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Franz Wegner,1,* Anselm von Gladiss,2,* Julian Haegele,1,3 Ulrike Grzyska,1 Malte Maria Sieren,1 Erik Stahlberg,1 Thekla Helene Oechtering,1 Kerstin Lüdtke-Buzug,2 Joerg Barkhausen,1 Thorsten M Buzug,2,4 Thomas Friedrich2,4 1Department of Radiology and Nuclear Medicine, University of Lübeck, Lübeck, Germany; 2Institute of Medical Engineering, University of Lübeck, Lübeck, Germany; 3Zentrum für Radiologie und Nuklearmedizin Rheinland, Dormagen, Germany; 4Fraunhofer Research Institution for Individualized and Cell-Based Medical Engineering, Lübeck, Germany*These authors contributed equally to this workCorrespondence: Franz WegnerUniversity Hospital Schleswig-Holstein, Campus Lübeck, Department of Radiology and Nuclear Medicine, Ratzeburger Allee 160, Lübeck 23538, GermanyTel +004945150017001Fax +004945150017004Email franz.wegner@uksh.dePurpose: Endovascular stents are medical devices, which are implanted in stenosed blood vessels to ensure sufficient blood flow. Due to a high rate of in-stent re-stenoses, there is the need of a noninvasive imaging method for the early detection of stent occlusion. The evaluation of the stent lumen with computed tomography (CT) and magnetic resonance imaging (MRI) is limited by material-induced artifacts. The purpose of this work is to investigate the potential of the tracer-based modality magnetic particle imaging (MPI) for stent lumen visualization and quantification.Methods: In this in vitro study, 21 endovascular stents were investigated in a preclinical MPI scanner. Therefore, the stents were implanted in vessel phantoms. For the signal analysis, the phantoms were scanned without tracer material, and the signal-to-noise-ratio was analyzed. For the evaluation of potential artifacts and the lumen quantification, the phantoms were filled with diluted tracer agent. To calculate the stent lumen diameter a calibrated threshold value was applied.Results: We can show that it is possible to visualize the lumen of a variety of endovascular stents without material induced artifacts, as the stents do not generate sufficient signals in MPI. The stent lumen quantification showed a direct correlation between the calculated and nominal diameter (r = 0.98).Conclusion: In contrast to MRI and CT, MPI is able to visualize and quantify stent lumina very accurately.Keywords: magnetic particle imaging, endovascular stents, artifacts, superparamagnetic iron oxide nanoparticles, lumen quantification

Nikolaos Panagiotopoulos,1 Robert L Duschka,1 Mandy Ahlborg,2 Gael Bringout,2 Christina Debbeler,2 Matthias Graeser,2 Christian Kaethner,2 Kerstin Lüdtke-Buzug,2 Hanne Medimagh,2 Jan Stelzner,2 Thorsten M Buzug,2 Jörg Barkhausen,1 Florian M Vogt,1 Julian Haegele1 1Clinic for Radiology and Nuclear Medicine, University Hospital Schleswig Holstein, Campus Lübeck, 2Institute of Medical Engineering, University of Lübeck, Lübeck, Germany Abstract: Magnetic particle imaging (MPI) is a novel imaging method that was first proposed by Gleich and Weizenecker in 2005. Applying static and dynamic magnetic fields, MPI exploits the unique characteristics of superparamagnetic iron oxide nanoparticles (SPIONs). The SPIONs’ response allows a three-dimensional visualization of their distribution in space with a superb contrast, a very high temporal and good spatial resolution. Essentially, it is the SPIONs’ superparamagnetic characteristics, the fact that they are magnetically saturable, and the harmonic composition of the SPIONs’ response that make MPI possible at all. As SPIONs are the essential element of MPI, the development of customized nanoparticles is pursued with the greatest effort by many groups. Their objective is the creation of a SPION or a conglomerate of particles that will feature a much higher MPI performance than nanoparticles currently available commercially. A particle’s MPI performance and suitability is characterized by parameters such as the strength of its MPI signal, its biocompatibility, or its pharmacokinetics. Some of the most important adjuster bolts to tune them are the particles’ iron core and hydrodynamic diameter, their anisotropy, the composition of the particles’ suspension, and their coating. As a three-dimensional, real-time imaging modality that is free of ionizing radiation, MPI appears ideally suited for applications such as vascular imaging and interventions as well as cellular and targeted imaging. A number of different theories and technical approaches on the way to the actual implementation of the basic concept of MPI have been seen in the last few years. Research groups around the world are working on different scanner geometries, from closed bore systems to single-sided scanners, and use reconstruction methods that are either based on actual calibration measurements or on theoretical models. This review aims at giving an overview of current developments and future directions in MPI about a decade after its first appearance. Keywords: magnetic particle imaging, superparamagnetic iron oxide nanoparticles, magnetic particle spectrometer, peripheral nerve stimulation, cardiovascular interventions

Julian Haegele,1 Robert L Duschka,1 Matthias Graeser,2 Catharina Schaecke,1 Nikolaos Panagiotopoulos,1 Kerstin Lüdtke-Buzug,2 Thorsten M Buzug,2 Jörg Barkhausen,1 Florian M Vogt1 1Clinic for Radiology and Nuclear Medicine, 2Institute of Medical Engineering, University Hospital Schleswig Holstein, Lübeck, Schleswig-Holstein, Germany Background: Magnetic particle imaging (MPI) uses magnetic fields to visualize superparamagnetic iron oxide nanoparticles (SPIO). Today, Resovist® is still the reference SPIO for MPI. The objective of this study was to evaluate the in vivo blood half-life of two different types of Resovist (one from Bayer Pharma AG, and one from I’rom Pharmaceutical Co Ltd) in MPI. Methods: A Resovist concentration of 50 µmol/kg was injected into the ear artery of ten New Zealand White rabbits. Five animals received Resovist distributed by I’rom Pharmaceutical Co Ltd and five received Resovist by Bayer Pharma AG. Blood samples were drawn before and directly after injection of Resovist, at 5, 10, and 15 minutes, and then every 15 ­minutes until 120 minutes after the injection. The MPI signal of the blood samples was evaluated using magnetic particle spectroscopy. Results: The average decline of the blood MPI signal from the two distributions differed significantly (P=0.0056). Resovist distributed by Bayer Pharma AG showed a slower decline of the MPI signal (39.7% after 5 minutes, 20.5% after 10 minutes, and 12.1% after 15 minutes) compared with Resovist produced by I’rom Pharmaceutical Co Ltd (20.4% after 5 minutes, 7.8% after 10 minutes, no signal above noise level after 15 minutes). Conclusion: In MPI, the blood half-life of an SPIO tracer cannot be equalized to the blood half-life of its MPI signal. Resovist shows a very rapid decline of blood MPI signal and is thus not suitable as a long circulating tracer. For cardiovascular applications in MPI, it may be used as a bolus tracer. Keywords: magnetic particle imaging, superparamagnetic iron oxide nanoparticles, magnetic particle spectroscopy, blood half-life time, Resovist®

Disabled Children and Young People in Sport, Physical Activity and Physical Education A. Maher & J. Haegele, Eds. (2024). New York, NY: Routledge. 98 pp. ISBN 978-1032935584. Hardcover & ebook [...]

To date, studies using cross-sectional methodologies make up a majority of the literature surrounding children with autism spectrum disorders and participation in physical activity and screen time. Longitudinal studies are needed to examine how physical activity and screen time behaviors co-develop for children with and without an autism spectrum disorder. To address this research gap, this study compared how physical activity and screen time levels changed over time (9 to 18 years of age) between youth with autism spectrum disorder and youth with neurotypical development. Data on the levels of moderate-to-vigorous physical activity, light physical activity, television-, and video game-based screen time, collected as a part of the "Growing up in Ireland" study, were compared between youth with autism spectrum disorder and a propensity-matched sample of youth with neurotypical development (n = 88 per group; 176 in total). Robust regression analyses indicated that children with autism spectrum disorder became less active over time compared to children with neurotypical development and that video game screen time also differed significantly between the groups when children were 9 years old. These findings elucidate important disparities present between these groups of children during pivotal developmental times.

This needs-assessment study evaluated the physical activity levels, needs, preferences, and requirements for exercise among individuals with visual impairments, aiming to establish evidence for the codesign of a subsequent home-based exercise program. The questionnaire, comprising 35 questions, was developed by a research team of disability and adapted physical activity experts. It was implemented for the online survey, collecting data from 145 adults with severe low vision and blindness between January 15 and January 29, 2024. Descriptive statistical analysis and content analysis were employed. Seventy-five participants (62.5%) were classified as overweight or obese, and only 15 participants reported engaging in the recommended levels of physical activity. Regarding the requirements for future home-based exercise programs, seven themes were identified: accessibility, nonvisual learning support, safety management, personalization, motivation, education, and technology. The results emphasized the urgent need for adapted home-based exercise programs that align with individuals' specific health conditions and abilities.

Arrayed CRISPR libraries extend the scope of gene-perturbation screens to non-selectable cell phenotypes. However, library generation requires assembling thousands of vectors expressing single-guide RNAs (sgRNAs). Here, by leveraging massively parallel plasmid-cloning methodology, we show that arrayed libraries can be constructed for the genome-wide ablation (19,936 plasmids) of human protein-coding genes and for their activation and epigenetic silencing (22,442 plasmids), with each plasmid encoding an array of four non-overlapping sgRNAs designed to tolerate most human DNA polymorphisms. The quadruple-sgRNA libraries yielded high perturbation efficacies in deletion (75-99%) and silencing (76-92%) experiments and substantial fold changes in activation experiments. Moreover, an arrayed activation screen of 1,634 human transcription factors uncovered 11 novel regulators of the cellular prion protein PrP C , screening with a pooled version of the ablation library led to the identification of 5 novel modifiers of autophagy that otherwise went undetected, and 'post-pooling' individually produced lentiviruses eliminated template-switching artefacts and enhanced the performance of pooled screens for epigenetic silencing. Quadruple-sgRNA arrayed libraries are a powerful and versatile resource for targeted genome-wide perturbations., Competing Interests: Competing interests: J.-A.Y., L.F. and A. Aguzzi are listed as inventors on a patent (Molecular Cloning Method and Vector Therefore, WO/2023/089153) owned by the University of Zurich, whose claims are supported by the present study. L.P. has ownership interest in Sagimet Biosciences, Apricot Therapeutics and Element Biosciences. M.K. is an inventor on US Patent 11,254,933 related to CRISPRi and CRISPRa screening, serves on the Scientific Advisory Boards of Engine Biosciences, Casma Therapeutics, Cajal Neuroscience, Alector and Montara Therapeutics, and is an advisor to Modulo Bio and Recursion Therapeutics. All authors with the affiliation ‘Novartis Institutes for Biomedical Research’ are employees of Novartis Pharma AG and may own stock in the company. The other authors declare no competing interests., (© 2024. The Author(s).)

Purpose: Magnetic particle imaging (MPI) is a tomographic imaging modality with the potential for cardiovascular applications. In this context, the extent to which stents are heated should be estimated from safety perspective. Furthermore, the influence of the measurement parameters and stent distance to the isocenter of the MPI scanner on stent heating were evaluated., Materials and Methods: Nine different endovascular stents and stent grafts were tested in polyvinyl-chloride tubes. The stents had diameters from 10 to 31 mm, lengths between 25 and 100 mm and were made from stainless steel, nitinol or cobalt-chromium. The temperature differences were recorded with fiber-optic thermometers. All measurements were performed in a preclinical commercial MPI scanner. The measurement parameters were varied (drive field strengths: 3, 6, 9, 12 mT and selection field gradients: 0, 1.25 and 2.5 T/m). Furthermore, measurements with different distances to the scanner's isocenter were performed (100 to 0 mm)., Results: All stents showed heating (maximum 53.1 K, minimum 4.6 K). The stent diameter directly correlated with the temperature increase. The drive field strength influenced the heating of the stents, whereas the selection field gradient had no detectable impact. The heating of the stents decreased with increasing distance from the scanner's isocenter and thus correlated with the loss of the scanner's magnetic field., Conclusion: Stents can cause potentially harmful heating in MPI. In addition to the stent diameter and design, the drive field strength and the distance to the MPI scanner's isocenter must be kept in mind as influencing parameters., (© 2022. The Author(s).)

Background: Physical inactivity among children and adolescents with disabilities (CAWD) is a global public health issue. Policy efforts to promote physical activity (PA) among CAWD have increased. This study summarizes the international policy trend for promoting PA among CAWD, with behavioral and policy insights specific to CAWD from country/regional indicators from the Active Healthy Kids Global Alliance Matrix on Physical Activity for Children and Adolescents to determine policy translation into practice., Methods: International and national PA policy documents on CAWD were assessed. Data from the Global Matrix Para Report Cards on the behavioral and government indicators from 14 countries or regions (grouped by human development index) were reviewed and compared., Results: Policy instruments began promoting PA for CAWD in 1989 via the Convention on the Rights of the Child. International policy has been advocating PA specifically for CAWD recently. In 2020, the World Health Organization published specific PA guidelines for CAWD. Data from the 14 Para Report Car found 14 grades on the average behavioral indicator and 12 on the government indicator. A gap between the average behavioral indicator (D-) and the government indicator (C+) was found in the Para Report Card data., Conclusions: Although international policies are consistent in their attention to the needs of CAWD, national/regional policies vary. Coverage ranges from nonexistent to embedded in broader inclusion concepts. A gap in policies to promote PA of CAWD is prevalent and is more prominent in countries or regions with a lower human development index ranking.

The purpose of this work was to develop instrument markers that are visible in both magnetic particle imaging (MPI) and magnetic resonance imaging (MRI). The instrument markers were based on two different magnetic nanoparticle types (synthesized in-house KLB and commercial Bayoxide E8706). Coatings containing one of both particle types were fabricated and measured with a magnetic particle spectrometer (MPS) to estimate their MPI performance. Coatings based on both particle types were then applied on a segment of a nonmetallic guidewire. Imaging experiments were conducted using a commercial, preclinical MPI scanner and a preclinical 1 tesla MRI system. MPI image reconstruction was performed based on system matrices measured with dried KLB and Bayoxide E8706 coatings. The bimodal markers were clearly visible in both methods. They caused circular signal voids in MRI and areas of high signal intensity in MPI. Both the signal voids as well as the areas of high signal intensity were larger than the real marker size. Images that were reconstructed with a Bayoxide E8706 system matrix did not show sufficient MPI signal. Instrument markers with bimodal visibility are essential for the perspective of monitoring cardiovascular interventions with MPI/MRI hybrid systems.

Off-target editing is one of the main safety concerns for the use of CRISPR-Cas9 genome editing in gene therapy. These unwanted modifications could lead to malignant transformation, which renders tumorigenicity assessment of gene therapy products indispensable. In this study, we established two in vitro transformation assays, the soft agar colony-forming assay (SACF) and the growth in low attachment assay (GILA) as alternative methods for tumorigenicity evaluation of genome-edited cells. Using a CRISPR-Cas9-based approach to transform immortalized MCF10A cells, we identified PTPN12 , a known tumor suppressor, as a valid positive control in GILA and SACF . Next, we measured the limit of detection for both assays and proved that SACF is more sensitive than GILA (0.8% versus 3.1% transformed cells). We further validated SACF and GILA by identifying a set of positive and negative controls and by testing the suitability of another cell line (THLE-2). Moreover, in contrast to SACF and GILA, an in vivo tumorigenicity study failed to detect the known tumorigenic potential of PTPN12 deletion, demonstrating the relevance of GILA and SACF in tumorigenicity testing. In conclusion, SACF and GILA are both attractive and valuable additions to preclinical safety assessment of gene therapy products., Competing Interests: M.L., B.F., M.Z., L.R., G.K., A.d.R.-E., F.S., D.M., V.D., A.P., A.M., U.P.-H., U.N., J.H., H.-J.M., and S.L. were employees of the Novartis Institutes for Biomedical Research at the time this research was conducted. A.O. declares no competing interests., (© 2021 The Authors.)

Quality physical education can play a critical role in helping students become more active, physically literate, and develop the skills and interests to remain physically active throughout their lives. The healthy, physically active student is more likely to be academically motivated, alert, and successful in school. Unfortunately, findings from multiple studies interviewing students with disabilities suggest that students with disabilities are often less active and feel more socially separated from the class compared to their classmates without disabilities in general physical education. Clearly, more research is needed to identify best practices or strategies for creating a positive learning environment in physical education for all students. This paper examines future research considerations based on what we currently know about the physical education experiences and concerns of students with disabilities as well as concerns voiced by general physical educators. Considerations include: (1) What evidence do we have and what evidence do we need to show students with 3 disabilities are receiving appropriate physical education whether included or in a separate setting? (2) What evidence do we have and what evidence do we need to show that physical educators are properly trained and qualified to provide physical education to students with disabilities? (3) What evidence do we have and what evidence do we need to show that particular curricular and teaching models are effective when including students with disabilities in general physical education and when working in small groups or one-on-one? (4) What evidence do we have and what evidence do we need to show that students with disabilities are socially part of the class and not simply physically present.

Purpose: To evaluate heating of a redilatable stent for the treatment of aortic coarctation in neonates and small children in the new imaging modality magnetic particle imaging and established magnetic resonance imaging., Materials and Methods: The cobalt-chromium stent (BabyStent, OSYPKA AG, Rheinfelden, Germany) has a stent design which allows for redilatation and adjustment of the diameter from 6 to 16 mm for a use in aortic coarctation. The stent loses its radial integrity while opening at predetermined breaking points at a diameter of 14 mm or 16 mm, respectively. We measured the temperature increase in the stent at different diameters during 7-min magnetic particle imaging and magnetic resonance imaging scans with fiber optic thermometers under static conditions surrounded by air. In magnetic particle imaging, stents with diameters from 6 to 16 mm were tested while in magnetic resonance imaging only stents with diameters of 6 mm and 14 mm were investigated exemplarily., Result: In magnetic particle imaging, the measured temperature differences increased up to 4.7 K with growing diameters, whereas the opened stents with discontinuous struts at 14 and 16 mm showed only minimal heating of max. 0.5 K. In contrast to magnetic particle imaging, our measurements showed no heating of the stents during magnetic resonance imaging under identical conditions., Conclusion: The BabyStent did show only slight heating in magnetic particle imaging and no detectable temperature increase in magnetic resonance imaging.

The purposes of this study were (a) to examine the proportions of adolescents in China who partially or fully meet three 24-h movement guidelines on physical activity, screen-time, and sleep duration and (b) to examine whether there were gender differences in the proportion of boys and girls meeting these guidelines. The sample was made up of high school adolescents from an eastern province of China ( N = 1338). The participants completed a self-reported survey on demographic variables and weekly health behaviors including physical activity, screen-time, and sleep duration. A frequency analysis was conducted to summarize the number of 24-h movement guidelines met of the total sample and by gender; chi-squared tests were used to examine the gender differences in the proportion of students meeting different guidelines, independently and jointly. A high proportion of adolescents did not meet physical activity (97.2%, 95% CI = 96.2-98.0%), or sleep (92.1%, 95% CI = 90.6-93.5%) guidelines, but met screen-time (93.6%, 95% CI = 92.4-94.7%) guidelines. Overall, only 0.3% (95%CI = 0.1-0.6%) of the sample met all three guidelines, 8.8% (95%CI = 7.5-10.2%) met two, 85.8%% (95%CI = 84.0-87.4%) met one, and 5.1% (95%CI = 4.0-6.4%) met none. There was no statistically significant percentage difference between female and male participants in meeting physical activity, screen-time viewing, or sleep duration guidelines, independently or jointly ( p values > 0.05). These figures of participants meeting all three guidelines or physical activity and sleep independently are much lower than many estimates in prior research internationally. Considerations to improve adherence to physical activity and sleep guidelines are critical in this population.

Purpose: To illustrate the potential of magnetic particle imaging (MPI) for stent lumen imaging in comparison with clinical computed tomography (CT) and magnetic resonance imaging (MRI)., Materials and Methods: Imaging of eight tracer-filled, stented vessel phantoms and a tracer-filled, non-stented reference phantom for each diameter was performed on a preclinical MPI scanner: eight commercially available coronary stents of different dimensions (diameter: 3-4 mm; length: 11-38 mm) and materials (stainless steel, platinum-chromium) were implanted into silicone vessel phantoms. For comparison, all vessel phantoms were also visualized by MRI and CT. Two radiologists assessed the images regarding stent-induced artifacts using a 5-point grading scale., Results: The visualization of all stented vessel phantoms was achieved without stent-induced artifacts with MPI. In contrast, MRI and CT images revealed multiform stent-induced artifacts., Conclusion: Given its clinical introduction, MPI has the potential to overcome the disadvantages of MRI and CT concerning the visualization of the stent lumen.

In non-small cell lung cancer (NSCLC), immune checkpoint inhibitors (ICIs) significantly improve overall survival (OS). Tumor mutational burden (TMB) has emerged as a predictive biomarker for patients treated with ICIs. Here, we evaluated the predictive power of TMB measured by the Oncomine™ Tumor Mutational Load targeted sequencing assay in 76 NSCLC patients treated with ICIs. TMB was assessed retrospectively in 76 NSCLC patients receiving ICI therapy. Clinical data (RECIST 1.1) were collected and patients were classified as having either durable clinical benefit (DCB) or no durable benefit (NDB). Additionally, genetic alterations and PD-L1 expression were assessed and compared with TMB and response rate. TMB was significantly higher in patients with DCB than in patients with NDB (median TMB = 8.5 versus 6.0 mutations/Mb, Mann-Whitney p = 0.0244). 64% of patients with high TMB (cut-off = third tertile, TMB ≥ 9) were responders (DCB) compared to 33% and 29% of patients with intermediate and low TMB, respectively (cut-off = second and first tertile, TMB = 5-9 and TMB ≤ 4, respectively). TMB-high patients showed significantly longer progression-free survival (PFS) and OS (log-rank test p = 0.0014 for PFS and 0.0197 for OS). While identifying different subgroups of patients, combining PD-L1 expression and TMB increased the predictive power (from AUC 0.63 to AUC 0.65). Our results show that the TML panel is an effective tool to stratify patients for ICI treatment. A combination of biomarkers might maximize the predictive precision for patient stratification. Our study supports TMB evaluation through targeted NGS in NSCLC patient samples as a tool to predict response to ICI therapy. We offer recommendations for a reliable and cost-effective assessment of TMB in a routine diagnostic setting. © 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland., (© 2019 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.)