorbidities traditionally associated with greater risk for acute kidney injury do not appear to predispose for renal decline after contrast media exposure. • Underlying hypertension and eGFR less than or equal to 30 mL/min/1.73 m2seem to predispose for post-contrast acute kidney injury. • Propensity score matching cannot account for unmeasured influences on AKI incidence, which needs to be addressed in the interpretation of results.

Maps of the synapses made and neurotransmitters released by all neurons in model systems, such as Caenorhabditis elegans have left still unresolved how neural circuits integrate and respond to neurotransmitter signals. Using the egg-laying circuit of C. elegans as a model, we mapped which cells express each of the 26 neurotransmitter GPCRs of this organism and also genetically analyzed the functions of all 26 GPCRs. We found that individual neurons express many distinct receptors, epithelial cells often express neurotransmitter receptors, and receptors are often positioned to receive extrasynaptic signals. Receptor knockouts reveal few egg-laying defects under standard laboratory conditions, suggesting that the receptors function redundantly or regulate egg-laying only in specific conditions; however, increasing receptor signaling through overexpression more efficiently reveals receptor functions. This map of neurotransmitter GPCR expression and function in the egg-laying circuit provides a model for understanding GPCR signaling in other neural circuits.SIGNIFICANCE STATEMENT Neurotransmitters signal through GPCRs to modulate activity of neurons, and changes in such signaling can underlie conditions such as depression and Parkinson's disease. To determine how neurotransmitter GPCRs together help regulate function of a neural circuit, we analyzed the simple egg-laying circuit in the model organism C. elegans We identified all the cells that express every neurotransmitter GPCR and genetically analyzed how each GPCR affects the behavior the circuit produces. We found that many neurotransmitter GPCRs are expressed in each neuron, that neurons also appear to use these receptors to communicate with other cell types, and that GPCRs appear to often act redundantly or only under specific conditions to regulate circuit function.

Background Idarucizumab is a monoclonal antibody fragment with high affinity for dabigatran reversing its anticoagulant effects within minutes. Thereby, patients with acute ischemic stroke who are on dabigatran treatment may become eligible for thrombolysis with recombinant tissue-type plasminogen activator (rt-PA). In patients on dabigatran with intracerebral hemorrhage idarucizumab could prevent lesion growth. Aims To provide insights into the clinical use of idarucizumab in patients under effective dabigatran anticoagulation presenting with signs of acute ischemic stroke or intracranial hemorrhage. Methods Retrospective data collected from German neurological/neurosurgical departments administering idarucizumab following product launch from January 2016 to August 2018 were used. Results One-hundred and twenty stroke patients received idarucizumab in 61 stroke centers. Eighty patients treated with dabigatran presented with ischemic stroke and 40 patients suffered intracranial bleeding (intracerebral hemorrhage (ICH) in n = 27). In patients receiving intravenous thrombolysis with rt-PA following idarucizumab, 78% showed a median improvement of 7 points in National Institutes of Health Stroke Scale. No bleeding complications were reported. Hematoma growth was observed in 3 out of 27 patients with ICH. Outcome was favorable with a median National Institutes of Health Stroke Scale improvement of 4 points and modified Rankin score 0–3 in 61%. Six out of 40 individuals (15%) with intracranial bleeding died during hospital stay. Conclusion Administration of rt-PA after reversal of dabigatran activity with idarucizumab in case of acute ischemic stroke seems feasible, effective, and safe. In dabigatran-associated intracranial hemorrhage, idarucizumab appears to prevent hematoma growth and to improve outcome.

Frontiers in immunology 13, 1-19 (2022). doi:10.3389/fimmu.2022.879157, Published by Frontiers Media, Lausanne