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Sex-specific thresholds of aortic valve calcification (AVC) correlate with aortic stenosis (AS) and may complement echocardiography to determine AS severity. Importantly, current guideline-recommended thresholds of AVC scores derived by multislice computed tomography do not distinguish between bicuspid and tricuspid aortic valves. The objective of this study was to evaluate the sex-specific differences in the amount of AVC in patients with severe AS and tricuspid (TAV) versus bicuspid (BAV) aortic valve morphologies, retrospectively evaluated by 2 tertiary care institutions. The inclusion criteria comprised patients with severe AS and a left ventricular ejection fraction ≥50% and suitable imaging examinations. The study included 1,450 patients (723 men; 49.9%) with severe AS, including 1,335 patients with TAV (92.1%) and 115 with BAV (17.9%). The calculated Agatston score was higher in BAV patients (men: BAV 4,358 [2,644 to 6,005] AU vs TAV 2,643 [1,727 to 3,794] AU, p 2 vs TAV 1,333 [872 to 1,913] AU/m2, p 2 vs TAV 930 [546 to 1,456] AU/m2, p

Aims To study sex-specific differences in the amount and distribution of aortic valve calcification (AVC) and to correlate the AVC load with paravalvular leakage (PVL) post-transcatheter aortic valve intervention (TAVI). Methods and results This registry included 1801 patients undergoing TAVI with a Sapien3 or Evolut valve in two tertiary care institutions. Exclusion criteria encompassed prior aortic valve replacement, suboptimal multidetector computed tomography (MDCT) quality, and suboptimal transthoracic echocardiography images. Calcium content and distribution were derived from MDCT. In this study, the median age was 81.7 (25th–75th percentile 77.5–85.3) and 54% male. Men, compared to women, were significantly younger [81.2 (25th–75th percentile 76.5–84.5) vs. 82.4 (78.2–85.9), P ≤ 0.01] and had a larger annulus area [512 mm2 (25th–75th percentile 463–570) vs. 405 mm2 (365–454), P < 0.01] and higher Agatston score [2567 (25th–75th percentile 1657–3913) vs. 1615 (25th–75th percentile 905–2484), P < 0.01]. In total, 1104 patients (61%) had none-trace PVL, 648 (36%) mild PVL, and 49 (3%) moderate PVL post-TAVI. There was no difference in the occurrence of moderate PVL between men and women (3% vs. 3%, P = 0.63). Cut-off values for the Agatston score as predictor for moderate PVL based on the receiver-operating characteristic curve were 4070 (sensitivity 0.73, specificity 0.79) for men and 2341 (sensitivity 0.74, specificity 0.73) for women. Conclusion AVC is a strong predictor for moderate PVL post-TAVI. Although the AVC load in men is higher compared to women, there is no difference in the incidence of moderate PVL. Sex-specific Agatston score cut-offs to predict moderate PVL were almost double as high in men vs. women.

Traumatic spinal cord injury causes rapid neuronal and vascular injury, and predictive biomarkers are needed to facilitate acute patient management. This study examined the progression of magnetic resonance imaging (MRI) biomarkers after spinal cord injury and their ability to predict long-term neurological outcomes in a rodent model, with an emphasis on diffusion-weighted imaging (DWI) markers of axonal injury and perfusion-weighted imaging of spinal cord blood flow (SCBF). Adult Sprague-Dawley rats received a cervical contusion injury of varying severity (injured = 30, sham = 9). MRI at 4 h, 48-h, and 12-weeks post-injury included T

Background: Type 3 von Willebrand disease (VWD) is the most severe form of this disease owing to the almost complete deficiency of von Willebrand factor (VWF). Replacement therapy with plasma-derived products containing VWF or recombinant VWF rarely cause the development of alloantibodies against VWF that may be accompanied by anaphylactic reactions. Objective: The objective of this study was to assess the prevalence of anti-VWF alloantibodies in subjects with type 3 VWD enrolled in the 3WINTERS-IPS. Methods: An indirect in-house enzyme-linked immunosorbent assay has been used to test all the alloantibodies against VWF. Neutralizing antibodies (inhibitors) have been tested with a Bethesda-based method by using a VWF collagen binding (VWF:CB) assay. Samples positive for anti-VWF antibodies were further tested with Bethesda-based methods by using the semiautomated gain-of-function glycoprotein-Ib binding (VWF:GPIbM) and a VWF antigen (VWF:Ag) enzyme-linked immunosorbent assay. Results: In total, 18 of the 213 (8.4%) subjects tested positive for anti-VWF antibodies and 13 of 213 (6%) had VWF:CB inhibitors. These 13 were among the 18 with anti-VWF antibodies. Of the 5 without VWF:CB inhibitors, 3 had non-neutralizing antibodies, 1 only inhibitor against VWF:GPIbM, and one could not be tested further. Ten of the 13 subjects with VWF:CB inhibitors also had VWF:GPIbM inhibitors, 6 of whom also had VWF:Ag inhibitors. Subjects with inhibitors were homozygous for VWF null alleles (11/14), homozygous for a missense variant (1/14), or partially characterized (2/14). Conclusions: Anti-VWF antibodies were found in 8.4% of subjects with type 3 VWD, whereas neutralizing VWF inhibitors were found in 6%, mainly in subjects homozygous for VWF null alleles. Because inhibitors may be directed toward different VWF epitopes, their detection is dependent on the assay used.

International audience; Nirmatrelvir/ritonavir (Paxlovid®) consists of a peptidomimetic inhibitor (Nirmatrelvir) of the SARS-CoV-2 main protease and a pharmacokinetic enhancer (Ritonavir). It is approved for the treatment of mild-to-moderate COVID-19. This combination of nirmatrelvir and ritonavir can mediate significant and complex drug-drug interactions (DDIs), primarily due to the ritonavir component. Indeed, ritonavir inhibits the metabolism of nirmatrelvir through cytochrome P450 3A (CYP3A) leading to higher plasma concentrations and a longer half-life of nirmatrelvir. Co-administration of nirmatrelvir/ritonavir with immunosuppressant drugs (ISDs) is particularly challenging given the major involvement of CYP3A in the metabolism of most of these drugs and their narrow therapeutic ranges. Exposure of ISDs will be drastically increased through the potent ritonavir-mediated inhibition of CYP3A, resulting in an increased risk of adverse drug reactions. While a decrease in the dosage of ISDs can prevent toxicity, an inappropriate dosage regimen may also result in insufficient exposure and a risk of rejection. Here we provide some general recommendations for therapeutic drug monitoring (TDM) of ISDs and dosing recommendations when co-administered with nirmatrelvir/ritonavir. Particularly, tacrolimus should be discontinued, or patients should be given a microdose on day-1, while cyclosporine dosage should be reduced to 20% of the initial dosage during the antiviral treatment. Dosages of mammalian target of rapamycin inhibitors (m-TORis) should also be adjusted while dosages of mycophenolic acid and corticosteroids are expected to be less impacted.

OBJECTIVE Spinal cord stress/strain during neck motion contributes to spinal cord dysfunction in degenerative cervical myelopathy (DCM), yet the effect of surgery on spinal cord biomechanics is unknown. It is expected that motion-preserving and fusion surgeries for DCM will have distinct effects on spinal cord biomechanics. The aim of this study was to compare changes in spinal cord biomechanics after laminectomy with fusion, laminectomy, and laminoplasty using a patient-specific finite element model (FEM) for DCM. METHODS A patient-specific FEM of the cervical spine and spinal cord was created using MRI from a subject with mild DCM. Multilevel laminectomy with fusion, laminectomy, and laminoplasty were simulated for DCM using the patient-specific FEM. Spinal cord von Mises stress and maximum principal strain during neck flexion-extension, lateral bending, and axial rotation were recorded. Segmental range of motion, intradiscal pressure, and capsular ligament strain were also measured. FEM outputs were calculated as a change with respect to the preoperative values and compared between the three models. RESULTS Across the surgical levels, spinal cord stress increased after laminectomy for neck flexion (+50%), neck extension (+37.8%), and axial rotation (+23%). Similarly, spinal cord strain increased in neck extension (+118.4%) and axial rotation (+75.1%) after laminectomy. Laminoplasty was associated with greater spinal cord stress in neck flexion (+57.4%) and increased strain in lateral bending (+56.7%) and axial rotation (+20.9%). Compared with laminectomy and laminoplasty, spinal cord biomechanics for laminectomy with fusion revealed significantly reduced median extension stress (13.7 kPa vs 9.7 kPa, p = 0.03), lateral bending strain (0.01 vs 0.007, p = 0.007), axial rotation stress (3.7 kPa vs 2.1 kPa, p = 0.04), and axial rotation strain (0.017 vs 0.009, p = 0.04). CONCLUSIONS Spinal cord strain decreased in neck flexion in all three models, yet spinal cord stress increased with neck flexion for laminectomy and laminoplasty. Changes in spinal cord biomechanics for laminoplasty parallel those for laminectomy with fusion except during neck flexion, lateral bending, and axial rotation. Compared with motion-preserving approaches such as laminectomy and laminoplasty, laminectomy with fusion was associated with the lowest spinal cord stress and strain in flexion-extension, lateral bending, and axial rotation of the neck.

Background In patients with stable coronary artery disease (CAD), revascularisation decisions are based mainly on the visual grading of the severity of coronary stenosis on invasive coronary angiography (ICA). However, invasive fractional flow reserve (FFR) is the current standard to determine the haemodynamic significance of coronary stenosis. Non-invasive and less-invasive imaging techniques such as computed-tomography-derived FFR (FFR-CT) and angiography-derived FFR (QFR) combine both anatomical and functional information in complex algorithms to calculate FFR. Trial design The iCORONARY trial is a prospective, multicentre, non-inferiority randomised controlled trial (RCT) with a blinded endpoint evaluation. It investigates the costs, effects and outcomes of different diagnostic strategies to evaluate the presence of CAD and the need for revascularisation in patients with stable angina pectoris who undergo coronary computed tomography angiography. Those with a Coronary Artery Disease—Reporting and Data System (CAD-RADS) score between 0–2 and 5 will be included in a prospective registry, whereas patients with CAD-RADS 3 or 4A will be enrolled in the RCT. The RCT consists of three randomised groups: (1) FFR-CT-guided strategy, (2) QFR-guided strategy or (3) standard of care including ICA and invasive pressure measurements for all intermediate stenoses. The primary endpoint will be the occurrence of major adverse cardiac events (death, myocardial infarction and repeat revascularisation) at 1 year. Clinicaltrials.gov-identifier: NCT04939207. Conclusion The iCORONARY trial will assess whether a strategy of FFR-CT or QFR is non-inferior to invasive angiography to guide the need for revascularisation in patients with stable CAD. Non-inferiority to the standard of care implies that these techniques are attractive, less-invasive alternatives to current diagnostic pathways.

Abstract Forests provide invaluable economic, ecological, and social services. At the same time, they are exposed to several threats, such as fragmentation, changing climatic conditions, or increasingly destructive pests and pathogens. Trees, the inherent species of forests, cannot be viewed as isolated organisms. Manifold (micro)organisms are associated with trees playing a pivotal role in forest ecosystems. Of these organisms, fungi may have the greatest impact on the life of trees. A multitude of molecular and genetic methods are now available to investigate tree species and their associated organisms. Due to their smaller genome sizes compared to tree species, whole genomes of different fungi are routinely compared. Such studies have only recently started in forest tree species. Here, we summarize the application of molecular and genetic methods in forest conservation genetics, tree breeding, and association genetics as well as for the investigation of fungal communities and their interrelated ecological functions. These techniques provide valuable insights into the molecular basis of adaptive traits, the impacts of forest management, and changing environmental conditions on tree species and fungal communities and can enhance tree-breeding cycles due to reduced time for field testing. It becomes clear that there are multifaceted interactions among microbial species as well as between these organisms and trees. We demonstrate the versatility of the different approaches based on case studies on trees and fungi. Key points • Current knowledge of genetic methods applied to forest trees and associated fungi. • Genomic methods are essential in conservation, breeding, management, and research. • Important role of phytobiomes for trees and their ecosystems.

Novice teachers experience language about literacy instruction from a variety of sources. This longitudinal case study uses Bakhtin’s notions of authoritative and internally persuasive discourse to consider how four novice teachers negotiated messages regarding literacy instruction from the conclusion of preservice education through their first 2 years of teaching. Although the challenges of the initial years of teaching have been studied, limited attention has been given to the ways in which novice teachers negotiate and take up language about literacy instruction within their school contexts. Interviews and email journals were used as data sources. Findings reveal that novice teachers perceived authoritative discourse from curricula, programs and assessments, and instructional expectations of administrators or senior colleagues. Participants accessed internally persuasive literacy discourses through questioning, supplementing, and changing literacy programs they perceived as required by authorities. Implications for teacher educators, researchers, and school personnel are discussed.

Mitochondria generate energy through oxidative phosphorylation (OXPHOS). The function of key OXPHOS proteins can be altered by variation in mitochondria-related genes, which may increase the risk of mental illness. We investigated the association of mitochondria-related genes and their genetic risk burden with cognitive performance.We leveraged cross-sectional data from 1320 individuals with a severe psychiatric disorder and 466 neurotypical individuals from the PsyCourse Study. The cognitive tests analyzed were the Trail-Making Test, Verbal Digit Span Test, Digit-Symbol Test, and Multiple Choice Vocabulary Intelligence Test. Association analyses between the cognitive tests, and single-nucleotide polymorphisms (SNPs) mapped to mitochondria-related genes, and their polygenic risk score (PRS) for schizophrenia (SCZ) were performed with PLINK 1.9 and R program.We found a significant association (FDR-adjusted p < 0.05) in the Cytochrome C Oxidase Assembly Factor 8 (COA8) gene locus of the OXPHOS pathway with the Verbal Digit Span (forward) test. Mitochondrial PRS was not significantly associated with any of the cognitive tests.Moderate statistical power due to relatively small sample size.COA8 encodes a poorly characterized mitochondrial protein involved in apoptosis. Here, this gene was associated with the Verbal Digit Span (forward) test, which evaluates short-term memory. Our results warrant replication and may lead to better understanding of cognitive impairment in mental disorders.

Zusammenfassung Einleitung Der Begriff Victim Blaming bezeichnet die Situation, wenn Betroffene von Gewalt selbst für ihre Viktimisierung verantwortlich gemacht werden, indem ihnen auf Grundlage persönlicher oder kontextbezogener Merkmale unterstellt wird, einen Anreiz zur Gewalt geboten zu haben. Insbesondere im Bereich sexueller Gewalt ist Victim Blaming verbreitet und geschlechtlich konnotiert. Spezifische Muster des Victim Blamings werden nachfolgend mit Fokus auf sexuelle Grenzverletzungen mittels digitaler Medien unter jugendlichen Schüler*innen exploriert. Forschungsziele Ziel der Studie ist die Analyse der Orientierungen von Schüler*innen und Lehrkräften auf die nicht-konsensuelle Weitergabe intimer Bilder, um Prozesse des Victim Blamings unter geschlechterreflektierender Perspektive zu differenzieren. Methoden Grundlage der nachfolgenden Analysen bilden zwölf Gruppendiskussionen im Sinne von natürlichen Gruppen mit 46 Schüler*innen und zehn Gruppendiskussionen mit 34 Lehrer*innen von weiterführenden Schulen in Norddeutschland, die mit dokumentarischer Methode nach Bohnsack (Bohnsack et al. 2007) ausgewertet wurden. Das Sampling erfolgte entsprechend nach vorab festgelegten Kriterien und wurde nach dem Prinzip der Sättigung beendet. Ergebnisse In den auf den Gruppendiskussionen basierenden Fallbeschreibungen lassen sich drei Orientierungsmuster unterscheiden: implizites, nicht-reflektiertes und explizites Victim Blaming. Gemeinsam ist den Mustern, dass sie die Verantwortung für Grenzverletzungen mittels digitaler Medien ausschließlich individualisierend bei betroffenen Mädchen verorten, welche als charakterschwach, abhängig von Fremdanerkennung sowie unbedacht geschildert werden. Weder diejenigen, die die Bilder nicht-konsensuell weiterleiten, noch die Bystander spielen in den Orientierungen der Befragten eine Rolle. Dies gilt für Schüler*innen wie Lehrer*innen gleichermaßen. Handlungsoptionen werden entsprechend vor allem in abstinentem Verhalten gesehen, wodurch eine restriktive Sexualmoral vertreten wird, die Betroffene von sexuellen Grenzverletzungen (mit-)verantwortlich für ihre Erfahrungen macht. Schlussfolgerung Der Beitrag zeigt die weit geteilten Verantwortungszuschreibungen von schulischen Akteur*innen zuungunsten von Mädchen. Pädagogische Abstinenzbotschaften untergraben einen selbstbestimmten Umgang mit intimen Bildern, indem sie Mädchen adressieren und somit Lehrkräfte implizit darin bestärken, keine pädagogische Verantwortung für Betroffene von sexueller Gewalt zu übernehmen.

Tonic current through hyperpolarization-activated cyclic nucleotide-gated cation (HCN) channels is influencing neuronal firing properties and channel function is strongly influenced by the brain-specific auxiliary subunit tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b). Since Kv1.2 channels and TRIP8b were also suggested to interact, we assessed brain Kv1.2 mRNA and protein expression as well as the reduction of K+ outward currents by Kv1.2-blocking compounds (Psora-4; tityustoxin-Kα, TsTX-Kα) in different brain areas of TRIP8b-deficient (TRIP8b −/− ) compared to wildtype (WT) mice. We found that transcription levels of Kv1.2 channels were not different between genotypes. Furthermore, Kv1.2 current amplitude was not affected upon co-expression with TRIP8b in oocytes. However, Kv1.2 immunofluorescence was stronger in dendritic areas of cortical and hippocampal neurons. Furthermore, the peak net outward current was increased and the inactivation of the Psora-4-sensitive current component was less pronounced in cortical neurons in TRIP8b −/− mice. In current clamp recordings, application of TsTX increased the excitability of thalamocortical (TC) neurons with increased number of elicited action potentials upon step depolarization. We conclude that TRIP8b may not preferentially influence the amplitude of current through Kv1.2 channels but seems to affect current inactivation and channel localization. In TRIP8b −/− a compensatory upregulation of other Kv channels was observed.

Context: Professional athletes showed excellent results after hip preserving procedures. However, there is still a lack of knowledge regarding the rate of return to activity and the rehabilitation time of recreational athletes. Thus, the aim of this study was to investigate factors that were associated with an extended return-to-activity time in nonprofessional athletes. Design: Retrospective, quantitative case–control study. Methods: This study included 47 cases (45 nonprofessional athletes), which were divided according to return-to-activity time (short term: 0.0–7.0 mo vs long term: >7.0 mo). The clinical outcome were evaluated with the modified Harris hip score, the nonarthritic hip score, the Western Ontario and McMaster Universities Osteoarthritis Index, and the University of California, Los Angeles activity score. For statistical analysis between both groups, an unpaired student t test and a paired Wilcoxon test were used. In addition, the sports behavior, intraoperative findings, and surgical procedures were also assessed. Results: After a mean follow-up of 4.3 years (±0.6; 3.4–5.6), the overall postoperative modified Harris hip score was 81.8 points, the nonarthritic hip score was 75.8 points, the Western Ontario and McMaster Universities Osteoarthritis Index was 36.7 points, and the University of California, Los Angeles activity score was 7.9. Compared with the preoperative results, all scores improved significantly (P P = .024). Conclusions: After mini-open arthrotomy for femoroacetabular impingement syndrome treatment, 92.5% of the recreational athletes returned to sports activity. The findings did not detect factors influencing the return-to-activity time. However, a higher preoperative diversity of activities and a shift to high-level impact sport activities might support a shorter rehabilitation.

The Phosphatidylinositol 3-phosphate 5-kinase Type III PIKfyve is the main source for selectively generated phosphatidylinositol 3,5-bisphosphate (PI(3,5)P2), a known regulator of membrane protein trafficking. PI(3,5)P2 facilitates the cardiac KCNQ1/KCNE1 channel plasma membrane abundance and therewith increases the macroscopic current amplitude. Functional-physical interaction of PI(3,5)P2 with membrane proteins and its structural impact is not sufficiently understood. This study aimed to identify molecular interaction sites and stimulatory mechanisms of the KCNQ1/KCNE1 channel via the PIKfyve-PI(3,5)P2 axis. Mutational scanning at the intracellular membrane leaflet and nuclear magnetic resonance (NMR) spectroscopy identified two PI(3,5)P2 binding sites, the known PIP2 site PS1 and the newly identified N-terminal α–helix S0 as relevant for functional PIKfyve effects. Cd2+ coordination to engineered cysteines and molecular modeling suggest that repositioning of S0 stabilizes the channel s open state, an effect strictly dependent on parallel binding of PI(3,5)P2 to both sites.

Modulation of two-pore domain potassium (K2P) channels has emerged as a novel field of therapeutic strategies as they may regulate immune cell activation and metabolism, inflammatory signals, or barrier integrity. One of these ion channels is the TWIK-related potassium channel 1 (TREK1). In the current study, we report the identification and validation of new TREK1 activators. Firstly, we used a modified potassium ion channel assay to perform high-throughput-screening of new TREK1 activators. Dose-response studies helped to identify compounds with a high separation between effectiveness and toxicity. Inside-out patch-clamp measurements of Xenopus laevis oocytes expressing TREK1 were used for further validation of these activators regarding specificity and activity. These approaches yielded three substances, E1, B3 and A2 that robustly activate TREK1. Functionally, we demonstrated that these compounds reduce levels of adhesion molecules on primary human brain and muscle endothelial cells without affecting cell viability. Finally, we studied compound A2 via voltage-clamp recordings as this activator displayed the strongest effect on adhesion molecules. Interestingly, A2 lacked TREK1 activation in the tested neuronal cell type. Taken together, this study provides data on novel TREK1 activators that might be employed to pharmacologically modulate TREK1 activity.

Einzelne Klimaschutzmaßnahmen werden bereits von vielen Unternehmen erfolgreich umgesetzt. Doch oftmals fehlen ein systematischer Ansatz sowie die finanziellen Ressourcen zur Umsetzung eines konsequenten Klimaschutzes unter Beibehaltung des wirtschaftlichen Erfolgs. In diesem Beitrag wird ein Vorgehensmodell zur zielgerichteten und potenzialorientierten Ableitung und Umsetzung von Klimaschutzmaßnahmen im Rahmen eines betrieblichen Klimamanagements vorgestellt. Der Fokus liegt dabei auf kleinen und mittleren Unternehmen des produzierenden Gewerbes.

The long-term outcomes of solid organ transplantation remain suboptimal. Therefore, appropriate biomarkers are needed in addition to immunosuppressive drugs and other traditional approaches for graft monitoring to achieve personalized immunosuppression and reduce premature graft loss.Donor-derived cell-free DNA (dd-cfDNA) is a minimally invasive biomarker of cell death due to graft injury. It can be quantified using droplet digital polymerase chain reaction and next-generation sequencing. Fractional dd-cfDNA determination can be affected by changes in recipient cfDNA, such as those caused by leukopenia or infection, leading to false positive or negative results, respectively. Absolute quantification of dd-cfDNA helps in overcoming this limitation.Overall, there is sufficient evidence of the clinical validity of dd-cfDNA. It detects rejection episodes early at an actionable stage and reflects the severity of graft injury without being rejection-specific. Owing to its high negative predictive value, dd-cfDNA is very useful for ruling out graft injury. Dd-cfDNA complements histological findings and can help in avoiding unnecessary biopsies. It indicates a response to rejection treatment and detects under-immunosuppression.Monitoring changes in dd-cfDNA over time may be helpful in adapting immunosuppression to prevent graft rejection. Moreover, serial dd-cfDNA determination may increase the effectiveness of transplant recipient surveillance and facilitate personalized immunosuppression when combined with other relevant clinical and diagnostic findings.

Background Coronary computed tomography angiography (CCTA) is widely used in the diagnostic work-up of patients with stable chest pain. CCTA has an excellent negative predictive value, but a moderate positive predictive value for detecting coronary stenosis. Computed tomography-derived fractional flow reserve (FFRct) is a non-invasive, well-validated technique that provides functional assessment of coronary stenosis, improving the positive predictive value of CCTA. However, to determine the value of FFRct in routine clinical practice, a pragmatic randomised, controlled trial (RCT) is required. We will conduct an RCT to investigate the impact of adding FFRct analysis in the diagnostic pathway of patients with a coronary stenosis on CCTA on the rate of unnecessary invasive coronary angiography, cost-effectiveness, quality of life and clinical outcome. Methods The FUSION trial is a prospective, multicentre RCT that will randomise 528 patients with stable chest pain and anatomical stenosis of ≥ 50% but Conclusion The FUSION trial will evaluate the use of FFRct in stable chest pain patients from the Dutch perspective. The trial is funded by the Dutch National Health Care Institute as part of the research programme ‘Potentially Promising Care’ and the results will be used to assess if FFRct reimbursement should be included in the standard health care package.

El objetivo de este artículo es analizar las percepciones de estudiantes de Pedagogía y Ciencias de la Educación sobre la inclusión educativa de universitarios en situación de discapacidad. Se realizó un estudio cualitativo bajo un diseño descriptivo fenomenológico haciendo uso de entrevistas semiestructuradas. Los resultados indican que la discapacidad sigue considerándose desde un paradigma médico-deficitario. Por otro lado, el alumnado entrevistado ha expresado demostrar una actitud positiva ante sus compañeros en tal condición. Sin embargo, la deficiente infraestructura y la falta de formación del profesorado en dicha materia son las principales barreras que según los participantes enfrenta el estudiantado en situación de discapacidad. Las discusiones apuntan a que se deben implementar mecanismos que posibiliten erradicar la exclusión, segregación y discriminación en la enseñanza superior hondureña.

Dementia involves several factors, and it is required to administer an agent with several efficiencies for its treatment. Sake is known to have antioxidant and anti-inflammatory properties and improves the serum concentration of BDNF. This study aimed to evaluate the neuroprotective action of Japanese sake yeast on dementia of the Alzheimer disease type in rats by behavioral evaluation and neurobiochemical assessment. The rats were grouped as non-Alzheimer rats (control rats) and Alzheimer rats administrated with 0 (AD), 10 (10-AD), 20 (20-AD), 30 (30-AD), and 40 mg/kg (40-AD) of sake. Anxiety-like and depression-like behaviors, the concentrations of brain-derived neurotrophic factor (BDNF), malondialdehyde (MDA), and ferric reducing ability of plasma (FRAP) were evaluated. The expressions of IL-1β, TNF-α, and IL-6 were assessed. The results showed that Alzheimer disease caused anxiety-like and depression-like behaviors (p = 0.000), decreased the concentrations of BDNF (p = 0.000) and FRAP (p = 0.000), increased the concentration of MDA (p = 0.000), and increased the expressions of IL-1β (p = 0.000), TNF-α (p = 0.000), and IL-6 (p = 0.000). The results showed that oral gavage of sake in higher doses decreased anxiety-like and depression-like behaviors (p = 0.000), increased the concentrations of BDNF (p = 0.000) and FRAP (p = 0.000), and reduced the concentration of MDA (p = 0.000) and the expressions of IL-1β (p = 0.000), TNF-α (p = 0.000), and IL-6 (p = 0.000). In sum, Japanese sake yeast can have roles in treating dementia of the Alzheimer disease type, but its mechanisms must be assessed in future studies.

La hemofilia A adquirida (HAA) es una enfermedadhematológica infrecuente, caracterizada por la presencia de anticuerpos contra el factor VIII circulante. Se presenta en personas adultas y en la mitad de los casos en asociación a procesos autoinmunitarios, malignos (oncohematológicos y tumores sólidos), enfermedades dermatológicas, alergias y en mujeres durante embarazo, parto o puerperio. Las manifestaciones hemorrágicas son diversas, predominando el sangrado cutáneo espontáneo. El diagnóstico se realiza midiendo la actividad del factor VIII y la presencia de su inhibidor. Reportamos el caso de una paciente de 36 años cursando 36° día de puerperio que se presenta con hematomas espontáneos, sangrado visceral y tiempos de coagulación prolongados. Se realizó diagnóstico de HAA posparto con buena evolución posterior al tratamiento inmunosupresor. La HAA posparto presenta muy baja incidencia y, en consecuencia, existen pocos casos descriptos. Su retraso en el diagnóstico es un condicionante para el elevado porcentaje de mortalidad. De aquí el interés en la publicación de este caso.

N-Methyl-D-aspartate receptors (NMDARs) are central for learning and information processing in the brain. Dysfunction of NMDARs can play a key role in the pathogenesis of neurodegeneration and drug addiction. The development of selective NMDAR modulators represents a promising strategy to target these diseases. Among such modulating compounds are ifenprodil and its 3-benzazepine derivatives. Classically, the effects of these NMDAR modulators have been tested by techniques like two-electrode voltage clamp (TEVC), patch clamp, or fluorescence-based assays. However, testing their functional effects in complex human systems requires more advanced approaches. Here, we established a human induced pluripotent stem cell-derived (hiPSC-derived) neural cell system and proved its eligibility as a test system for investigating NMDAR modulators and pharmaceutical effects on human neurons.

Acquired von Willebrand syndrome (aVWS) has been reported in patients with congenital heart diseases associated with shear stress caused by significant blood flow gradients. Its etiology and impact on intraoperative bleeding during pediatric cardiac surgery have not been systematically studied. This single-center, prospective, observational study investigated appropriate diagnostic tools of aVWS compared with multimer analysis as diagnostic criterion standard and aimed to clarify the role of aVWS in intraoperative hemorrhage. A total of 65 newborns and infants aged 0 to 12 months scheduled for cardiac surgery at our tertiary referral center from March 2018 to July 2019 were included in the analysis. The glycoprotein Ib M assay (GPIbM)/von Willebrand factor antigen (VWF:Ag) ratio provided the best predictability of aVWS (area under the receiver operating characteristic curve [AUC], 0.81 [95% CI, 0.75-0.86]), followed by VWF collagen binding assay/VWF:Ag ratio (AUC, 0.70 [0.63-0.77]) and peak systolic echocardiographic gradients (AUC, 0.69 [0.62-0.76]). A cutoff value of 0.83 was proposed for the GPIbM/VWF:Ag ratio. Intraoperative high-molecular-weight multimer ratios were inversely correlated with cardiopulmonary bypass (CPB) time (r = −0.57) and aortic cross-clamp time (r = −0.54). Patients with intraoperative aVWS received significantly more fresh frozen plasma (P = .016) and fibrinogen concentrate (P = .011) than those without. The amounts of other administered blood components and chest closure times did not differ significantly. CPB appears to trigger aVWS in pediatric cardiac surgery. The GPIbM/VWF:Ag ratio is a reliable test that can be included in routine intraoperative laboratory workup. Our data provide the basis for further studies in larger patient cohorts to achieve definitive clarification of the effects of aVWS and its potential treatment on intraoperative bleeding.

Objective To describe the prevalence and consequences of incidental findings when implementing routine noncontrast CT prior to cardiac surgery. Methods In the multicenter randomized controlled CRICKET study, 862 adult patients scheduled for cardiac surgery were randomized 1:1 to undergo standard of care (SoC), which included a chest-radiograph, or an additional preoperative noncontrast chest CT-scan (SoC+CT). In this subanalysis, all incidental findings detected on the chest radiograph and CT-scan were analyzed. The influence of smoking status on incidental findings was also evaluated, adjusting for sex, age, and group allocation. Results Incidental findings were observed in 11.4% (n = 49) of patients in the SoC+CT group and in 3.7% (n = 16) of patients in the SoC-group (p < 0.001). The largest difference was observed in findings requiring follow-up (SoC+CT 7.7% (n = 33) vs SoC 2.3% (n = 10), p < 0.001). Clinically relevant findings changing the surgical approach or requiring specific treatment were observed in 10 patients (1.2%, SoC+CT: 1.6% SoC: 0.7%), including lung cancer in 0.5% of patients (n = 4) and aortic dilatation requiring replacement in 0.2% of patients (n = 2). Incidental findings were more frequent in patients who stopped smoking (OR 1.91, 1.03–3.63) or who actively smoked (OR 3.91, 1.85–8.23). Conclusions Routine CT-screening increases the rate of incidental findings, mainly by identifying more pulmonary findings requiring follow-up. Incidental findings are more prevalent in patients with a history of smoking, and preoperative CT might increase the yield of identifying lung cancer in these patients. Incidental findings, but not specifically the use of routine CT, are associated with delay of surgery. Key Points • Clinically relevant incidental findings are identified more often after a routine preoperative CT-scan, when compared to a standard of care workup, with some findings changing patient management. • Patients with a history of smoking have a higher rate of incidental findings and a lung cancer rate comparable to that of lung cancer screening trials. • We observed no clear delay in the time to surgery when adding routine CT screening.

Metal–organic frameworks (MOFs) possess a modular construction. By varying the functional groups on the linker unit, the refractive index n of UiO-66 MOFs can be tuned over a wide range, as high-level band structure calculations show.

Hyperexcitability-induced neuronal damage plays a role both in epilepsy as well as in inflammatory brain diseases such as multiple sclerosis (MS) and as such represents an important disease pathway which potentially can be targeted to mitigate neuronal damage. Dimethyl fumarate (DMF) and its pharmacologically active metabolite monomethyl fumarate (MMF) are FDA-approved therapeutics for MS, which can induce immunosuppressive and antioxidant pathways, and their neuroprotective capacity has been demonstrated in other preclinical neurological disease models before. In this study, we used an unbiased proteomic approach to identify potential new targets upon the treatment of MMF in glio-neuronal hippocampal cultures. MMF treatment results in induction of antioxidative (HMOX1, NQO1) and anaplerotic metabolic (GAPDH, PC) pathways, which correlated with reduction in ROS production, increased mitochondrial NADH-redox index and decreased NADH pool, independent of glutathione levels. Additionally, MMF reduced glycolytic capacity indicating individual intra-cellular metabolic programs within different cell types. Furthermore, we demonstrate a neuroprotective effect of MMF upon hyperexcitability in vitro (low magnesium model), where MMF prevents glio-neuronal death via reduced ROS production. These results highlight MMF as a potential new therapeutic opportunity in hyperexcitability-induced neurodegeneration.

Immunosuppressant; Quality of life; Transplantation Immunosupressor; Qualitat de vida; Trasplantament Inmunosupresor; Calidad de vida; Trasplante Introduction: Patient-Reported Outcomes (PRO) integrate a wide range of holistic dimensions that arenot captured within clinical outcomes. Particularly, from induction treatment to maintenance therapy, patient quality-of-life (QoL) of kidney transplant recipients have been sparsely investigated in international settings. Methods: In a prospective, multi-centric cohort study, including nine transplant centers in four countries, we explored the QoL during the year following transplantation using validated elicitation instruments (EQ-5D-3L index with VAS) in a population of kidney transplant patients receiving immunosuppressive therapies. Calcineurin inhibitors (tacrolimus and ciclosporin), IMPD inhibitor (mycophenolate mofetil), and mTOR inhibitors (everolimus and sirolimus) were the standard-of-care (SOC) medications, together with tapering glucocorticoid therapy. We used EQ-5D and VAS data as QoL measures alongside descriptive statistics at inclusion, per country and hospital center. We computed the proportions of patients with different immunosuppressive therapy patterns, and using bivariate and multivariate analyses, assessed the variations of EQ-5D and VAS between baseline (i.e., inclusion Month 0) and follow up visits (Month 12). Results: Among 542 kidney transplant patients included and followed from November 2018 to June 2021, 491 filled at least one QoL questionnaire at least at baseline (Month 0). The majority of patients in all countries received tacrolimus and mycophenolate mofetil, ranging from 90.0% in Switzerland and Spain to 95.8% in Germany. At M12, a significant proportion of patients switched immunosuppressive drugs, with proportion varying from 20% in Germany to 40% in Spain and Switzerland. At visit M12, patients who kept SOC therapy had higher EQ-5D (by 8 percentage points, p < 0.05) and VAS (by 4 percentage points, p < 0.1) scores than switchers. VAS scores were generally lower than EQ-5D (mean 0.68 [0.5–0.8] vs. 0.85 [0.8–1]). Discussion: Although overall a positive trend in QoL was observed, the formal analyses did not show any significant improvements in EQ-5D scores or VAS. Only when the effect of a therapy use was separated from the effect of switching, the VAS score was significantly worse for switchers during the follow up period, irrespective of the therapy type. If adjusted for patient characteristics and medical history (e.g., gender, BMI, eGRF, history of diabetes), VAS and EQ-5D delivered sound PRO measures for QoL assessments during the year following renal transplantation. The project has received funding from the European Union’s Horizon 2020 research and innovation program under grant agreement No 754995. Open access funding by University of Lausanne.

The ZUMA-7 (Efficacy of Axicabtagene Ciloleucel Compared to Standard of Care Therapy in Subjects With Relapsed/Refractory Diffuse Large B Cell Lymphoma) study showed that axicabtagene ciloleucel (axi-cel) improved event-free survival (EFS) compared with standard of care (SOC) salvage chemoimmunotherapy followed by autologous stem cell transplant in primary refractory/early relapsed diffuse large B-cell lymphoma (DLBCL); this led to its recent US Food and Drug Administration approval in this setting. We modeled a hypothetical cohort of US adults (mean age, 65 years) with primary refractory/early relapsed DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of second-line axi-cel compared with SOC using a range of plausible long-term outcomes. EFS and OS were estimated from ZUMA-7. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year EFS of 35% with second-line axi-cel and 10% with SOC, axi-cel was cost-effective at a WTP of $150 000 per QALY ($93 547 per QALY). axi-cel was no longer cost-effective if its 5-year EFS was ≤26.4% or if it cost more than $972 061 at a WTP of $150 000. Second-line axi-cel was the cost-effective strategy in 73% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in EFS is maintained over time, second-line axi-cel for aggressive relapsed/refractory DLBCL is cost-effective compared with SOC at a WTP of $150 000 per QALY. However, its cost-effectiveness is highly dependent on long-term outcomes. Routine use of second-line chimeric antigen receptor T-cell therapy would add significantly to health care expenditures in the United States (more than $1 billion each year), even when used in a high-risk subpopulation. Further reductions in the cost of chimeric antigen receptor T-cell therapy are needed to be affordable in many regions of the world.

Background: Multislice computed tomography (MSCT) may reveal hypo-attenuated leaflet thickening (HALT) and/or reduced leaflet motion (RELM) in approximately 15 % of patients after transcatheter aortic valve replacement (TAVR). These supposedly thrombogenic phenomena may be associated with neurological events and increased transprosthetic gradients. It is unclear whether oral anticoagulant therapy -specifically a factor Xa inhibitor- could affect the incidence of HALT/RELM. Study design: The Rotterdam EDOXaban (REDOX) trial is an investigator-initiated, single-center, prospective registry in which 100 patients with no formal indication for oral anticoagulant drugs or dual antiplatelet therapy, will receive a 3-month treatment with edoxaban, followed by a MSCT to detect HALT/RELM. The primary endpoint is the incidence of HALT at 3-months follow-up. Secondary endpoints include the incidence of RELM at 3 months; change in transprosthetic gradients at 1 year and the clinical composite endpoint of all-cause death, myocardial infarction (MI), ischemic stroke, systemic thromboembolism, valve thrombosis and major bleeding (International Society on Thrombosis and Hemostasis [ISTH] definition) at 1 year follow up. The study is powered to demonstrate with 90 % statistical power and a 0.025 alpha a 4 % incidence of HALT with edoxaban as compared to the expected 15 % rate with an antiplatelet regimen and will enroll 100 patients to account for loss of follow-up or CT-drop out. Conclusion: The REDOX trial will investigate the short-term effect of an Xa-inhibitor on the incidence of HALT after TAVR. (ClinicalTrials.gov Identifier: NCT04171726).

Purpose:A phase I/II study evaluating the safety and activity of memory-enriched CD19-directed chimeric antigen receptor (CD19-CAR) T cells in adults with relapsed/refractory B-cell acute lymphoblastic leukemia (ALL).Patients and Methods:In phase I, we tested sequentially two cell populations for CAR transduction: (i) central memory (Tcm) or (ii) naïve, stem, and central memory (Tn/mem) T cells. The study employed an activity constrained for toxicity design to determine the recommended phase II dose (RP2D), which was tested in phase II.Results:The Tcm cohort was closed early due to lack of activity. The 200 ×106 Tn/mem-derived CD19-CAR T-cell dose was found to be safe and active, and was declared the RP2D. At RP2D, 58 participants underwent leukapheresis and 46 received CD19-CAR T cells. Median age for treated participants was 38 years (range, 22–72). Twenty-nine (63%) participants had relapsed post-allogeneic hematopoietic cell transplantation (alloHCT), 18 (39%) had Philadelphia-like (Ph-like) genotype, and 16 (35%) had extramedullary disease (EMD) at lymphodepletion (LD). Three (7%) participants had grade 3 cytokine release syndrome (CRS), and none had grade ≥ 4 CRS. Eight (17%) participants had grade ≥ 3 neurotoxicity, including one fatal cerebral edema. Forty (87%) patients achieved complete remission (CR)/CR with incomplete hematologic recovery, 2 (4%) progressed, and 4 (9%) were unevaluable for response. Among 42 response-evaluable participants, 16/17 with Ph-like ALL and 13/15 with EMD at LD responded. Twenty-one (53%) responders underwent alloHCT consolidation, which was associated with improved relapse-free survival (adjusted HR = 0.16; 95% confidence interval, 0.05–0.48; P = 0.001).Conclusions:Tn/mem-derived CD19-CAR T cells were safe and active, including in Ph-like ALL and EMD.See related commentary by El Marabti and Abdel-Wahab, p. 694

Sexuelle Repräsentationen, Normen, Werte und Praktiken sind eng verknüpft mit jeweils spezifischen historischen und kulturellen Kontexten. Im Laufe der sexuellen Sozialisation und in Auseinandersetzung mit gesellschaftlichen Sexualnormen und Werte bildet sich eine sexuelle Identität als Mischung aus individuellen Begehrensstrukturen, sexualitätsbezogenen Haltungen und Einstellungen. Durch Digitalisierung haben sich die sexuellen Sozialisationsbedingungen von Jugendlichen in den vergangenen Jahrzehnten in hohem Tempo verändert. Digitale Medien werden genutzt, um sexuelle Interaktionen und Kommunikation online zu gestalten. Doch erweitern sich nicht nur Möglichkeitsräume für selbstbestimmte Sexualität, sondern auch Risiken durch sexuelle Grenzverletzungen. Ein besonderes Phänomen ist das sogenannte Sexting, also der einvernehmliche Austausch selbstproduzierter freizügiger Bilder. Noch gibt es im deutschen Sprachraum allerdings kaum empirische Daten darüber, wie Sexting von Jugendlichen erlebt und genutzt wird, ebenso existieren nur wenige, überwiegend quantitative Studien zu den Erfahrungen Jugendlicher mit nicht-konsensuellem Sexting. Ziel dieses Beitrags ist es, basierend auf den Befunden einer rekonstruktiven Interviewstudie zu einer Differenzierung des Diskurses um Sexting und die damit einhergehenden geschlechtsbezogenen Zuschreibungen beizutragen. Dazu wird zunächst der Stand der Forschung dargestellt, bevor die dem Beitrag zugrunde liegende Studie vorgestellt wird. Anhand der dokumentarischen Analyse von Gruppendiskussionen werden Einblicke in die Orientierungen von Schüler:innen gegeben. Besonderes Augenmerk liegt auf der Rekonstruktion der Orientierungen Jugendlicher auf Normalität und Geschlecht. Es lassen sich mit den «Experimentierenden», den «Kritisch-Reflexiven» sowie den «Abstinenten» drei relationale Typen differenzieren, die im Fazit in Bezug auf Normalitätskonstruktionen und Geschlechterdimensionen dargestellt werden.

Background and aims – Chilgoza pine (Pinus gerardiana) is a near-threatened tree species from the north-western Himalayas. This species is the economically most important pine in Afghanistan because of its edible nuts; however, its distribution range is disjunct and restricted to a few isolated regions. The IUCN lists Chilgoza as a near threatened species because of overexploitation of its nuts and a declining population trend. This research is the first in-depth analysis of the genetic variability and structure of Chilgoza in Afghanistan using microsatellite markers. Material and methods –We tested cross-amplification of 44 SSR markers developed for pine species. Eight polymorphic EST-SSRs were genotyped in a natural Chilgoza population in Gardiz, Afghanistan. To evaluate the genetic diversity, fine-scale spatial genetic structure (SGS), signatures of bottleneck events, and the effective population size, 191 trees were sampled and genotyped. Based on the diameter at breast height, individuals were classified as young or old trees. Key results – Genetic variation in the whole population was moderate. For individual markers, He ranged from 0.130 to 0.515 (mean = 0.338) and Ho from 0.118 to 0.542 (mean = 0.328). The expected heterozygosity in young trees was slightly lower than in old trees. The SGS was stronger for young trees (Sp = 0.0100) than for old trees (Sp = 0.0029). Heterozygosity excess analysis detected no recent population size reduction, but the M ratio revealed an ancient and prolonged bottleneck in the Chilgoza population. Conclusion – Identification of suitable EST-SSRs for future studies of natural Chilgoza populations provides important tools for the conservation of the species. Despite the moderate genetic variation in Gardiz, scarcity of natural regeneration is likely to reduce the genetic variation and adaptability in future generations. Our results indicated a slight decrease in genetic diversity and stronger SGS in young trees calling for conservation measures fostering natural regeneration.

It is known that kidney transplantation (KTx) decreases mortality rate and increases life expectancy about 10 years compared with dialysis, particularly in patients with diabetes. However, cardiovascular disease is still the most common cause of death after transplantation.The evaluation of the cardiovascular risk after successful KTx in diabetic and nondiabetic patients.We enrolled 344 patients after KTx (mean age 52.7 years, M -62.5%). The cohort was divided into 2 groups diabetes (+) and diabetes (-). Arterial stiffness parameters (brachial-ankle and carotid-femoral pulse wave velocity, pulse pressure, pulsatile stress was assessed by an automated oscillometric device. All body composition parameters were evaluated based on bioelectrical impedance analysis and laboratory parameters were obtained from medical files of the patients.Arterial stiffness parameters were higher in the diabetes (+) compared with diabetes (-) group, significantly. Body mass index was significantly higher in the diabetes (+) group, as well as body fat mass and visceral fat area. In the diabetes (+) group compared with the diabetes (-) group, whole-body phase angle was lower (4.54 vs 4.90 P = .006). Visceral fat area and whole-body phase angle correlated significantly with arterial stiffness parameters.The evaluation of arterial stiffness and phase angle is a useful method for identifying patients at high cardiovascular risk. Therefore, we suggest that patients with diabetes after successful KTx due to the baseline high cardiolovascular risk, should be regularly assessed to monitor changes in blood vessels, body composition and undergo dietary intervention.

PURPOSE Mosunetuzumab is a bispecific antibody targeting CD20 and CD3 that redirects T cells to engage and eliminate malignant B cells and is being developed for relapsed or refractory (R/R) B-cell non-Hodgkin lymphomas (B-NHLs). METHODS This first-in-human trial (ClinicalTrials.gov identifier: NCT02500407 ) evaluated the safety and tolerability and efficacy of mosunetuzumab in patients with R/R B-NHL and established the recommended phase II dose. Data from dose escalation are presented. Single-agent mosunetuzumab was administered intravenously in 3-week cycles, at full dose in cycle 1 day 1 (group A) or with ascending (step-up) doses during cycle 1 on days 1, 8, and 15 (group B), for eight or 17 cycles on the basis of tumor response. RESULTS Two hundred thirty patients were enrolled. Doses up to 2.8 mg and 60 mg were assessed in groups A and B, respectively; maximum tolerated dose was not exceeded. In group B (n = 197), common adverse events (≥ 20% of patients) were neutropenia (28.4%), cytokine release syndrome (27.4%), hypophosphatemia (23.4%), fatigue (22.8%), and diarrhea (21.8%). Cytokine release syndrome was mostly low-grade (grade ≥ 3: 1.0%) and mainly confined to cycle 1. Across the doses investigated (group B), best overall response rates were 34.9% and 66.2% in patients with aggressive and indolent B-NHL, respectively, and complete response rates were 19.4% and 48.5%. Among patients with a complete response, the median duration of response was 22.8 months (95% CI, 7.6 to not estimable) and 20.4 (95% CI, 16 to not estimable) in patients with aggressive and indolent B-NHL, respectively. CONCLUSION Mosunetuzumab, administered with step-up dosing, has a manageable safety profile and induces durable complete responses in R/R B-NHL. The expansion stage of the study is ongoing at the dose level of 1/2/60/60/30 mg selected for further study.

Despite the need to generate valid and reliable estimates of protection against SARS-CoV-2 infection and severe course of COVID-19 for the German population in summer 2022, there was a lack of systematically collected population-based data allowing for the assessment of the protection level in real-time.In the IMMUNEBRIDGE project, we harmonised data and biosamples for nine population-/hospital-based studies (total number of participants n=33,637) to provide estimates for protection levels against SARS-CoV-2 infection and severe COVID-19 between June and November 2022. Based on evidence synthesis, we formed a combined endpoint of protection levels based on the number of self-reported infections/vaccinations in combination with nucleocapsid/spike antibody responses (“confirmed exposures”). Four confirmed exposures represented the highest protection level, and no exposure represented the lowest.Most participants were seropositive against the spike antigen; 37% of the participants ≥79 years had less than four confirmed exposures (highest level of protection) and 5% less than three. In the subgroup of participants with comorbidities, 46-56% had less than four confirmed exposures. We found major heterogeneity across federal states, with 4%-28% of participants having less than three confirmed exposures.Using serological analyses, literature synthesis and infection dynamics during the survey period, we observed moderate to high levels of protection against severe COVID-19, whereas the protection against SARS-CoV-2 infection was low across all age groups. We found relevant protection gaps in the oldest age group and amongst individuals with comorbidities, indicating a need for additional protective measures in these groups.

The digital transformation is a complex and multi-faceted phenomenon, which companies hamper to manage effectively. One particular facet of this phenomenon is the role of managers, which is still underrepresented in research. This study aims to identify and explain why and what managerial practices and competencies are particularly needed to effectively govern through this transformation. We choose the case study methodology as the research design with eight manufacturing companies in Western Europe, where we applied within- and cross-case analyses. Specific barriers for digital transformation and four aggregated managerial practices, such as strategy/organization, collaboration, cross-functionality and data-driven use cases, were identified. These were supported by 13 competencies to facilitate digitalization. We explicate these practices based on the change management theory and provide a model describing the impact of these practices on profitability. This study contributes to the emergent change theory by analyzing practices and competencies that managers should be equipped with to foster digitalization.