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Alexander Sekita,1 Harald Unterweger,1 Sonja Berg,1 Sabine Ohlmeyer,2 Tobias Bäuerle,3 Kang H Zheng,4 Bram F Coolen,5 Aart J Nederveen,6 Claudia Cabella,7 Silvia Rossi,7 Erik SG Stroes,4 Christoph Alexiou,1 Stefan Lyer,1,* Iwona Cicha1,* 1ENT-Department, Section of Experimental Oncology Und Nanomedicine (SEON), Else Kröner-Fresenius-Stiftung-Professorship, Universitätsklinikum Erlangen, Erlangen, Germany; 2Institute of Radiology, Universitätsklinikum Erlangen, Erlangen, Germany; 3Preclinical Imaging Platform Erlangen (PIPE), Universitätsklinikum Erlangen, Erlangen, Germany; 4Department of Vascular Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 5Department of Biomedical Engineering and Physics, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 6Department of Radiology and Nuclear Medicine, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, the Netherlands; 7Bracco Imaging SpA, Centro Ricerche Bracco, Colleretto Giacosa, Turin, Italy*These authors contributed equally to this workCorrespondence: Iwona Cicha, Universitätsklinikum Erlangen, Glückstr, 10a, Erlangen, 91054, Germany, Tel +49 9131 85 43953, Fax +49 9131 85 34828, Email Iwona.Cicha@uk-erlangen.dePurpose: In this study, a detailed characterization of a rabbit model of atherosclerosis was performed to assess the optimal time frame for evaluating plaque vulnerability using superparamagnetic iron oxide nanoparticle (SPION)-enhanced magnetic resonance imaging (MRI).Methods: The progression of atherosclerosis induced by ballooning and a high-cholesterol diet was monitored using angiography, and the resulting plaques were characterized using immunohistochemistry and histology. Morphometric analyses were performed to evaluate plaque size and vulnerability features. The accumulation of SPIONs (novel dextran-coated SPIONDex and ferumoxytol) in atherosclerotic plaques was investigated by histology and MRI and correlated with plaque age and vulnerability. Toxicity of SPIONDex was evaluated in rats.Results: Weak positive correlations were detected between plaque age and intima thickness, and total macrophage load. A strong negative correlation was observed between the minimum fibrous cap thickness and plaque age as well as the mean macrophage load. The accumulation of SPION in the atherosclerotic plaques was detected by MRI 24 h after administration and was subsequently confirmed by Prussian blue staining of histological specimens. Positive correlations between Prussian blue signal in atherosclerotic plaques, plaque age, and macrophage load were detected. Very little iron was observed in the histological sections of the heart and kidney, whereas strong staining of SPIONDex and ferumoxytol was detected in the spleen and liver. In contrast to ferumoxytol, SPIONDex administration in rabbits was well tolerated without inducing hypersensitivity. The maximum tolerated dose in rat model was higher than 100 mg Fe/kg.Conclusion: Older atherosclerotic plaques with vulnerable features in rabbits are a useful tool for investigating iron oxide-based contrast agents for MRI. Based on the experimental data, SPIONDex particles constitute a promising candidate for further clinical translation as a safe formulation that offers the possibility of repeated administration free from the risks associated with other types of magnetic contrast agents.Keywords: atherosclerosis, plaque vulnerability, rabbit model, macrophages, histology, tissue iron, SPION-enhanced MRI

Objective: The Plants for Joints (PFJ) intervention significantly improved pain, stiffness, and physical function, and metabolic outcomes, in people with metabolic syndrome-associated osteoarthritis (MSOA). This secondary analysis investigated its effects on body composition. Method: In the randomized PFJ study, people with MSOA followed a 16-week intervention based on a whole-food plant-based diet, physical activity, and stress management, or usual care. For this secondary analysis, fat mass, muscle mass, and bone mineral density were measured using dual-energy X-ray absorptiometry (DEXA) for all participants. Additionally, in a subgroup (n ​= ​32), hepatocellular lipid (HCL) content and composition of visceral adipose tissue (VAT) were measured using magnetic resonance spectroscopy (MRS). An intention-to-treat analysis with a linear-mixed model adjusted for baseline values was used to analyse between-group differences. Results: Of 66 people randomized, 64 (97%) completed the study. The PFJ group experienced significant weight loss (−5.2 ​kg; 95% CI –6.9, −3.6) compared to controls, primarily from fat mass reduction (−3.9 ​kg; 95% CI –5.3 to −2.5). No significant differences were found in lean mass, muscle strength, or bone mineral density between groups. In the subgroup who underwent MRI scans, the PFJ group had a greater reduction in HCL (−6.5%; 95% CI –9.9, 3.0) compared to controls, with no observed differences in VAT composition. Conclusion: The PFJ multidisciplinary intervention positively impacted clinical and metabolic outcomes, and appears to significantly reduce body fat, including liver fat, while preserving muscle mass and strength.

Covid data show that wealth is not health. What then are the major variables that affect public health in the Covid–19 pandemic? Based on onsite research in 26 countries across the world this paper singles out three variables – knowledge, state capability and social cooperation. If one of these is dysfunctional or absent Covid–19 performance suffers. The variables work best in combination. Under consideration are three phases of Covid–19 – virus control, vaccines, and the race with variants. Which types of society best combine these variables? Comparing varieties of market economies – liberal, coordinated and state-led market economies (with four variants), Covid–19 data indicate that coordinated and developmental state-led market economies tend to generate the best combination of variables and public health outcomes, and liberal market economies and rightwing populist countries produce the worst combination. Comparative Covid–19 research points to the limitations of macro theories and methodological nationalism, the importance of the unit of analysis and the database, and how variables interact. At a time when multiple crises interact it leads to reflection on glaring limitations of global governance.

Aging is accompanied by a loss of muscle mass and function, termed sarcopenia, which causes numerous morbidities and economic burdens in human populations. Mechanisms implicated in age-related sarcopenia or frailty include inflammation, muscle stem cell depletion, mitochondrial dysfunction, and loss of motor neurons, but whether there are key drivers of sarcopenia are not yet known. To gain deeper insights into age-related muscle loss, we performed transcriptome profiling on lower limb muscle biopsies from 72 young, elderly, and frail human subjects using bulk RNA-seq (N = 72) and single-nuclei RNA-seq (N = 17). This combined approach revealed changes in gene expression that occur with age and frailty in multiple cell types comprising mature skeletal muscle. Notably, we found increased expression of the genes MYH8 and PDK4, and decreased expression of the gene IGFN1, in aged muscle. We validated several key genes changes in fixed human muscle tissue using digital spatial profiling. We also identified a small population of nuclei that express CDKN1A, present only in aged samples, consistent with p21cip1-driven senescence in this subpopulation. Overall, our findings identify unique cellular subpopulations in aged and sarcopenic skeletal muscle, which will facilitate the development of new therapeutic strategies to combat age-related frailty.

Background Enteroaggregative E. coli (EAEC) is associated with acute and chronic diarrhea worldwide. EAEC is thought to form thick biofilms on the intestinal mucosa. Epidemiological data suggest that SepA, a serine protease autotransporter of Enterobacteriaceae (SPATE), is important for EAEC disease. The genes for SepA, and some proteins that are important for EAEC biofilm formation and aggregative adherence, are encoded by the pAA plasmid. Methods We deleted sepA 49-4043 from six EAEC clinical isolates and inserted a chloramphenicol resistance gene ( cat) in place of the sepA coding sequence. In vitro biofilm formation was assessed after growth in 96-well plates. Complementation studies were conducted with genetic and protein-based techniques. We moved the pAA plasmid from EAEC strains into a commensal E. coli. Finally, we sequenced the pAA of several strains. Results All of the wild-type EAEC strains secreted similar amounts of SepA as assessed by Western blot analysis. Four of the six mutant EAEC strains exhibited increased biofilm staining when sepA was deleted. Additionally, we found that introduction of pAAΔ sepA K261 into a nalidixic acid resistant commensal E. coli strain, (HSNal R) resulted in significantly increased biofilm staining relative to HSNal R (pAA K261). Therefore, pAAΔ sepA K261 alone was sufficient to confer the elevated biofilm phenotype onto HSNal R. However, introduction of sepA via a plasmid or on the pAA did not restore biofilm staining to wild-type levels in the Δ sepA mutant strains that showed elevated biofilm staining. Furthermore, the addition of exogenous SepA to the biofilm in vitro did not reduce biofilm staining. Conclusions Taken together, our results suggest that deletion of sepA causes elevated biofilm formation in some EAEC strains, but that the increased biofilm staining is not directly due to the loss of SepA.

Here I reflect on the main themes of Global Culture, Nationalism, Globalization and Modernity. On these themes, where are we 30 years later? I sidestep the fine print of the 1990 conversations and share notes in brief format on where I have come to in the decades that have passed. I round off with notes on the 2020 conjuncture.

Objective. To present some resources developed as part of the technical support of the Pan American Health Organization (PAHO) to Member States to reduce population dietary sodium intake, and to discuss the main challenges and opportunities to accelerate action toward sodium intake reduction in the Americas. Methods. Sources of information include a mapping of salt reduction policies conducted in 2019, reports from working group meetings, interviews conducted in 2020 and 2021 in seven countries, and technical documents developed around the Updated PAHO Regional Sodium Reduction Targets. Results. These tools show that, despite progress, challenges to succeed in this agenda persist. Priority given to sodium reduction is low in most countries, with insufficient resource allocation. There is a lack of intersectoral coordinated action, and a systemic approach to food systems is commonly missing. Surveillance mechanisms of sodium intake are insufficient, and industry interference in policy processes is commonly identified, undermining policy progress and success. There are also important regional opportunities to address these challenges. These include common ground for future collaborations by updating, strengthening, and complementing these existing tools, and technical and financial support for data generation. Conclusions. PAHO is committed to continue to support countries in the process of promoting, implementing, and monitoring cost-effective sodium reduction interventions. One key policy priority in this agenda is the adoption of the Updated PAHO Regional Sodium Reduction Targets with a mandatory approach, together with the comprehensive and complementary implementation of other strategies. Strong political will and commitment of countries will be critical to translate goals into concrete achievements in the Americas.

Abstract Background A new 72-channel receive array coil and sensitivity encoding, compressed (C-SENSE) and noncompressed (SENSE), were investigated to decrease the number of breath-holds (BHs) for cardiac magnetic resonance (CMR). Methods Three-T CMRs were performed using the 72-channel coil with SENSE-2/4/6 and C-SENSE-2/4/6 accelerated short-axis cine two-dimensional balanced steady-state free precession sequences. A 16-channel coil with SENSE-2 served as reference. Ten healthy subjects were included. BH-time was kept under 15 s. Data were compared in terms of image quality, biventricular function, number of BHs, and scan times. Results BHs decreased from 7 with C-SENSE-2 (scan time 70 s, 2 slices/BH) to 3 with C-SENSE-4 (scan time 42 s, 4–5 slices/BH) and 2 with C-SENSE-6 (scan time 28 s, 7 slices/BH). Compared to reference, image sharpness was similar for SENSE-2/4/6, slightly inferior for C-SENSE-2/4/6. Blood-to-myocardium contrast was unaffected. C-SENSE-4/6 was given lower qualitative median scores, but images were considered diagnostically adequate to excellent, with C-SENSE-6 suboptimal. Biventricular end-diastolic (EDV), end-systolic (ESV) and stroke volumes, ejection fractions (EF), cardiac outputs, and left ventricle (LV)-mass were similar for SENSE-2/4/6 with no systematic bias and clinically appropriate limits of agreements. C-SENSE slightly underestimated LV-EDV (-6.38 ± 6.0 mL, p < 0.047), LV-ESV (-7.94 ± 6.0 mL, p < 0.030) and overestimated LV-EF (3.16 ± 3.10%; p < 0.047) with C-SENSE-4. Bland-Altman analyses revealed minor systematic biases in these variables with C-SENSE-2/4/6 and for LV-mass with C-SENSE-6. Conclusions Using the 72-channel coil, short-axis CMR for quantifying biventricular function was feasible in two BHs where SENSE slightly outperformed C-SENSE.