Viral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been... Show moreViral infections have been associated with the progression of atherosclerosis and CD8+ T-cells directed against common viruses, such as influenza, Epstein-Barr virus, and cytomegalovirus, have been detected inside human atherosclerotic lesions. These virus-specific CD8+ T-cells have been hypothesized to contribute to the development of atherosclerosis; however, whether they affect disease progression directly remains unclear. In this study, we aimed to characterize the activation status of virus-specific CD8+ T-cells in the atherosclerotic lesion.\nThe presence, clonality, tissue enrichment, and phenotype of virus-associated CD8+ T-cells in atherosclerotic lesions were assessed by exploiting bulk T-cell receptor-β sequencing and single-cell T-cell receptor (α and β) sequencing datasets on human endarterectomy samples and patient-matched blood samples. To investigate if virus-specific CD8+ T-cells can be activated through T-cell receptor stimulation in the atherosclerotic lesion, the immunopeptidome of human plaques was determined.\nVirus-associated CD8+ T-cells accumulated more in the atherosclerotic lesion (mean=2.0%), compared with patient-matched blood samples (mean=1.4%; P=0.05), and were more clonally expanded and tissue enriched in the atherosclerotic lesion in comparison with nonassociated CD8+ T-cells from the lesion. Single-cell T-cell receptor sequencing and flow cytometry revealed that these virus-associated CD8+ T-cells were phenotypically highly similar to other CD8+ T-cells in the lesion and that both exhibited a more activated phenotype compared with circulating T-cells. Interestingly, virus-associated CD8+ T-cells are unlikely to be activated through antigen-specific interactions in the atherosclerotic lesion, as no virus-derived peptides were detected on HLA-I in the lesion.\nThis study suggests that virus-specific CD8+ T-cells are tissue enriched in atherosclerotic lesions; however, their potential contribution to inflammation may involve antigen-independent mechanisms. Show less
Advanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety... Show moreAdvanced in vitro models that recapitulate the structural organization and function of the human heart are highly needed for accurate disease modeling, more predictable drug screening, and safety pharmacology. Conventional 3D Engineered Heart Tissues (EHTs) lack heterotypic cell complexity and culture under flow, whereas microfluidic Heart-on-Chip (HoC) models in general lack the 3D configuration and accurate contractile readouts. In this study, an innovative and user-friendly HoC model is developed to overcome these limitations, by culturing human pluripotent stem cell (hPSC)-derived cardiomyocytes (CMs), endothelial (ECs)- and smooth muscle cells (SMCs), together with human cardiac fibroblasts (FBs), underflow, leading to self-organized miniaturized micro-EHTs (µEHTs) with a CM-EC interface reminiscent of the physiological capillary lining. µEHTs cultured under flow display enhanced contractile performance and conduction velocity. In addition, the presence of the EC layer altered drug responses in µEHT contraction. This observation suggests a potential barrier-like function of ECs, which may affect the availability of drugs to the CMs. These cardiac models with increased physiological complexity, will pave the way to screen for therapeutic targets and predict drug efficacy. Show less
Rijs, Z.; Kawsar, K.A.; Saha, P.; Sande, M. van de; Lui, D.R. 2024
This study evaluated artefacts on computed tomography (CT) images using Hounsfeld units (HU) in patients with spinal oligometastatic disease who received carbon-fber (CF; n= 11) or titanium (n= 11)... Show moreThis study evaluated artefacts on computed tomography (CT) images using Hounsfeld units (HU) in patients with spinal oligometastatic disease who received carbon-fber (CF; n= 11) or titanium (n= 11) spine implants and underwent stereotactic ablative radiotherapy (SABR). Pre- and postoperative HU were measured at the vertebral body, pedicle, and spinal cord at three diferent levels: the lower instrumented vertebra, the level of metastatic spinal cord compression, and an uninvolved level. Areas measured at each level were delicately matched pre- and postoperatively. Signifcant diferences in HU were observed at the vertebral body, the pedicle, and the spinal cord at the lowest instrumented vertebra level for both CF and titanium (average increase 1.54-fold and 5.11-fold respectively). At the metastatic spinal cord compression level, a trend towards a higher HU-increase was observed in titanium compared with CF treated patients (average increase 2.51-fold and 1.43-fold respectively). The relatively high postoperative HU-increase after insertion of titanium implants indicated CT artefacts, while the relatively low HU-increase of CF implants was not associated with artefacts. Less CT artefacts could facilitate an easier contouring phase in radiotherapy planning. In addition, we propose a CT artefact grading system based on postoperative HU-increase. This system could serve as a valuable tool in future research to assess if less CT artefacts lead to time savings during radiotherapy treatment planning and, potentially, to better tumoricidal efects and less adverse efects if particle therapy would be administered. Show less
Importance Multiple patient-reported outcome measures (PROMs) for health-related quality of life (HRQL) exist for patients with psoriasis. Evidence for the content validity and other measurement... Show moreImportance Multiple patient-reported outcome measures (PROMs) for health-related quality of life (HRQL) exist for patients with psoriasis. Evidence for the content validity and other measurement properties of these PROMs is critical to determine which HRQL PROMs could be recommended for use.Objective To systematically review the validity of HRQL-focused PROMs used in patients with psoriasis.Evidence Review Using PubMed and Embase, full-text articles published in English or Spanish on development or validation studies for psoriasis-specific, dermatology-specific, or generic HRQL PROMs were included. Development studies included original development studies, even if not studied in psoriasis patients per Consensus-Based Standards for the Selection of Health Measurement Instruments (COSMIN) recommendations. If a study included multiple diagnoses, more than 50% of patients had to have psoriasis or psoriasis-specific subgroup analyses available. Data extraction and analysis followed the COSMIN guidelines. Two independent reviewers extracted and analyzed the data, including PROM characteristics, quality of measurement properties (structural validity, internal consistency, cross-cultural validity, reliability, measurement error, criterion validity, construct validity, and responsiveness), and level of evidence. PROMs were classified into 3 levels of recommendations: (1) PROM recommended for use; (2) PROM requires further validation; and (3) PROM not recommended for use.Findings Overall, 97 articles were identified for extraction. This included 19 psoriasis-specific, 8 skin-specific, and 6 generic PROMs. According to COSMIN standards, most measures identified received a B recommendation for use, indicating their potential but requiring further validation. Only the Rasch reduced version of the Impact of Psoriasis Questionnaire (IPSO-11 Rasch) received an A recommendation for use given that it had sufficient content validity, structural validity, and internal consistency.Conclusions and Relevance This study identified a significant lack of information concerning the quality of HRQL measures in psoriasis. This gap in knowledge can be attributed to the fact that traditional measures were developed using validation criteria that differ from the current standards in use. Consequently, additional validation studies in accordance with contemporary standards will be useful in aiding researchers and clinicians in determining the most suitable measure for assessing HRQL in patients with psoriasis. Show less
Yordanova, N.; Khokhlova, A.; Ershova, A.; Schmidt, F. D.; Glavaš, G. 2024
BACKGROUND\nOBJECTIVES\nMETHODS\nRESULTS\nDISCUSSION\nUnderstanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as... Show moreBACKGROUND\nOBJECTIVES\nMETHODS\nRESULTS\nDISCUSSION\nUnderstanding the variability across the human population with respect to toxicodynamic responses after exposure to chemicals, such as environmental toxicants or drugs, is essential to define safety factors for risk assessment to protect the entire population. Activation of cellular stress response pathways are early adverse outcome pathway (AOP) key events of chemical-induced toxicity and would elucidate the estimation of population variability of toxicodynamic responses.\nWe aimed to map the variability in cellular stress response activation in a large panel of primary human hepatocyte (PHH) donors to aid in the quantification of toxicodynamic interindividual variability to derive safety uncertainty factors.\n signaling. Using a population mixed-effect framework, the distribution of benchmark concentrations (BMCs) and maximum fold change were modeled to evaluate the influence of PHH donor panel size on the correct estimation of interindividual variability for the various stimuli.\n signaling-related genes, respectively. Population modeling revealed that small PHH panel sizes systematically underestimated the variance and gave low probabilities in estimating the correct human population variance. Estimated toxicodynamic variability factors of stress response activation in PHHs based on this dataset ranged between 1.6 and 6.3.\nOverall, by combining high-throughput transcriptomics and population modeling, improved understanding of interindividual variability in chemical-induced activation of toxicity relevant stress pathways across the human population using a large panel of plated cryopreserved PHHs was established, thereby contributing toward increasing the confidence of in vitro-based prediction of adverse responses, in particular hepatotoxicity. https://doi.org/10.1289/EHP11891. Show less
Purpose: This clinical fluoroscopy study investigated knee kinematics of two different cemented fixed‐bearing, posterior‐stabilised (PS) total knee arthroplasty (TKA) designs: an asymmetric tibial... Show morePurpose: This clinical fluoroscopy study investigated knee kinematics of two different cemented fixed‐bearing, posterior‐stabilised (PS) total knee arthroplasty (TKA) designs: an asymmetric tibial component including an asymmetric insert designed to optimise personalised balance and fit and its precursor symmetrical design with symmetric insert. Methods: A consecutive series of patients (16 TKAs from each treatment group) participating in a randomised controlled trial comparing TKA migration was included. The exclusion criterion was the use of walking aids. Flat‐panel fluoroscopic recordings of step‐up and lunge motions were acquired 1‐year postoperatively. Medial and lateral contact points (CPs) were determined to calculate CP displacement, femoral axial rotation and pivot position. Using linear mixed‐effects modelling techniques, kinematics between TKA designs were compared. Results: During knee extension between 20° flexion and full extension, the CPs moved anteriorly combined with a small internal femoral rotation (a screw‐home mechanism). Whereas CP movement was reversed: femoral rollback, external femoral rotation while flexing the knee between full extension and 20° knee flexion, At larger flexion angles, femoral axial rotation (FAR) occurred around a lateral pivot point both during step‐up and lunge. The symmetric design had a 2.3° larger range of FAR compared to the asymmetric design during lunge (p = 0.02). All other kinematics were comparable. Conclusion: Despite the differences in design, this study showed that the asymmetric and symmetric PS TKA designs had mostly comparable knee kinematics during step‐up and lunge motions. It is therefore expected that the functionality of the successor TKA design is similar to that of its precursor design. Show less
Smeekens, M.V.; De Vries Robbé, M.; Popma, A.; Kempes M.M 2024
Introduction: Physical and verbal violence toward staff or other detained individuals is a reoccurring problem within correctional facilities. Screening for violence risk within the prison setting... Show moreIntroduction: Physical and verbal violence toward staff or other detained individuals is a reoccurring problem within correctional facilities. Screening for violence risk within the prison setting could provide a valuable first step in the prevention of institutional violence. The brief and compact Risk Screener Violence (RS-V) has shown to be an efficient new method for assessing concerns regarding post-release violent offending for incarcerated persons. This study aimed to find out whether the RS-V is also able to predict future violent and aggressive incidents during imprisonment.Methods: The predictive validity of the RS-V for future violent and aggressive incidents during a follow-up time of 4 months within prison was analyzed, using a file-based design. Violent incidents toward staff and other inmates (physical violence and violent threats), other aggressive incidents (aggression toward objects and verbal disruptive behavior), and both categories combined, were included as outcome measures based on disciplinary reports.Results: The RS-V showed medium to large predictive values for both violent and aggressive behavior during prison stay. In particular, good predictive values of the RS-V were found for violence toward prison staff.Discussion: This study shows that, besides post-release violent recidivism, the RS-V is able to accurately predict future violent and aggressive incidents during prison stay. By correctly differentiating between low concern and high concern individuals, the RS-V aims to contribute to more personalized interventions and risk management and, subsequently, to improved prison safety. Future studies using prospective prison practice data are needed to further support the validity of the RS-V regarding institutional violence. Show less
Laméris, T.J.; Kubota, M.; Kupisch, T.; Cabrelli, J.; Snape, N.; Rothman, J. 2024
Excitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of... Show moreExcitatory amino acid transporters (EAATs) are important regulators of amino acid transport and in particular glutamate. Recently, more interest has arisen in these transporters in the context of neurodegenerative diseases. This calls for ways to modulate these targets to drive glutamate transport, EAAT2 and EAAT3 in particular. Several inhibitors (competitive and noncompetitive) exist to block glutamate transport; however, activators remain scarce. Recently, GT949 was proposed as a selective activator of EAAT2, as tested in a radioligand uptake assay. In the presented research, we aimed to validate the use of GT949 to activate EAAT2-driven glutamate transport by applying an innovative, impedance-based, whole-cell assay (xCELLigence). A broad range of GT949 concentrations in a variety of cellular environments were tested in this assay. As expected, no activation of EAAT3 could be detected. Yet, surprisingly, no biological activation of GT949 on EAAT2 could be observed in this assay either. To validate whether the impedance-based assay was not suited to pick up increased glutamate uptake or if the compound might not induce activation in this setup, we performed radioligand uptake assays. Two setups were utilized; a novel method compared to previously published research, and in a reproducible fashion copying the methods used in the existing literature. Nonetheless, activation of neither EAAT2 nor EAAT3 could be observed in these assays. Furthermore, no evidence of GT949 binding or stabilization of purified EAAT2 could be observed in a thermal shift assay. To conclude, based on experimental evidence in the present study GT949 requires specific assay conditions, which are difficult to reproduce, and the compound cannot simply be classified as an activator of EAAT2 based on the presented evidence. Hence, further research is required to develop the tools needed to identify new EAAT modulators and use their potential as a therapeutic target. Show less
