Search

Abstract Dose management systems (DMS) are an essential tool for quality assurance and optimising patient radiation exposure. For radiologists and medical physicists, they are important for managing many radiation protection tasks. In addition, they help fulfil the requirements of Directive 2013/59/EURATOM regarding the electronic transmission of dosimetric data and the detection of unintended patient exposures. The EuroSafe Imaging Clinical Dosimetry and Dose Management Working Group launched a questionnaire on the use of DMS in European member states and analysed the results in terms of modalities, frequency of radiological procedures, involvement of medical physics experts (MPEs), legal requirements, and local issues (support by information technology (IT), modality interfaces, protocol mapping, clinical workflow, and associated costs). Critical relevance statement Despite the great advantages of dose management systems for optimising radiation protection, distribution remains insufficient. This questionnaire shows that reasons include: a lack of DICOM interfaces, insufficient harmonisation of procedure names, lack of medical physicist and IT support, and costs. Key Points Quantitative radiation dose information is essential for justification and optimisation in medical imaging. Guidelines are required to ensure radiation dose management systems quality and for acceptance testing. Verifying dose data management is crucial before dose management systems clinical implementation. Medical physics experts are professionals who have important responsibilities for the proper management of dose monitoring. Graphical Abstract

Abstract Background Immunoglobulin (Ig) glycosylation modulates the immune response and plays a critical role in ageing and diseases. Studies have mainly focused on IgG glycosylation, and little is known about the genetics and epidemiology of IgA glycosylation. Methods We generated, using a novel liquid chromatography-mass spectrometry method, the first large-scale IgA glycomics dataset in serum from 2423 twins, encompassing 71 N- and O-glycan species. Results We showed that, despite the lack of a direct genetic template, glycosylation is highly heritable, and that glycopeptide structures are sex-specific, and undergo substantial changes with ageing. We observe extensive correlations between the IgA and IgG glycomes, and, exploiting the twin design, show that they are predominantly influenced by shared genetic factors. A genome-wide association study identified eight loci associated with both the IgA and IgG glycomes (ST6GAL1, ELL2, B4GALT1, ABCF2, TMEM121, SLC38A10, SMARCB1, and MGAT3) and two novel loci specifically modulating IgA O-glycosylation (C1GALT1 and ST3GAL1). Validation of our findings in an independent cohort of 320 individuals from Qatar showed that the underlying genetic architecture is conserved across ancestries. Conclusions Our study delineates the genetic landscape of IgA glycosylation and provides novel potential functional links with the aetiology of complex immune diseases, including genetic factors involved in IgA nephropathy risk.

Abstract Background Microglia play important roles in maintaining brain homeostasis and neurodegeneration. The discovery of genetic variants in genes predominately or exclusively expressed in myeloid cells, such as Apolipoprotein E (APOE) and triggering receptor expressed on myeloid cells 2 (TREM2), as the strongest risk factors for Alzheimer’s disease (AD) highlights the importance of microglial biology in the brain. The sequence, structure and function of several microglial proteins are poorly conserved across species, which has hampered the development of strategies aiming to modulate the expression of specific microglial genes. One way to target APOE and TREM2 is to modulate their expression using antisense oligonucleotides (ASOs). Methods In this study, we identified, produced, and tested novel, selective and potent ASOs for human APOE and TREM2. We used a combination of in vitro iPSC-microglia models, as well as microglial xenotransplanted mice to provide proof of activity in human microglial in vivo. Results We proved their efficacy in human iPSC microglia in vitro, as well as their pharmacological activity in vivo in a xenografted microglia model. We demonstrate ASOs targeting human microglia can modify their transcriptional profile and their response to amyloid-β plaques in vivo in a model of AD. Conclusions This study is the first proof-of-concept that human microglial can be modulated using ASOs in a dose-dependent manner to manipulate microglia phenotypes and response to neurodegeneration in vivo.

Abstract The presence of autoantibodies is a defining feature of many autoimmune diseases. The number of unique autoantibody clones is conceivably limited by immune tolerance mechanisms, but unknown due to limitations of the currently applied technologies. Here, we introduce an autoantigen-specific liquid chromatography-mass spectrometry-based IgG1 Fab profiling approach using the anti-citrullinated protein antibody (ACPA) repertoire in rheumatoid arthritis (RA) as an example. We show that each patient harbors a unique and diverse ACPA IgG1 repertoire dominated by only a few antibody clones. In contrast to the total plasma IgG1 antibody repertoire, the ACPA IgG1 sub-repertoire is characterised by an expansion of antibodies that harbor one, two or even more Fab glycans, and different glycovariants of the same clone can be detected. Together, our data indicate that the autoantibody response in a prominent human autoimmune disease is complex, unique to each patient and dominated by a relatively low number of clones.

Abstract Background Interferon-γ-inducible protein of 10 kDa (IP-10/CXCL10) is a dual-function CXC chemokine that coordinates chemotaxis of activated T cells and natural killer (NK) cells via interaction with its G protein-coupled receptor (GPCR), CXC chemokine receptor 3 (CXCR3). As a consequence of natural posttranslational modifications, human CXCL10 exhibits a high degree of structural and functional heterogeneity. However, the biological effect of natural posttranslational processing of CXCL10 at the carboxy (C)-terminus has remained partially elusive. We studied CXCL10(1–73), lacking the four endmost C-terminal amino acids, which was previously identified in supernatant of cultured human fibroblasts and keratinocytes. Methods Relative levels of CXCL10(1–73) and intact CXCL10(1–77) were determined in synovial fluids of patients with rheumatoid arthritis (RA) through tandem mass spectrometry. The production of CXCL10(1–73) was optimized through Fmoc-based solid phase peptide synthesis (SPPS) and a strategy to efficiently generate human CXCL10 proteoforms was introduced. CXCL10(1–73) was compared to intact CXCL10(1–77) using surface plasmon resonance for glycosaminoglycan (GAG) binding affinity, assays for cell migration, second messenger signaling downstream of CXCR3, and flow cytometry of CHO cells and primary human T lymphocytes and endothelial cells. Leukocyte recruitment in vivo upon intraperitoneal injection of CXCL10(1–73) was also evaluated. Results Natural CXCL10(1–73) was more abundantly present compared to intact CXCL10(1–77) in synovial fluids of patients with RA. CXCL10(1–73) had diminished affinity for GAG including heparin, heparan sulfate and chondroitin sulfate A. Moreover, CXCL10(1–73) exhibited an attenuated capacity to induce CXCR3A-mediated signaling, as evidenced in calcium mobilization assays and through quantification of phosphorylated extracellular signal-regulated kinase-1/2 (ERK1/2) and protein kinase B/Akt. Furthermore, CXCL10(1–73) incited significantly less primary human T lymphocyte chemotaxis in vitro and peritoneal ingress of CXCR3+ T lymphocytes in mice. In contrast, loss of the four endmost C-terminal residues did not affect the inhibitory properties of CXCL10 on migration, proliferation, wound closure, phosphorylation of ERK1/2, and sprouting of human microvascular endothelial cells. Conclusion Our study shows that the C-terminal residues Lys74-Pro77 of CXCL10 are important for GAG binding, signaling through CXCR3A, T lymphocyte chemotaxis, but dispensable for angiostasis. Graphical Abstract

PurposeHolmium-166 has emerged as a promising option for selective internal radiotherapy (SIRT) for hepatic malignancies, but data on routine clinical use are lacking. The purpose of this study was to describe the safety and effectiveness of Holmium-166 SIRT in real-world practice through retrospective analysis of a multicenter registry.MethodsRetrospective analysis was conducted on Holmium-166 SIRT procedures performed between July 15, 2019, and July 15, 2021, across seven European centers. Treatment planning, treatment realization and post-treatment follow-up were conducted according to routine local practice. Safety and effectiveness data were extracted from the patients’ health records. Primary endpoint analysis was assessed for the entire study population with separate analysis for subgroups with hepatocellular carcinoma, metastatic colorectal cancer and intrahepatic cholangiocarcinoma.ResultsA total of 167 SIRT procedures in 146 patients (mean age 66 ± 11 years, 68% male) were retrospectively evaluated. Most common tumor entities were hepatocellular carcinoma (n=55), metastatic colorectal cancer (n=35), intrahepatic cholangiocarcinoma (n=19) and metastatic neuroendocrine tumors (n=10). Nine adverse events grade ≥ 3 according to Common Terminology Criteria for Adverse Events were recorded, including one fatal case of radioembolization-induced liver disease. Response rates and median overall survival for the above mentioned subgroups were comparable to results from previous Holmium-166 trials as well as to results from Yttrium-90 registries.ConclusionThis study confirms that the safety and effectiveness of Holmium-166 SIRT derived from prospective trials also applies in routine clinical practice, reinforcing its potential as a viable treatment option for primary and secondary liver cancer.

Abstract Objectives Contact shielding (CS) of patients during X-ray studies has been used for decades to protect radiosensitive organs. This practice has not changed much despite increasing evidence that CS is not useful in many cases. The Gonad And Patient Shielding (GAPS) group—founded by representatives of the main European bodies involved in radiology—promoted this survey to assess the current practice of CS among European radiology departments and the attitude towards a non-shielding policy. Methods Over a four-month period (15 May–15th September 2021) European Society of Radiology and European Society of Paediatric Radiology radiologist members were invited to respond to a web-based questionnaire consisting of 59 questions. Results 225 centres from 35 countries responded to this survey. CS was routinely applied in at least one radiological modality in 49.2% of centres performing studies in adults, 57.5% of centres performing studies in children, and 47.8% of centres performing studies on pregnant women. CS was most frequently used in conventional radiography, where the most frequently shielded organs were the gonads, followed by thyroid, female breasts, and eye lens. 83.6% respondents would follow European recommendations on the use of CS when provided by the main European bodies involved in radiology. Conclusions This review shows that CS is still largely used across Europe. However, a non-shielding policy could be adopted in most departments if European professional societies provided recommendations. In this regard, a strong commitment by European and national professional societies to educate and inform practitioners, patients and carers is paramount. Clinical relevance statement According to this survey expectations of patients and carers, and skepticism among professionals about the limited benefits of CS are the most important obstacles to the application of a no-shielding policy. A strong commitment from European and national professional societies to inform practitioners, patients and carers is fundamental. Graphical Abstract

IntroductionUpon vaccination against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) humans will start to produce antibodies targeting virus specific antigens that will end up in circulation. In lactating women such antibodies will also end up in breastmilk, primarily in the form of secretory immunoglobulin A1 (SIgA1), the most abundant immunoglobulin (Ig) in human milk. Here we set out to investigate the SIgA1 clonal repertoire response to repeated SARS-CoV-2 vaccination, using a LC–MS fragment antigen-binding (Fab) clonal profiling approach.MethodsWe analyzed the breastmilk of six donors from a larger cohort of 109 lactating mothers who received one of three commonly used SARS-CoV-2 vaccines. We quantitatively monitored the SIgA1 Fab clonal profile over 16 timepoints, from just prior to the first vaccination until 15 days after the second vaccination.ResultsIn all donors, we detected a population of 89–191 vaccine induced clones. These populations were unique to each donor and heterogeneous with respect to individual clonal concentrations, total clonal titer, and population size. The vaccine induced clones were dominated by persistent clones (68%) which came up after the first vaccination and were retained or reoccurred after the second vaccination. However, we also observe transient SIgA1 clones (16%) which dissipated before the second vaccination, and vaccine induced clones which uniquely emerged only after the second vaccination (16%). These distinct populations were observed in all analyzed donors, regardless of the administered vaccine.DiscussionOur findings suggest that while individual donors have highly unique human milk SIgA1 clonal profiles and a highly personalized SIgA1 response to SARS-CoV-2 vaccination, there are also commonalities in vaccine induced responses.

Abstract Background Primary ciliary dyskinesia (PCD) is a genetic disorder characterized by recurrent airway infection and inflammation. There is no cure for PCD and to date there are no specific treatments available. Neutrophils are a crucial part of the immune system and are known to be dysfunctional in many inflammatory diseases. So far, the role of the neutrophils in PCD airways is largely unknown. The purpose of this study was to investigate the phenotype and function of airway neutrophils in PCD, and compare them to blood neutrophils. Methods Paired peripheral blood and spontaneously expectorated sputum samples from patients with PCD (n = 32) and a control group of patients with non-PCD, non-cystic fibrosis bronchiectasis (n = 5) were collected. The expression of neutrophil-specific surface receptors was determined by flow cytometry. Neutrophil function was assessed by measuring the extent of actin polymerization, production of reactive oxygen species (ROS) and release of neutrophil extracellular traps (NETs) in response to activating stimuli. Results Sputum neutrophils displayed a highly activated phenotype and were unresponsive to stimuli that would normally induce ROS production, actin polymerization and the expulsion of NETs. In addition, PCD sputum displayed high activity of neutrophil elastase, and impaired the efferocytosis by healthy donor macrophages. Conclusions Sputum neutrophils in PCD are dysfunctional and likely contribute to ongoing inflammation in PCD airways. Further research should focus on anti-inflammatory therapies and stimulation of efferocytosis as a strategy to treat PCD.

Profiling antibody repertoires using proteomic approaches may provide a way of screening for antibody cross-reactivity against SARS-CoV-2 variants. Here the authors use a IgG1 specific cleavage method to analyse the IgG1 repertoire within recovered patients and relate this to antibody binding and neutralisation.

Within the wheat starchy endosperm, the protein content increases biexponentially from the inner to outer endosperm. Here, we studied how this protein gradient is reflected in mill fractions using three cultivars (Claire, Apache, and Akteur) grown without and with N-fertilization (300 kg N ha−1). The increasing protein content in successive break fractions was shown to reflect the protein gradient within the starchy endosperm. The increasing protein content in successive reduction fractions was primarily due to more aleurone contamination and protein-rich material being harder to reduce in particle size. The miller’s bran fractions had the highest protein content because of their high sub-aleurone and aleurone content. Additionally, the break fractions were used to deepen our understanding of the protein composition gradient. The gradient in relative gluten content, increasing from inner to outer endosperm, was more pronounced without N-fertilization than with and reached levels up to 87.3%. Regarding the gluten composition gradient, no consistent trends were observed over cultivars when N-fertilization was applied. This could, at least partly, explain why there is no consensus on the gluten composition gradient in the literature. This study aids millers in managing fluctuations in the functionality of specific flour streams, producing specialized flours, and coping with lower-quality wheat.