Longitudinal Evaluation of Aortic Haemodynamics in Patients after Repair of Aortic Coarctation: A 4D Flow MRI Follow-Up Study

Background: Patients after repair of Aortic Coarctation (CoA) have high risk of secondary vessel pathologies, regular monitoring is absolutely essential. Objective: To investigate aortic hemodynamics and wall parameters in adolescent patients and young adults after repair of CoA by 4D flow MRI in a longitudinal study. Materials and methods: Time-resolved flow-sensitive 4D MRI was acquired twice in 28 patients (age t1: 14.6±7.8, t2: 18.9±8.3 years) with a mean follow-up duration of 4.4±1.2 years. Quantitative analysis included segmentation of the aorta using 9 manually-placed planes to calculate regional time-averaged absolute Wall Shear Stress (WSS), Peak Velocities (Vmax), Oscillatory Shear Index (OSI) and aortic diameters. Two independent readers assessed blood flow visualisation depicting helical and vertical flow patterns. For statistical analysis, patients who underwent re-intervention and patients with Bicuspid Aortic Valve (BAV) were evaluated separately. Results: Quantitative analysis showed an overall decrease in WSS (mean t1: 0.48±0.13 N/m², t2: 0.33±0.11 N/m²; p0.05). The total number of secondary flow patterns decreased except for an increase in additional local AAo helices. Conclusion: 4D flow MRI enables us to evaluate qualitative and quantitative aortic changes in patients with repaired CoA over time that are not limited to the CoA site. BAV patients exhibit particular characteristics in quantitative parameters

Shell Disease Syndrome Is Associated with Reduced and Shifted Epibacterial Diversity on the Carapace of the Crustacean Cancer pagurus

Crustaceans increasingly suffer from the black spot shell disease syndrome, which principally results from bacterial breakdown of their chitinous exoskeleton. Since Cancer pagurus is highly susceptible to this disease, we compared the bacterial communities of black spot affected and non-affected areas of the carapace by amplicon sequencing of 16S rRNA genes and 16S rRNA. Within each spot, bacterial communities of affected areas were less diverse compared to communities from non-affected areas. Communities of different affected spots were, however, more divergent from each other, compared to those of different nonaffected areas. This indicates a reduced and shifted microbial community composition caused by the black spot disease. Different communities found in black spots likely indicate different stages of the disease. In affected areas, Flavobacteriaceae rose up to one of the most abundant and active families, due to massive increase of Aquimarina spp., suggesting a significant role in shell disease syndrome. We isolated 75 bacterial strains from diseased and healthy areas, which primarily affiliated with Proteobacteria and Bacteroidetes, thus reflecting the dominant phyla detected by amplicon sequencing. The ability to degrade chitin was mainly found for Gammaproteobacteria and Aquimarina spp. within the Flavobacteriia, while the ability to use N-acetylglucosamine, the monomer of the polysaccharide chitin, was observed for most isolates, including many Alphaproteobacteria. Furthermore, one third of the isolates showed antagonistic properties. The combination of bacterial community analysis and the physiological properties of the isolates provides insights into a functional complex epibacterial community on the carapace of C. pagurus. Importance In recent years, the shell disease syndrome was detected for several ecologically and economically important crustacean species. Large proportions of populations are affected, e.g., >60% of the widely distributed species Cancer pagurus in different North Sea areas. Bacteria play a significant role in the development of different forms of shell disease, all characterized by microbial chitinolytic degradation of the outer shell. By comparing the bacterial communities of healthy and diseased areas of the shell of C. pagurus we could demonstrate that the disease causes a reduced bacterial diversity within affected areas, a phenomenon co-occurring also with many other diseases. Furthermore, the community composition dramatically changed, with some taxa rising to high relative abundances and showing increased activity, indicating a strong participation in shell disease. Characterization of bacterial isolates obtained from affected and non-affected spots provided deeper insights in their physiological properties and thus the possible role within the microbiome

Reprogramming human T cell function and specificity with non-viral genome targeting.

Decades of work have aimed to genetically reprogram T cells for therapeutic purposes1,2 using recombinant viral vectors, which do not target transgenes to specific genomic sites3,4. The need for viral vectors has slowed down research and clinical use as their manufacturing and testing is lengthy and expensive. Genome editing brought the promise of specific and efficient insertion of large transgenes into target cells using homology-directed repair5,6. Here we developed a CRISPR-Cas9 genome-targeting system that does not require viral vectors, allowing rapid and efficient insertion of large DNA sequences (greater than one kilobase) at specific sites in the genomes of primary human T cells, while preserving cell viability and function. This permits individual or multiplexed modification of endogenous genes. First, we applied this strategy to correct a pathogenic IL2RA mutation in cells from patients with monogenic autoimmune disease, and demonstrate improved signalling function. Second, we replaced the endogenous T cell receptor (TCR) locus with a new TCR that redirected T cells to a cancer antigen. The resulting TCR-engineered T cells specifically recognized tumour antigens and mounted productive anti-tumour cell responses in vitro and in vivo. Together, these studies provide preclinical evidence that non-viral genome targeting can enable rapid and flexible experimental manipulation and therapeutic engineering of primary human immune cells

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

Digitaler Stress in Deutschland: Eine Befragung von Erwerbstätigen zu Belastung und Beanspruchung durch Arbeit mit digitalen Technologien

Die voranschreitende Digitalisierung verändert das Belastungs- und Beanspruchungs-profil am Arbeitsplatz. Technostress ist ein Phänomen und Problem über alle Regionen, Branchen, Tätigkeitsarten und individuellen demographischen Faktoren hinweg. Übermäßiger Technostress reduziert die Leistung von Arbeitnehmern, wirkt sich negativ auf ihre Psyche und ihr Leben aus und verschlechtert ihre Gesundheit. Die vorliegende Studie präsentiert eine umfassende Bestandsaufnahme

Unsupervised argument reframing with a counterfactual-based approach

Heinisch P, Mindlin D, Cimiano P. Unsupervised argument reframing with a counterfactual-based approach. In: Alshomary M, Chen C-C, Muresan S, Park J, Romberg J, eds. Proceedings of the 10th Workshop on Argument Mining. Stroudsburg, PA, USA: Association for Computational Linguistics; 2023: 107-119