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Liquid argon time projection chambers (LArTPCs) are now a standard detector technology for making accelerator neutrino measurements, due to their high material density, precise tracking, and calorimetric capabilities. An electric field (E-field) is required in such detectors to drift ionization electrons to the anode where they are collected. The E-field of a TPC is often approximated to be uniform between the anode and the cathode planes. However, significant distortions can appear from effects such as mechanical deformations, electrode failures, or the accumulation of space charge generated by cosmic rays. The latter effect is particularly relevant for detectors placed near the Earth's surface and with large drift distances and long drift time. To determine the E-field in situ, an ultraviolet (UV) laser system is installed in the MicroBooNE experiment at Fermi National Accelerator Laboratory. The purpose of this system is to provide precise measurements of the E-field, and to make it possible to correct for 3D spatial distortions due to E-field non-uniformities. Here we describe the methodology developed for deriving spatial distortions, the drift velocity and the E-field from UV-laser measurements.

We describe a method used to calibrate the position- and time-dependent response of the MicroBooNE liquid argon time projection chamber anode wires to ionization particle energy loss. The method makes use of crossing cosmic-ray muons to partially correct anode wire signals for multiple effects as a function of time and position, including cross-connected TPC wires, space charge effects, electron attachment to impurities, diffusion, and recombination. The overall energy scale is then determined using fully-contained beam-induced muons originating and stopping in the active region of the detector. Using this method, we obtain an absolute energy scale uncertainty of 2% in data. We use stopping protons to further refine the relation between the measured charge and the energy loss for highly-ionizing particles. This data-driven detector calibration improves both the measurement of total deposited energy and particle identification based on energy loss per unit length as a function of residual range. As an example, the proton selection efficiency is increased by 2% after detector calibration.

We present results on the reconstruction of electromagnetic (EM) activity from photons produced in charged current νμ interactions with final state π0s. We employ a fully-automated reconstruction chain capable of identifying EM showers of (100) MeV energy, relying on a combination of traditional reconstruction techniques together with novel machine-learning approaches. These studies demonstrate good energy resolution, and good agreement between data and simulation, relying on the reconstructed invariant π0 mass and other photon distributions for validation. The reconstruction techniques developed are applied to a selection of νμ + Ar → μ + π0 + X candidate events to demonstrate the potential for calorimetric separation of photons from electrons and reconstruction of π0 kinematics.

Cosmic ray (CR) interactions can be a challenging source of background for neutrino oscillation and cross-section measurements in surface detectors. We present methods for CR rejection in measurements of charged-current quasielastic-like (CCQE-like) neutrino interactions, with a muon and a proton in the final state, measured using liquid argon time projection chambers (LArTPCs). Using a sample of cosmic data collected with the MicroBooNE detector, mixed with simulated neutrino scattering events, a set of event selection criteria is developed that produces an event sample with minimal contribution from CR background. Depending on the selection criteria used a purity between 50 and 80% can be achieved with a signal selection efficiency between 50 and 25%, with higher purity coming at the expense of lower efficiency. While using a specific dataset and selection criteria values optimized for the MicroBooNE detector, the concepts presented here are generic and can be adapted for various studies of exclusive νμ CCQE interactions in LArTPCs.

The MicroBooNE detector utilizes a liquid argon time projection chamber (LArTPC) with an 85 t active mass to study neutrino interactions along the Booster Neutrino Beam (BNB) at Fermilab. With a deployment location near ground level, the detector records many cosmic muon tracks in each beam-related detector trigger that can be misidentified as signals of interest. To reduce these cosmogenic backgrounds, we have designed and constructed a TPC-external Cosmic Ray Tagger (CRT) . This sub-system was developed by the Laboratory for High Energy Physics (LHEP), Albert Einstein center for fundamental physics, University of Bern. The system utilizes plastic scintillation modules to provide precise time and position information for TPC-traversing particles. Successful matching of TPC tracks and CRT data will allow us to reduce cosmogenic background and better characterize the light collection system and LArTPC data using cosmic muons. In this paper we describe the design and installation of the MicroBooNE CRT system and provide an overview of a series of tests done to verify the proper operation of the system and its components during installation, commissioning, and physics data-taking.

We measure a large set of observables in inclusive charged current muon neutrino scattering on argon with the MicroBooNE liquid argon time projection chamber operating at Fermilab. We evaluate three neutrino interaction models based on the widely used GENIE event generator using these observables. The measurement uses a data set consisting of neutrino interactions with a final state muon candidate fully contained within the MicroBooNE detector. These data were collected in 2016 with the Fermilab Booster Neutrino Beam, which has an average neutrino energy of 800MeV, using an exposure corresponding to 5.0 × 10 19 protons-on-target. The analysis employs fully automatic event selection and charged particle track reconstruction and uses a data-driven technique to separate neutrino interactions from cosmic ray background events. We find that GENIE models consistently describe the shapes of a large number of kinematic distributions for fixed observed multiplicity.

The single-phase liquid argon time projection chamber (LArTPC) provides a large amount of detailed information in the form of fine-grained drifted ionization charge from particle traces. To fully utilize this information, the deposited charge must be accurately extracted from the raw digitized waveforms via a robust signal processing chain. Enabled by the ultra-low noise levels associated with cryogenic electronics in the MicroBooNE detector, the precise extraction of ionization charge from the induction wire planes in a single-phase LArTPC is qualitatively demonstrated on MicroBooNE data with event display images, and quantitatively demonstrated via waveform-level and track-level metrics. Improved performance of induction plane calorimetry is demonstrated through the agreement of extracted ionization charge measurements across different wire planes for various event topologies. In addition to the comprehensive waveform-level comparison of data and simulation, a calibration of the cryogenic electronics response is presented and solutions to various MicroBooNE-specific TPC issues are discussed. This work presents an important improvement in LArTPC signal processing, the foundation of reconstruction and therefore physics analyses in MicroBooNE.

We describe the concept and procedure of drifted-charge extraction developed in the MicroBooNE experiment, a single-phase liquid argon time projection chamber (LArTPC). This technique converts the raw digitized TPC waveform to the number of ionization electrons passing through a wire plane at a given time. A robust recovery of the number of ionization electrons from both induction and collection anode wire planes will augment the 3D reconstruction, and is particularly important for tomographic reconstruction algorithms. A number of building blocks of the overall procedure are described. The performance of the signal processing is quantitatively evaluated by comparing extracted charge with the true charge through a detailed TPC detector simulation taking into account position-dependent induced current inside a single wire region and across multiple wires. Some areas for further improvement of the performance of the charge extraction procedure are also discussed.

We discuss a technique for measuring a charged particle's momentum by means of multiple Coulomb scattering (MCS) in the MicroBooNE liquid argon time projection chamber (LArTPC). This method does not require the full particle ionization track to be contained inside of the detector volume as other track momentum reconstruction methods do (range-based momentum reconstruction and calorimetric momentum reconstruction). We motivate use of this technique, describe a tuning of the underlying phenomenological formula, quantify its performance on fully contained beam-neutrino-induced muon tracks both in simulation and in data, and quantify its performance on exiting muon tracks in simulation. Using simulation, we have shown that the standard Highland formula should be re-tuned specifically for scattering in liquid argon, which significantly improves the bias and resolution of the momentum measurement. With the tuned formula, we find agreement between data and simulation for contained tracks, with a small bias in the momentum reconstruction and with resolutions that vary as a function of track length, improving from about 10% for the shortest (one meter long) tracks to 5% for longer (several meter) tracks. For simulated exiting muons with at least one meter of track contained, we find a similarly small bias, and a resolution which is less than 15% for muons with momentum below 2 GeV/c. Above 2 GeV/c, results are given as a first estimate of the MCS momentum measurement capabilities of MicroBooNE for high momentum exiting tracks.

The MicroBooNE liquid argon time projection chamber (LArTPC) has been taking data at Fermilab since 2015 collecting, in addition to neutrino beam, cosmic-ray muons. Results are presented on the reconstruction of Michel electrons produced by the decay at rest of cosmic-ray muons. Michel electrons are abundantly produced in the TPC, and given their well known energy spectrum can be used to study MicroBooNE's detector response to low-energy electrons (electrons with energies up to ∼ 50 MeV). We describe the fully-automated algorithm developed to reconstruct Michel electrons, with which a sample of ∼ 14,000 Michel electron candidates is obtained. Most of this article is dedicated to studying the impact of radiative photons produced by Michel electrons on the accuracy and resolution of their energy measurement. In this energy range, ionization and bremsstrahlung photon production contribute similarly to electron energy loss in argon, leading to a complex electron topology in the TPC. By profiling the performance of the reconstruction algorithm on simulation we show that the ability to identify and include energy deposited by radiative photons leads to a significant improvement in the energy measurement of low-energy electrons. The fractional energy resolution we measure improves from over 30% to ∼ 20% when we attempt to include radiative photons in the reconstruction. These studies are relevant to a large number of analyses which aim to study neutrinos by measuring electrons produced by νe interactions over a broad energy range.

The low-noise operation of readout electronics in a liquid argon time projection chamber (LArTPC) is critical to properly extract the distribution of ionization charge deposited on the wire planes of the TPC, especially for the induction planes. This paper describes the characteristics and mitigation of the observed noise in the MicroBooNE detector. The MicroBooNE's single-phase LArTPC comprises two induction planes and one collection sense wire plane with a total of 8256 wires. Current induced on each TPC wire is amplified and shaped by custom low-power, low-noise ASICs immersed in the liquid argon. The digitization of the signal waveform occurs outside the cryostat. Using data from the first year of MicroBooNE operations, several excess noise sources in the TPC were identified and mitigated. The residual equivalent noise charge (ENC) after noise filtering varies with wire length and is found to be below 400 electrons for the longest wires (4.7 m). The response is consistent with the cold electronics design expectations and is found to be stable with time and uniform over the functioning channels. This noise level is significantly lower than previous experiments utilizing warm front-end electronics.

We present several studies of convolutional neural networks applied to data coming from the MicroBooNE detector, a liquid argon time projection chamber (LArTPC). The algorithms studied include the classification of single particle images, the localization of single particle and neutrino interactions in an image, and the detection of a simulated neutrino event overlaid with cosmic ray backgrounds taken from real detector data. These studies demonstrate the potential of convolutional neural networks for particle identification or event detection on simulated neutrino interactions. We also address technical issues that arise when applying this technique to data from a large LArTPC at or near ground level.

Background: Coronary calcification can lead to over-estimation of the degree of coronary stenosis. Purpose: To evaluate whether thinner reconstruction thickness improves the diagnostic performance of 64-slice CT coronary angiography (CTCA) in angina patients with a positive calcium score. Material and Methods: We selected 20 scans from a clinical study comparing CTCA to conventional coronary angiography (CCA) in stable and unstable angina patients based on a low number of motion artifacts and a positive calcium score. All images were acquired at 64 x 0.625 mm and each CTCA scan was reconstructed at slice thickness/increment 0.67 mm/0.33 mm, 0.9 mm/0.45 mm, and 1.4 mm/0.7 mm. Two reviewers blinded for CCA results independently evaluated the scans for the presence of significant coronary artery disease (CAD) in three randomly composed series, with > or =2 weeks in between series. The diagnostic performance of CTCA was compared for the different slice thicknesses using a pooled analysis of both reviewers. Significant CAD was defined as >50% diameter narrowing on quantitative CCA. Image noise (standard deviation of CT numbers) was measured in all scans. Inter-observer variability was assessed with kappa. Results: Significant CAD was present in 8% of 304 available segments. Median total Agatston calcium score was 181.8 (interquartile range 34.9-815.6). Sensitivity at 0.67 mm, 0.9 mm, and 1.4 mm slice thickness was 70% (95% confidence interval 57-83%), 74% (62-86%), and 70% (57-83%), respectively. Specificity was 85% (82-88%), 84% (81-87%), and 84% (81-87%), respectively. The positive predictive value was 30 (21-38%), 29 (21-37%), and 28 (20-36%), respectively. The negative predictive value was 97% (95-98%), 97% (96-99%), and 97% (96-99%), respectively. Kappa for inter-observer agreement was 0.56, 0.58, and 0.59. Noise decreased from 32.9 HU at 0.67 mm, to 23.2 HU at 1.4 mm (P<0.001). Conclusion: Diagnostic performance of CTCA in angina patients with a positive calcium score was not markedly affected by modest variations in reconstruction slice thickness. [ABSTRACT FROM AUTHOR]

Spinocerebellar ataxia type 3 (SCA3)/Machado-Joseph disease (MJD) is a heritable proteinopathy disorder, whose causative gene, ATXN3, undergoes alternative splicing. Ataxin-3 protein isoforms differ in their toxicity, suggesting that certain ATXN3 splice variants may be crucial in driving the selective toxicity in SCA3. Using RNA-seq datasets we identified and determined the abundance of annotated ATXN3 transcripts in blood (n = 60) and cerebellum (n = 12) of SCA3 subjects and controls. The reference transcript (ATXN3-251), translating into an ataxin-3 isoform harbouring three ubiquitin-interacting motifs (UIMs), showed the highest abundance in blood, while the most abundant transcript in the cerebellum (ATXN3-208) was of unclear function. Noteworthy, two of the four transcripts that encode full-length ataxin-3 isoforms but differ in the C-terminus were strongly related with tissue expression specificity: ATXN3-251 (3UIM) was expressed in blood 50-fold more than in the cerebellum, whereas ATXN3-214 (2UIM) was expressed in the cerebellum 20-fold more than in the blood. These findings shed light on ATXN3 alternative splicing, aiding in the comprehension of SCA3 pathogenesis and providing guidance in the design of future ATXN3 mRNA-lowering therapies., Competing Interests: Declaration of competing interest TK is receiving research support from the Bundesministerium für Bildung und Forschung (BMBF), the National Institutes of Health (NIH) and Servier. Within the last 24 months, he has received consulting fees from Biogen, UCB and Vico Therapeutics. BvdW is supported by grants from ZonMw, NOW, Hersenstichting, Gossweiler Foundation, and Radboud university medical center; he has served on the scientific advisory boards or steering committees of uniQure, VICO Therapeutics, and Servier. LS is receiving research support from the European Commission, the Bundesministerium für Bildung und Forschung (BMBF) and the Bundesministerium für Gesundheit (BMG) as well as the Deutsche Forschungsgemeinschaft (DFG), Servier and Vigil Neuroscience. Within the last 24 months, he has received consulting fees from Vico Therapeutics. The remaining authors declare that they have nothing to report., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

In patients with Alzheimer's disease pathophysiological changes of the brain that initiate the onset of Alzheimer's disease include accumulation of amyloid-β plaques and phosphorylation of tau-tangles. A rather recently considered risk factor for the onset of Alzheimer's disease is poor oral health. The aim of this systematic review of the literature was to assess the potential association(s) of oral health as a risk factor for the onset of Alzheimer's disease. After a systematic search of Pubmed, Embase and Web of Science. A total of 1962 studies were assessed, of which 17 studies demonstrated possible associations between oral health diseases and Alzheimer's disease. 4 theories could be distinguished that describe the possible links between oral health and the development or onset of Alzheimer's disease; 1) role of pathogens, 2) role of inflammatory mediators, 3) role of APOE alleles and 4) role of Aβ peptide. The main common denominator of all the theories is the neuroinflammation due to poor oral health. Yet, there is insufficient evidence to prove a link due to the diversity of the designs used and the quality of the study design of the included studies. Therefore, further research is needed to find causal links between oral health and neuroinflammation that possibly can lead to the onset of Alzheimer's disease with the future intention to prevent cognitive decline by better dental care., Competing Interests: The authors have no conflicts of interest to declare.

Background: Clot composition, contraction, and mechanical properties are likely determinants of endovascular thrombectomy success. A pre-interventional estimation of these properties is hypothesized to aid in selecting the most suitable treatment for different types of thrombi. Here we determined the association between the aforementioned properties and computed tomography (CT) characteristics using human blood clot analogues., Methods: Clot analogues were prepared from the blood of 4 healthy human donors with 5 red blood cell (RBC) volume suspensions: 0%, 20%, 40%, 60% and 80% RBCs. Contraction was measured as the weight of the contracted clots as a percentage of the original suspension. The clots were imaged using CT with and without contrast to quantify clot density and density increase. Unconfined compression was performed to determine the high strain compressive stiffness. The RBC content was analysed using H&E staining., Results: The 5 RBC suspensions formed only two groups of clots, fibrin-rich (0% RBCs) and RBC-rich (>90% RBCs), as determined by histology. The density of the fibrin-rich clots was significantly lower (31-38HU) compared to the RBC-rich clots (72-89HU), and the density increase of the fibrin-rich clots was significantly higher (82-127HU) compared to the RBC-rich clots (3-17HU). The compressive stiffness of the fibrin-rich clots was higher (178-1624 kPa) than the stiffness of the RBC-rich clots (6-526 kPa). Additionally, the degree of clot contraction was higher for the fibrin-rich clots (89-96%) compared to the RBC-rich clots (11-77%)., Conclusions: CT imaging clearly reflects clot RBC content and seems to be related to the clot contraction and stiffness. CT imaging might be a useful tool in predicting the thrombus characteristics. However, future studies should confirm these findings by analysing clots with intermediate RBC and platelet content., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: AL and HB received research grants from Stryker and Penumbra for stroke research, all paid to the institution. This does not alter our adherence to PLOS ONE policies on sharing data and materials., (Copyright: © 2023 Cruts et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Transcriptional dysregulation has been described in spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), an autosomal dominant ataxia caused by a polyglutamine expansion in the ataxin-3 protein. As ataxin-3 is ubiquitously expressed, transcriptional alterations in blood may reflect early changes that start before clinical onset and might serve as peripheral biomarkers in clinical and research settings. Our goal was to describe enriched pathways and report dysregulated genes, which can track disease onset, severity or progression in carriers of the ATXN3 mutation (pre-ataxic subjects and patients). Global dysregulation patterns were identified by RNA sequencing of blood samples from 40 carriers of ATXN3 mutation and 20 controls and further compared with transcriptomic data from post-mortem cerebellum samples of MJD patients and controls. Ten genes-ABCA1, CEP72, PTGDS, SAFB2, SFSWAP, CCDC88C, SH2B1, LTBP4, MEG3 and TSPOAP1-whose expression in blood was altered in the pre-ataxic stage and simultaneously, correlated with ataxia severity in the overt disease stage, were analysed by quantitative real-time PCR in blood samples from an independent set of 170 SCA3/MJD subjects and 57 controls. Pathway enrichment analysis indicated the Gαi signalling and the oestrogen receptor signalling to be similarly affected in blood and cerebellum. SAFB2, SFSWAP and LTBP4 were consistently dysregulated in pre-ataxic subjects compared to controls, displaying a combined discriminatory ability of 79%. In patients, ataxia severity was associated with higher levels of MEG3 and TSPOAP1. We propose expression levels of SAFB2, SFSWAP and LTBP4 as well as MEG3 and TSPOAP1 as stratification markers of SCA3/MJD progression, deserving further validation in longitudinal studies and in independent cohorts., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Endovascular thrombectomy procedures are significantly influenced by the mechanical response of thrombi to the multi-axial loading imposed during retrieval. Compression tests are commonly used to determine compressive ex vivo thrombus and clot analogue stiffness. However, there is a shortage of data in tension. This study compares the tensile and compressive response of clot analogues made from the blood of healthy human donors in a range of compositions. Citrated whole blood was collected from six healthy human donors. Contracted and non-contracted fibrin clots, whole blood clots and clots reconstructed with a range of red blood cell (RBC) volumetric concentrations (5-80%) were prepared under static conditions. Both uniaxial tension and unconfined compression tests were performed using custom-built setups. Approximately linear nominal stress-strain profiles were found under tension, while strong strain-stiffening profiles were observed under compression. Low- and high-strain stiffness values were acquired by applying a linear fit to the initial and final 10% of the nominal stress-strain curves. Tensile stiffness values were approximately 15 times higher than low-strain compressive stiffness and 40 times lower than high-strain compressive stiffness values. Tensile stiffness decreased with an increasing RBC volume in the blood mixture. In contrast, high-strain compressive stiffness values increased from 0 to 10%, followed by a decrease from 20 to 80% RBC volumes. Furthermore, inter-donor differences were observed with up to 50% variation in the stiffness of whole blood clot analogues prepared in the same manner between healthy human donors., (© 2023. The Author(s).)

Background  Fibrinogen variants as a result of alternative messenger RNA splicing or protein degradation can affect fibrin(ogen) functions. The levels of these variants might be altered during coronavirus disease 2019 (COVID-19), potentially affecting disease severity or the thrombosis risk. Aim  To investigate the levels of fibrinogen variants in plasma of patients with COVID-19. Methods  In this case-control study, we measured levels of functional fibrinogen using the Clauss assay. Enzyme-linked immunosorbent assays were used to measure antigen levels of total, intact (nondegraded Aα chain), extended Aα chain (α E ), and γ' fibrinogen in healthy controls, patients with pneumococcal infection in the intensive care unit (ICU), ward patients with COVID-19, and ICU patients with COVID-19 (with and without thrombosis, two time points). Results  Healthy controls and ward patients with COVID-19 ( n  = 10) showed similar fibrinogen (variant) levels. ICU patients with COVID-19 who later did ( n  = 19) or did not develop thrombosis ( n  = 18) and ICU patients with pneumococcal infection ( n  = 6) had higher absolute levels of functional, total, intact, and α E fibrinogen than healthy controls ( n  = 7). The relative α E fibrinogen levels were higher in ICU patients with COVID-19 than in healthy controls, while relative γ' fibrinogen levels were lower. After diagnosis of thrombosis, only the functional fibrinogen levels were higher in ICU patients with COVID-19 and thrombosis than in those without, while no differences were observed in the other fibrinogen variants. Conclusion  Our results show that severe COVID-19 is associated with increased levels of α E fibrinogen and decreased relative levels of γ' fibrinogen, which may be a cause or consequence of severe disease, but this is not associated with the development of thrombosis., Competing Interests: Conflicts of Interest J.J.d.V., C.V., E.v.N., E.C.M.v.G., M.G., J.P.C.v.d.A., H.E., D.C.R., and M.P.M.d.M. declare to have no conflicts of interest. C.R. reports research grants from ViiV Healthcare, Gilead Sciences, Janssen, and Health-Holland for research outside the submitted work and participated in advisory boards for ViiV Healthcare and Gilead sciences. M.J.H.A.K. has received unrestricted grants paid to the Department for Research outside this work from Sobi, and has received a speaker's fee paid to the department from Sobi, Roche, and Bristol Myers Squibb. M.v.O., M.W., and J.K. are employees and shareholders of Fibriant BV., (The Author(s). This is an open access article published by Thieme under the terms of the Creative Commons Attribution License, permitting unrestricted use, distribution, and reproduction so long as the original work is properly cited. ( https://creativecommons.org/licenses/by/4.0/ ).)

Visibility of the tumour and its surroundings during the ablative procedure is crucial for optimal treatment planning, needle placement, ablation zone coverage and postprocedural control. The use of transcatheter CT arteriography providing real-time image guidance has proven to be of additional value for thermal liver ablation. The general advantages of the technique could be of value for other indications and ablation techniques as well, especially when requiring multiple needle placements in the vicinity of precarious vascular structures. This pictorial essay presents six clinical cases that illustrate transcatheter CT arteriography guidance during the treatment of locally advanced pancreatic cancer with irreversible electroporation. The illustrations highlight the technique's ability to improve visibility of vascular structures and the advantage of real-time monitoring and treatment of intraprocedural vascular complications. The use of transcatheter CT arteriography can support the interventionalist with respect to periprocedural safety and accuracy of electrode placement for pancreatic irreversible electroporation., (© 2023 The Authors. Journal of Medical Imaging and Radiation Oncology published by John Wiley & Sons Australia, Ltd on behalf of Royal Australian and New Zealand College of Radiologists.)

Background and Objectives: The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of neurodegenerative disorders generally caused by single nucleotide variants (SNVs) or indels in coding regions or by repeat expansions in coding and noncoding regions of SCA genes. Copy number variants (CNVs) have now also been reported for 3 genes- ITPR1 , FGF14 , and SPTBN2 -but not all SCA genes have been screened for CNVs as the underlying cause of the disease in patients. In this study, we aim to assess the prevalence of CNVs encompassing 36 known SCA genes., Methods: A cohort of patients with cerebellar ataxia who were referred to the University Medical Center Groningen for SCA genetic diagnostics was selected for this study. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed using the Infinium Global Screening Array. Following data processing, genotyping data were uploaded into NxClinical software to perform CNV analysis per patient and to visualize identified CNVs in 36 genes with allocated SCA symbols. The clinical relevance of detected CNVs was determined using evidence from studies based on PubMed literature searches for similar CNVs and phenotypic features., Results: Of the 338 patients with cerebellar ataxia, we identified putative clinically relevant CNV deletions in 3 patients: an identical deletion encompassing ITPR1 in 2 patients, who turned out to be related, and a deletion involving PPP2R2B in another patient. Although the CNV deletion in ITPR1 was clearly the underlying cause of SCA15 in the 2 related patients, the clinical significance of the deletion in PPP2R2B remained unknown., Discussion: We showed that CNVs detectable with the limited resolution of SNP array are a very rare cause of SCA. Nevertheless, we suggest adding CNV analysis alongside SNV analysis to SCA gene diagnostics using next-generation sequencing approaches, at least for ITPR1 , to improve the genetic diagnostics for patients., Competing Interests: The authors report no disclosures relevant to the manuscript. Go to Neurology.org/NG for full disclosures., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Fibrous networks are essential structural components of biological and engineered materials. Accordingly, many approaches have been developed to quantify their structural properties, which define their material properties. However, a comprehensive overview and comparison of methods is lacking. Therefore, we systematically searched for automated tools quantifying network characteristics in confocal, stimulated emission depletion (STED) or scanning electron microscopy (SEM) images and compared these tools by applying them to fibrin, a prototypical fibrous network in thrombi. Structural properties of fibrin such as fiber diameter and alignment are clinically relevant, since they influence the risk of thrombosis. Based on a systematic comparison of the automated tools with each other, manual measurements, and simulated networks, we provide guidance to choose appropriate tools for fibrous network quantification depending on imaging modality and structural parameter. These tools are often able to reliably measure relative changes in network characteristics, but absolute numbers should be interpreted with care. STATEMENT OF SIGNIFICANCE: Structural properties of fibrous networks define material properties of many biological and engineered materials. Many methods exist to automatically quantify structural properties, but an overview and comparison is lacking. In this work, we systematically searched for all publicly available automated analysis tools that can quantify structural properties of fibrous networks. Next, we compared them by applying them to microscopy images of fibrin networks. We also benchmarked the automated tools against manual measurements or synthetic images. As a result, we give advice on which automated analysis tools to use for specific structural properties. We anticipate that researchers from a large variety of fields, ranging from thrombosis and hemostasis to cancer research, and materials science, can benefit from our work., Competing Interests: Declaration of Competing Interest The authors declare no competing financial interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Recently, an intronic biallelic (AAGGG) n repeat expansion in RFC1 was shown to be a cause of CANVAS and adult-onset ataxia in multiple populations. As the prevalence of the RFC1 repeat expansion in Dutch cases was unknown, we retrospectively tested 9 putative CANVAS cases and two independent cohorts (A and B) of 395 and 222 adult-onset ataxia cases, respectively, using the previously published protocol and, for the first time optical genome mapping to determine the size of the expanded RFC1 repeat. We identified the biallelic (AAGGG) n repeat expansion in 5/9 (55%) putative CANVAS patients and in 10/617 (1.6%; cohorts A + B) adult-onset ataxia patients. In addition to the AAGGG repeat motif, we observed a putative GAAGG repeat motif in the repeat expansion with unknown significance in two adult-onset ataxia patients. All the expanded (AAGGG) n repeats identified were in the range of 800-1299 repeat units. The intronic biallelic RFC1 repeat expansion thus explains a number of the Dutch adult-onset ataxia cases that display the main clinical features of CANVAS, and particularly when ataxia is combined with neuropathy. The yield of screening for RFC1 expansions in unselected cohorts is relatively low. To increase the current diagnostic yield in ataxia patients, we suggest adding RFC1 screening to the genetic diagnostic workflow by using advanced techniques that attain long fragments., (© 2022. The Author(s).)

Background: Disease severity in spinocerebellar ataxia type 3 (SCA3) is commonly defined by the Scale for the Assessment and Rating of Ataxia (SARA) sum score, but little is known about the contributions and progression patterns of individual items., Objectives: To investigate the temporal dynamics of SARA item scores in SCA3 patients and evaluate if clinical and demographic factors are differentially associated with evolution of axial and appendicular ataxia., Methods: In a prospective, multinational cohort study involving 11 European and 2 US sites, SARA scores were determined longitudinally in 223 SCA3 patients with a follow-up assessment after 1 year., Results: An increase in SARA score from 10 to 20 points was mainly driven by axial and speech items, with a markedly smaller contribution of appendicular items. Finger chase and nose-finger test scores not only showed the lowest variability at baseline, but also the least deterioration at follow-up. Compared with the full set of SARA items, omission of both tests would result in lower sample size requirements for therapeutic trials. Sex was associated with change in SARA sum score and appendicular, but not axial, subscore, with a significantly faster progression in men. Despite considerable interindividual variability, the average annual progression rate of SARA score was approximately three times higher in subjects with a disease duration over 10 years than in those within 10 years from onset., Conclusion: Our findings provide evidence for a difference in temporal dynamics between axial and appendicular ataxia in SCA3 patients, which will help inform the design of clinical trials and development of new (etiology-specific) outcome measures. © 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2022 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

The presence of blood flow influences the interaction between von Willebrand factor (VWF) and blood cells, affecting characteristics of forming blood clots. The interactions between coagulation and inflammation have mainly been studied in thrombosis models, but it remains unclear whether these interactions might also play a role in reduced bleeding in patients with bleeding disorders. In this systematic review, we provide an overview of the literature investigating the interactions between VWF and blood cells in flow models. For article selection, a systematic search was performed in Embase, Medline-Ovid, Cochrane Library, Web of Science databases, and Google Scholar. After selection, 24 articles were included. These articles describe direct or platelet-dependent interactions between VWF and neutrophils, monocytes, erythrocytes, or lymphocytes under different flow conditions. Almost all the described interactions required the presence of activated platelets. Only erythrocytes, monocytes, and natural killer cells were capable of directly binding the VWF multimers. Overall, interactions between VWF and blood cells mainly occurred in the presence of platelets. Because of the large variation in study design and used flow rates, further research is necessary to compare the results between studies and draw firm conclusions on when and under what conditions these interactions can occur. After our findings, many questions remained unanswered. This review might provide a starting point for future research. Extended knowledge on the influence of blood flow on VWF and blood cell interactions can contribute to improved understanding of the variation in bleeding in patients with bleeding disorders., (© 2022 by The American Society of Hematology. Licensed under Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0), permitting only noncommercial, nonderivative use with attribution. All other rights reserved.)

Carotid atherosclerotic plaque rupture and its sequelae are among the leading causes of acute ischemic stroke. The risk of rupture and subsequent thrombosis is, among others, determined by vulnerable plaque characteristics and linked to activation of the immune system, in which neutrophil extracellular traps (NETs) potentially play a role. The aim of this study was to investigate how plaque vulnerability is associated with NETs levels. We included 182 patients from the Plaque At RISK (PARISK) study in whom carotid imaging was performed to measure plaque ulceration, fibrous cap integrity, intraplaque hemorrhage, lipid-rich necrotic core, calcifications and plaque volume. Principal component analysis generated a 'vulnerability index' comprising all plaque characteristics. Levels of the NETs marker myeloperoxidase-DNA complex were measured in patient plasma. The association between the vulnerability index and low or high NETs levels (dependent variable) was assessed by logistic regression. No significant association between the vulnerability index and NETs levels was detected in the total population (odds ratio 1.28, 95% confidence interval 0.90-1.83, p = 0.18). However, in the subgroup of patients naive to statins or antithrombotic medication prior to the index event, this association was statistically significant (odds ratio 2.08, 95% confidence interval 1.04-4.17, p = 0.04). Further analyses revealed that this positive association was mainly driven by intraplaque hemorrhage, lipid-rich necrotic core and ulceration. In conclusion, plaque vulnerability is positively associated with plasma levels of NETs, but only in patients naive to statins or antithrombotic medication prior to the index event., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: MEK reports grants outside the submitted work from NWO Aspasia, NWO Hestia, and EU Horizon 2020 ITN and has research collaborations with PieMedical Systems, Machnet BV. This does not alter our adherence to PLOS ONE policies on sharing data and materials.

Background: Severe acute respiratory syndrome coronavirus 2 infection is associated with an increased incidence of thrombosis., Objectives: By studying the fibrin network structure of coronavirus disease 2019 (COVID-19) patients, we aimed to unravel pathophysiological mechanisms that contribute to this increased risk of thrombosis. This may contribute to optimal prevention and treatment of COVID-19 related thrombosis., Patients/methods: In this case-control study, we collected plasma samples from intensive care unit (ICU) patients with COVID-19, with and without confirmed thrombosis, between April and December 2020. Additionally, we collected plasma from COVID-19 patients admitted to general wards without thrombosis, from ICU patients with pneumococcal infection, and from healthy controls. Fibrin fiber diameters and fibrin network density were quantified in plasma clots imaged with stimulated emission depletion microscopy and confocal microscopy. Finally, we determined the sensitivity to fibrinolysis., Results: COVID-19 ICU patients (n = 37) and ICU patients with pneumococcal disease (n = 7) showed significantly higher fibrin densities and longer plasma clot lysis times than healthy controls (n = 7). No differences were observed between COVID-19 ICU patients with and without thrombosis, or ICU patients with pneumococcal infection. At a second time point, after diagnosis of thrombosis or at a similar time point in patients without thrombosis, we observed thicker fibers and longer lysis times in COVID-19 ICU patients with thrombosis (n = 19) than in COVID-19 ICU patients without thrombosis (n = 18)., Conclusions: Our results suggest that severe COVID-19 is associated with a changed fibrin network structure and decreased susceptibility to fibrinolysis. Because these changes were not exclusive to COVID-19 patients, they may not explain the increased thrombosis risk., (© 2022 The Authors. Journal of Thrombosis and Haemostasis published by Wiley Periodicals LLC on behalf of International Society on Thrombosis and Haemostasis.)

Spinocerebellar ataxia type 3 (SCA3) is a rare genetic neurodegenerative disease. The neurobiological basis of SCA3 is still poorly understood, and up until now resting-state fMRI (rs-fMRI) has not been used to study this disease. In the current study we investigated (multi-echo) rs-fMRI data from patients with genetically confirmed SCA3 (n = 17) and matched healthy subjects (n = 16). Using independent component analysis (ICA) and subsequent regression with bootstrap resampling, we identified a pattern of differences between patients and healthy subjects, which we coined the fMRI SCA3 related pattern (fSCA3-RP) comprising cerebellum, anterior striatum and various cortical regions. Individual fSCA3-RP scores were highly correlated with a previously published 18 F-FDG PET pattern found in the same sample (rho = 0.78, P = 0.0003). Also, a high correlation was found with the Scale for Assessment and Rating of Ataxia scores (r = 0.63, P = 0.007). No correlations were found with neuropsychological test scores, nor with levels of grey matter atrophy. Compared with the 18 F-FDG PET pattern, the fSCA3-RP included a more extensive contribution of the mediofrontal cortex, putatively representing changes in default network activity. This rs-fMRI identification of additional regions is proposed to reflect a consequence of the nature of the BOLD technique, enabling measurement of dynamic network activity, compared to the more static 18 F-FDG PET methodology. Altogether, our findings shed new light on the neural substrate of SCA3, and encourage further validation of the fSCA3-RP to assess its potential contribution as imaging biomarker for future research and clinical use., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Given that new therapeutic options for spinocerebellar ataxias are on the horizon, there is a need for markers that reflect disease-related alterations, in particular, in the preataxic stage, in which clinical scales are lacking sensitivity., Objective: The objective of this study was to quantify regional brain volumes and upper cervical spinal cord areas in spinocerebellar ataxia type 3 in vivo across the entire time course of the disease., Methods: We applied a brain segmentation approach that included a lobular subsegmentation of the cerebellum to magnetic resonance images of 210 ataxic and 48 preataxic spinocerebellar ataxia type 3 mutation carriers and 63 healthy controls. In addition, cervical cord cross-sectional areas were determined at 2 levels., Results: The metrics of cervical spinal cord segments C3 and C2, medulla oblongata, pons, and pallidum, and the cerebellar anterior lobe were reduced in preataxic mutation carriers compared with controls. Those of cervical spinal cord segments C2 and C3, medulla oblongata, pons, midbrain, cerebellar lobules crus II and X, cerebellar white matter, and pallidum were reduced in ataxic compared with nonataxic carriers. Of all metrics studied, pontine volume showed the steepest decline across the disease course. It covaried with ataxia severity, CAG repeat length, and age. The multivariate model derived from this analysis explained 46.33% of the variance of pontine volume., Conclusion: Regional brain and spinal cord tissue loss in spinocerebellar ataxia type 3 starts before ataxia onset. Pontine volume appears to be the most promising imaging biomarker candidate for interventional trials that aim at slowing the progression of spinocerebellar ataxia type 3. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Background: Individuals with a parental family history of dementia have an increased risk of developing dementia because they share their genes as well as their psychosocial behaviour. Due to this increased risk and their experience with dementia, they may be particularly eager to receive information regarding dementia risk reduction (DRR). This study evaluated the knowledge, beliefs and attitudes towards dementia and DRR among descendants of people with dementia., Method: Using a semi-structured topic guide, three focus group discussions were conducted consisting of 12 female (80%) and 3 male (20%) descendants of people with dementia with a mean (± SD) age of 48.8 (± 12) years. Focus group discussions were audio recorded and transcribed. Each transcript was analysed thoroughly, and where appropriate, a code was generated and assigned by two researchers independently. Then, similar codes were grouped together and categorized into themes., Results: The items in the topic guide could only be addressed after participants had been given the opportunity to share their experiences of having a parent with dementia. Participants were unaware or uncertain about the possibility of reducing the risk of developing dementia and therefore hesitant to assess their dementia risk without treatment options in sight. Moreover, participants indicated that their general practitioner only gave some information on heritability, not on DRR. Although participants identified a large number of modifiable risk factors as a group during the group discussions, they were eager to receive more information on dementia and DRR. In the end, participants adopted a more positive attitude towards a DRR programme and provided suggestions for the development of future DRR programmes., Conclusions: Although the research aim was to evaluate the knowledge, beliefs and attitudes towards dementia and DRR, sharing experiences of having a parent with dementia seemed a prerequisite for considering participants' own risk of developing dementia and participating in a DRR programme. Knowledge of dementia and DRR was limited. Due to unawareness of the possibility of reducing dementia risk, participants were hesitant about assessing their dementia risk. Group discussions positively changed the perception of dementia risk assessment and participants' willingness to participate in a DRR programme.

Background: Approximately 80% of patients with locally advanced pancreatic cancer (LAPC) are treated with chemotherapy, of whom approximately 10% undergo a resection. Cohort studies investigating local tumor ablation with radiofrequency ablation (RFA) have reported a promising overall survival of 26-34 months when given in a multimodal setting. However, randomized controlled trials (RCTs) investigating the effect of RFA in combination with chemotherapy in patients with LAPC are lacking., Methods: The "Pancreatic Locally Advanced Unresectable Cancer Ablation" (PELICAN) trial is an international multicenter superiority RCT, initiated by the Dutch Pancreatic Cancer Group (DPCG). All patients with LAPC according to DPCG criteria, who start with FOLFIRINOX or (nab-paclitaxel/)gemcitabine, are screened for eligibility. Restaging is performed after completion of four cycles of FOLFIRINOX or two cycles of (nab-paclitaxel/)gemcitabine (i.e., 2 months of treatment), and the results are assessed within a nationwide online expert panel. Eligible patients with RECIST stable disease or objective response, in whom resection is not feasible, are randomized to RFA followed by chemotherapy or chemotherapy alone. In total, 228 patients will be included in 16 centers in The Netherlands and four other European centers. The primary endpoint is overall survival. Secondary endpoints include progression-free survival, RECIST response, CA 19.9 and CEA response, toxicity, quality of life, pain, costs, and immunomodulatory effects of RFA., Discussion: The PELICAN RCT aims to assess whether the combination of chemotherapy and RFA improves the overall survival when compared to chemotherapy alone, in patients with LAPC with no progression of disease following 2 months of systemic treatment., Trial Registration: Dutch Trial Registry NL4997 . Registered on December 29, 2015. ClinicalTrials.gov NCT03690323 . Retrospectively registered on October 1, 2018.

We propose a modern approach to assist clinicians to recognize and diagnose inborn errors of metabolism (IEMs) in adolescents and adults that present with a movement disorder. IEMs presenting in adults are still largely unexplored. These disorders receive little attention in neurological training and daily practice, and are considered complicated by many neurologists. Adult-onset presentations of IEMs differ from childhood-onset phenotypes, which may lead to considerable diagnostic delay. The identification of adult-onset phenotypes at the earliest stage of the disease is important, since early treatment may prevent or lessen further brain damage. Our approach is based on a systematic review of all papers that concerned movement disorders due to an IEM in patients of 16 years or older. Detailed clinical phenotyping is the diagnostic cornerstone of the approach. An underlying IEM should be suspected in particular in patients with more than one movement disorder, or in patients with additional neurological, psychiatric, or systemic manifestations. As IEMs are all genetic disorders, we recommend next-generation sequencing (NGS) as the first diagnostic approach to confirm an IEM. Biochemical tests remain the first choice in acute-onset or treatable IEMs that require rapid diagnosis, or to confirm the metabolic diagnosis after NGS results. With the use of careful and systematic clinical phenotyping combined with novel diagnostic approaches such as NGS, the diagnostic yield of late-onset IEMs will increase, in particular in patients with mild or unusual phenotypes., (Copyright © 2021 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Objective: In spinocerebellar ataxia type 3/Machado-Joseph disease (SCA3/MJD), the expanded cytosine adenine guanine (CAG) repeat in ATXN3 is the causal mutation, and its length is the main factor in determining the age at onset (AO) of clinical symptoms. However, the contribution of the expanded CAG repeat length to the rate of disease progression after onset has remained a matter of debate, even though an understanding of this factor is crucial for experimental data on disease modifiers and their translation to clinical trials and their design., Methods: Eighty-two Dutch patients with SCA3/MJD were evaluated annually for 15 years using the International Cooperative Ataxia Rating Scale (ICARS). Using linear growth curve models, ICARS progression rates were calculated and tested for their relation to the length of the CAG repeat expansion and to the residual age at onset (RAO): The difference between the observed AO and the AO predicted on the basis of the CAG repeat length., Results: On average, ICARS scores increased 2.57 points/year of disease. The length of the CAG repeat was positively correlated with a more rapid ICARS progression, explaining 30% of the differences between patients. Combining both the length of the CAG repeat and RAO as comodifiers explained up to 47% of the interpatient variation in ICARS progression., Interpretation: Our data imply that the length of the expanded CAG repeat in ATXN3 is a major determinant of clinical decline, which suggests that CAG-dependent molecular mechanisms similar to those responsible for disease onset also contribute to the rate of disease progression in SCA3/MJD. ANN NEUROL 2021;89:66-73., (© 2020 American Neurological Association.)

The Deep Underground Neutrino Experiment (DUNE) will be a powerful tool for a variety of physics topics. The high-intensity proton beams provide a large neutrino flux, sampled by a near detector system consisting of a combination of capable precision detectors, and by the massive far detector system located deep underground. This configuration sets up DUNE as a machine for discovery, as it enables opportunities not only to perform precision neutrino measurements that may uncover deviations from the present three-flavor mixing paradigm, but also to discover new particles and unveil new interactions and symmetries beyond those predicted in the Standard Model (SM). Of the many potential beyond the Standard Model (BSM) topics DUNE will probe, this paper presents a selection of studies quantifying DUNE's sensitivities to sterile neutrino mixing, heavy neutral leptons, non-standard interactions, CPT symmetry violation, Lorentz invariance violation, neutrino trident production, dark matter from both beam induced and cosmogenic sources, baryon number violation, and other new physics topics that complement those at high-energy colliders and significantly extend the present reach., (© The Author(s) 2021.)

The Clauss assay is the assay most often used for measuring plasma fibrinogen levels. However, the FIBTEM-assay, determined using thromboelastometry (ROTEM) can also be used to estimate fibrinogen levels. A major advantage of the FIBTEM is that it can provide information about fibrinogen levels within minutes, while the Clauss assay needs 30-60 min before the result is available. The aim of this study was to investigate the correlation between fibrinogen levels measured by the Clauss assay and results from the FIBTEM-assay. We included 111 patients ≥18 years for whom both ROTEM analyses and a fibrinogen measurement using the Clauss assay were available. In addition, ROTEM and Clauss measurements from 75 healthy subjects were included. Spearman correlation was used to determine the association between the results of both assays. The patients included were mostly patients with major trauma or undergoing large surgery (e.g. cardiac surgery or liver transplantation). Strong correlations were found between FIBTEM clot firmness parameters and fibrinogen levels measured by the Clauss assay in patients (Spearman's correlation coefficients (r s ) above 0.80 ( p  < .001) for all subgroups) and healthy subjects (r s = 0.66, p  < .001). The correlation between early FIBTEM parameters (clot firmness at 5 or 10 min) and the maximum clot firmness was almost perfect (r s above 0.96). Also, the correlation between the α-angle and FIBTEM parameters was strong (r s above 0.7). In conclusion, strong correlations were found between early FIBTEM parameters and fibrinogen levels.

Subjects with diabetes mellitus (DM) have an increased risk of arterial thrombosis, to which changes in clot structure and mechanics may contribute. Another contributing factor might be an increased formation of neutrophil extracellular traps (NETs) in DM. NETs are mainly formed during the acute phase of disease and form a network within the fibrin matrix, thereby influencing clot properties. Previous research has shown separate effects of NETs and DM on clot properties, therefore our aim was to study how DM affects clot properties in a model resembling an acute phase of disease with NETs formation. Clots were prepared from citrated plasma from subjects with and without DM with the addition of NETs, induced in neutrophils by S. aureus bacteria or phorbol myristate acetate (PMA). Structural parameters were measured using scanning electron microscopy, mechanical properties using rheology, and sensitivity to lysis using a fluorescence-based fibrinolysis assay. Plasma clots from subjects with DM had significantly thicker fibers and fewer pores and branch points than clots from subjects without DM. In addition, fibrinolysis was significantly slower, while mechanical properties were similar between both groups. In conclusion, in a model of acute NETs formation, DM plasma shows prothrombotic effects on fibrin clots.