Investigation of performance and the influence of environmental conditions on strip detectors for the ATLAS Inner Tracker Upgrade

With the upgrade of the Large Hadron Collider (LHC) to the High-Luminosity LHC (HL-LHC) scheduled for installation in 2024, the Inner Detector will be replaced with the new all-silicon ATLAS Inner Tracker (ITk) to maintain tracking performance in this high-occupancy environment and to cope with the increase of approximately a factor of ten in the integrated radiation dose. The outer four layers in the barrel and six disks in the end-cap region will host strip modules, built with single-sided strip sensors and glued-on hybrids carrying the front-end electronics necessary for readout. The strip sensors are manufactured as n-in-p strip sensors from high-resistivity silicon, which allow operation even after the fluences expected towards the end of the proposed lifetime of the HL-LHC. Prototypes of different sensor designs have been extensively tested electrically as well as in testbeam setups, yielding generally satisfactory results, but also revealing ongoing challenges. During electrical sensor evaluation many prototype sensors are found to not comply with specifications for stable long-term operation. This outcome was attributed to the influence of humidity, which has been subsequently investigated in great detail and will have lasting consequences for sensor production and module assembly. Repeated measurements on continuously biased sensors revealed a decrease in tracking performance and increased charge-sharing due to the accumulation of charges in the Si-SiO$_2$ interface. The dynamics of this effect and how it will affect operation of the finished ITk have been examined with a novel approach using the time-development of inter-strip quantities and trap energy level characterisation in SiO$_2$ with Deep-level Transient Spectroscopy (DLTS)

MA-VAE: Multi-head Attention-based Variational Autoencoder Approach for Anomaly Detection in Multivariate Time-series Applied to Automotive Endurance Powertrain Testing

A clear need for automatic anomaly detection applied to automotive testing has emerged as more and more attention is paid to the data recorded and manual evaluation by humans reaches its capacity. Such real-world data is massive, diverse, multivariate and temporal in nature, therefore requiring modelling of the testee behaviour. We propose a variational autoencoder with multi-head attention (MA-VAE), which, when trained on unlabelled data, not only provides very few false positives but also manages to detect the majority of the anomalies presented. In addition to that, the approach offers a novel way to avoid the bypass phenomenon, an undesirable behaviour investigated in literature. Lastly, the approach also introduces a new method to remap individual windows to a continuous time series. The results are presented in the context of a real-world industrial data set and several experiments are undertaken to further investigate certain aspects of the proposed model. When configured properly, it is 9% of the time wrong when an anomaly is flagged and discovers 67% of the anomalies present. Also, MA-VAE has the potential to perform well with only a fraction of the training and validation subset, however, to extract it, a more sophisticated threshold estimation method is required.Comment: Accepted in NCTA202

Lineage-Specific Chimerism and Outcome After Hematopoietic Stem Cell Transplantation for DOCK8 Deficiency

Bi-allelic variants in the dedicator of cytokinesis 8 (DOCK8) gene cause a combined immunodeficiency, characterized by recurrent sinopulmonary and skin infections, food allergies, eczema, eosinophilia, and elevated IgE. Long-term outcome is poor given susceptibility to infections, malignancy, and vascular complications. Allogeneic hematopoietic stem cell transplantation is currently the only curative treatment option and has shown promising outcome. The impact of mixed chimerism on long-term outcome is unclear. We reasoned that reversal of disease phenotype would depend on cell lineage-specific chimerism. DOCK8 variants were confirmed by Sanger and/or exome sequencing and immunoblot and/or intracellular flow cytometry. Donor chimerism was analyzed by XY-fluorescence in situ hybridization or quantitative short tandem repeat PCR. Outcome was assessed by laboratory tests, lymphocyte subsets, intracellular DOCK8 protein flow cytometry, T-cell proliferation analysis, and multiparameter immunoblot allergy screening. We report on nine patients, four of whom with mixed chimerism, with a median follow-up of 78~months after transplantation. Overall, we report successful transplantation with improvement of susceptibility to infections and allergies, and resolution of eczema in all patients. Immunological outcome in patients with mixed chimerism suggests a selective advantage for wild-type donor T-cells but lower donor B-cell chimerism possibly results in a tendency to hypogammaglobulinemia. No increased infectious and allergic complications were associated with mixed chimerism. Aware of the relatively small cohort size, we could not demonstrate a consistent detrimental effect of mixed chimerism on clinical outcomes. We nevertheless advocate aiming for complete donor chimerism in treating DOCK8 deficiency, but recommend reduced toxicity conditioning

Percentile indices for assessing changes in heavy precipitation events

Many climate studies assess trends and projections in heavy precipitation events using precipitation percentile (or quantile) indices. Here we investigate three different percentile indices that are commonly used. We demonstrate that these may produce very different results and thus require great care with interpretation. More specifically, consideration is given to two intensity-based indices and one frequency-based index, namely (a) all-day percentiles, (b) wet-day percentiles, and (c) frequency indices based on the exceedance of a percentile threshold. Wet-day percentiles are conditionally computed for the subset of wet events (with precipitation exceeding some threshold, e.g. 1 mm/d for daily precipitation). We present evidence that this commonly used methodology can lead to artifacts and misleading results if significant changes in the wet-day frequency are not accounted for. Percentile threshold indices measure the frequency of exceedance with respect to a percentile-based threshold. We show that these indices yield an assessment of changes in heavy precipitation events that is qualitatively consistent with all-day percentiles, but there are substantial differences in quantitative terms. We discuss the reasons for these effects, present a theoretical assessment, and provide a series of examples using global and regional climate models to quantify the effects in typical applications. Application to climate model output shows that these considerations are relevant to a wide range of typical climate-change applications. In particular, wet-day percentiles generally yield different results, and in most instances should not be used for the impact-oriented assessment of changes in heavy precipitation events

Empagliflozin reduces kidney fibrosis and improves kidney function by alternative macrophage activation in rats with 5/6-nephrectomy

Background Sodium glucose cotransporter 2 (SGLT2) inhibitors originally developed for the treatment of type 2 diabetes are clinically very effective drugs halting chronic kidney disease progression. The underlying mechanisms are, however, not fully understood. Methods We generated single-cell transcriptomes of kidneys from rats with 5/6 nephrectomy before and after SGLT2 inhibitors treatment by single-cell RNA sequencing. Findings Empagliflozin treatment decreased BUN, creatinine and urinary albumin excretion compared to placebo by 39.8%, 34.1%, and 55%, respectively (p < 0.01 in all cases). Renal interstitial fibrosis and glomerulosclerosis was likewise decreased by 51% and 66.8%; respectively (p < 0.05 in all cases). 14 distinct kidney cell clusters could be identified by scRNA-seq. The polarization of M2 macrophages from state 1 (CD206-CD68- M2 macrophages) to state 5 (CD206+CD68+ M2 macrophages) was the main pro-fibrotic process, as CD206+CD68+ M2 macrophages highly expressed fibrosis-promoting genes and can convert into fibrocytes. Empagliflozin remarkably inhibited the expression of fibrosis-promoting (IFG1 and TREM2) and polarization-associated genes (GPNMB, LGALS3, PRDX5, and CTSB) in CD206+CD68+ M2 macrophages and attenuated inflammatory signals from CD8+ effector T cells. The inhibitory effect of empagliflozin on CD206+CD68+ M2 macrophages polarization was mainly achieved by affecting mitophagy and mTOR pathways. Interpretation We propose that the beneficial effects of empagliflozin on kidney function and morphology in 5/6 nephrectomyiced rats with established CKD are at least partially due to an inhibition of CD206+CD68+ M2 macrophage polarization by targeting mTOR and mitophagy pathways and attenuating inflammatory signals from CD8+ effector T cells. Fundings A full list of funding bodies that contributed to this study can be found in the Acknowledgements section

NM-300 Silver Characterisation, Stability, Homogeneity

This report describes the characteriation of NM-300, a nano-silver reference material used in the context of risk and exposure assessment studies. The material was produced in the context of the JRC IHCP activity on nano-materials. A representative set test items was handed over to the JRC IES analytical laboratory for further characterisation. First, inorganic chemical characterisation of the total silver content and the homogeneity of the Ag-distribution was done using ICP-AES. To this end, a dedicated method was developed and validated according to the requirements laid down in ISO 17025. This works were completed by different types of microscopy analyses (Scanning Electron Microscope, Transmission Electron Microscope and Nanoparticle Tracking Analysis) performed in close collaboration with the German Institute of Energy and Environmental Technology e.V. (IUTA), the Swiss Federal Laboratories for Materials Science and Technology (EMPA) and Belgium Veterinary and Agrochemical Research Centre (VAR). This report summarises all technical details and discusses the assessments made.JRC.DG.I.5-Nanobioscience