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In most cases new technology emergence does not guarantee overnight success nor is it developed overnight, rather it is a result of industry expertise spanning over several fields of research. 3D bioprinting is an industry that promises revolutionary implications for healthcare and scholars are discussing application areas such as tissue for oncology research, tissue for patient specific drug development and lastly complex organs for implantation. The promises and strides of the industry pose new prospects in healthcare, for instance printing new skin for burn victims & drug development all while being patient specific. The promises of bioprinting are practices that will lead to improved quality of life whether it be in the form of medicine or a new organ. The industry is characterized by fast pace and rapid technological advancements, research has explored these technological advancements and explained them in detail, but information on the market remains scarce. To contribute to filling this gap the thesis explores what the state of the market currently is and what the stage of market development is. In order to explore how the market has developed and the current state of it a longitudinal case study, in Sweden which is one of the most innovative countries in the world was conducted. Newspaper articles from three news outlets were collected, two of which are Swedens most reputable publishers regarding new technology and business and economic development, the third is an industry specific outlet to biotechnology advancement. This resulted in finding that while the dialog of bioprinting is promising, the degree of readiness remains the same, furthermore it shows that the industry is heavily dependent on external actors to further develop the market and technology. It was also found that there is no shortage in actors spanning across various industries that collaborate with bioprinting firms since not all industries need the full capacity of the technology that is necessary to print complex organ structures. It can be stated that while the bioprinting market is evolving the development of it is in early stages and is far from being established.

Background: Multiple sclerosis (MS) is one of the most prevalent chronic inflammatory diseases caused by demyelination and axonal damage in the central nervous system. Structural retinal imaging via optical coherence tomography (OCT) shows promise as a noninvasive biomarker for monitoring of MS. There are successful reports regarding the application of Artificial Intelligence (AI) in the analysis of cross-sectional OCTs in ophthalmologic diseases. However, the alteration of sub-retinal thicknesses in MS is noticeably subtle compared to other ophthalmologic diseases. Therefore, raw cross-sectional OCTs are replaced with multilayer segmented OCTs for discrimination of MS and healthy controls (HCs). Methods: To conform to the principles of trustworthy AI, interpretability is provided by visualizing the regional layer contribution to classification performance with the proposed occlusion sensitivity approach. The robustness of the classification is also guaranteed by showing the effectiveness of the algorithm while being tested on the new independent dataset. The most discriminative features from different topologies of the multilayer segmented OCTs are selected by the dimension reduction method. Support vector machine (SVM), random forest (RF), and artificial neural network (ANN) are used for classification. Patient-wise cross-validation (CV) is utilized to evaluate the performance of the algorithm, where the training and test folds contain records from different subjects. Results: The most discriminative topology is determined to square with a size of 40 pixels and the most influential sub-retinal layers are the ganglion cell and inner plexiform layer (GCIPL) and inner nuclear layer (INL). Linear SVM resulted in 88% Accuracy (with standard deviation (std) = 0.49 in 10 times of execution to indicate the repeatability), 78% precision (std=1.48), and 63% recall (std=1.35) in the discrimination of MS and HCs using macular multilayer segmented OCTs. Conclusion: The proposed classification algorithm is expected to help neurologists in the early diagnosis of MS. This paper distinguishes itself from other studies by employing two distinct datasets, which enhances the robustness of its findings in comparison with previous studies with lack of external validation. This study aims to circumvent the utilization of deep learning methods due to the limited quantity of the available data and convincingly demonstrates that favorable outcomes can be achieved without relying on deep learning techniques.

Background:Spectral-domain (SD-) optical coherence tomography (OCT) can reliably measure axonal (peripapillary retinal nerve fiber layer [pRNFL]) and neuronal (macular ganglion cell + inner plexiform layer [GCIPL]) thinning in the retina. Measurements from 2 commonly used SD-OCT devices are often pooled together in multiple sclerosis (MS) studies and clinical trials despite software and segmentation algorithm differences; however, individual pRNFL and GCIPL thickness measurements are not interchangeable between devices. In some circumstances, such as in the absence of a consistent OCT segmentation algorithm across platforms, a conversion equation to transform measurements between devices may be useful to facilitate pooling of data. The availability of normative data for SD-OCT measurements is limited by the lack of a large representative world-wide sample across various ages and ethnicities. Larger international studies that evaluate the effects of age, sex, and race/ethnicity on SD-OCT measurements in healthy control participants are needed to provide normative values that reflect these demographic subgroups to provide comparisons to MS retinal degeneration.Methods:Participants were part of an 11-site collaboration within the International Multiple Sclerosis Visual System (IMSVISUAL) consortium. SD-OCT was performed by a trained technician for healthy control subjects using Spectralis or Cirrus SD-OCT devices. Peripapillary pRNFL and GCIPL thicknesses were measured on one or both devices. Automated segmentation protocols, in conjunction with manual inspection and correction of lines delineating retinal layers, were used. A conversion equation was developed using structural equation modeling, accounting for clustering, with healthy control data from one site where participants were scanned on both devices on the same day. Normative values were evaluated, with the entire cohort, for pRNFL and GCIPL thicknesses for each decade of age, by sex, and across racial groups using generalized estimating equation (GEE) models, accounting for clustering and adjusting for within-patient, intereye correlations. Change-point analyses were performed to determine at what age pRNFL and GCIPL thicknesses exhibit accelerated rates of decline.Results:The healthy control cohort (n = 546) was 54% male and had a wide distribution of ages, ranging from 18 to 87 years, with a mean (SD) age of 39.3 (14.6) years. Based on 346 control participants at a single site, the conversion equation for pRNFL was Cirrus = -5.0 + (1.0 × Spectralis global value). Based on 228 controls, the equation for GCIPL was Cirrus = -4.5 + (0.9 × Spectralis global value). Standard error was 0.02 for both equations. After the age of 40 years, there was a decline of -2.4 m per decade in pRNFL thickness (P < 0.001, GEE models adjusting for sex, race, and country) and -1.4 m per decade in GCIPL thickness (P < 0.001). There was a small difference in pRNFL thickness based on sex, with female participants having slightly higher thickness (2.6 m, P = 0.003). There was no association between GCIPL thickness and sex. Likewise, there was no association between race/ethnicity and pRNFL or GCIPL thicknesses.Conclusions:A conversion factor may be required when using data that are derived between different SD-OCT platforms in clinical trials and observational studies; this is particularly true for smaller cross-sectional studies or when a consistent segmentation algorithm is not available. The above conversion equations can be used when pooling data from Spectralis and Cirrus SD-OCT devices for pRNFL and GCIPL thicknesses. A faster decline in retinal thickness may occur after the age of 40 years, even in the absence of significant differences across racial groups.

This thesis examines the algorithmic and practical challenges of solving systems of polynomial equations. We discuss the design and implementation of triangular decomposition to solve polynomials systems exactly by means of symbolic computation. Incremental triangular decomposition solves one equation from the input list of polynomials at a time. Each step may produce several different components (points, curves, surfaces, etc.) of the solution set. Independent components imply that the solving process may proceed on each component concurrently. This so-called component-level parallelism is a theoretical and practical challenge characterized by irregular parallelism. Parallelism is not an algorithmic property but rather a geometrical property of the particular input system’s solution set. Despite these challenges, we have effectively applied parallel computing to triangular decomposition through the layering and cooperation of many parallel code regions. This parallel computing is supported by our generic object-oriented framework based on the dynamic multithreading paradigm. Meanwhile, the required polynomial algebra is sup- ported by an object-oriented framework for algebraic types which allows type safety and mathematical correctness to be determined at compile-time. Our software is implemented in C/C++ and have extensively tested the implementation for correctness and performance on over 3000 polynomial systems that have arisen in practice. The parallel framework has been re-used in the implementation of Hensel factorization as a parallel pipeline to compute roots of a polynomial with multivariate power series coefficients. Hensel factorization is one step toward computing the non-trivial limit points of quasi-components.

We discuss design aspects of the open-source Basic Polynomial Algebra Subprograms (BPAS) library. We build on standard C++11 template mechanisms to improve ease of use and accessibility. The BPAS computer algebra library looks to enable end-users to do work more easily and efficiently through optimized C code wrapped in an object-oriented and user-friendly C++ interface. Two key aspects of this interface to be discussed are the encoding of the algebraic hierarchy as a class hierarchy and a mechanism to support the combination of algebraic types as a new type. Existing libraries, if encoding the algebraic hierarchy at all, use runtime value checks to determine if two elements belong to the same ring for an incorrect false sense of type safety in an otherwise statically-typed language. On the contrary, our template metaprogramming mechanism provides true compile-time type safety and compile-time code generation. The details of this mechanism are transparent to end-users, providing a very natural interface for an end-user mathematician.

The N-body problem is a classic problem involving a system of N discrete bodies mutually interacting in a dynamical system. At any moment in time there are N*(N - 1)/2 such interactions occurring. This scaling as N^2 leads to computational difficulties where simulations range from tens of thousands of bodies to many millions. Approximation algorithms, such as the famous Barnes-Hut algorithm, simplify the number of interactions to scale as N(log N). Even still, this improvement in complexity is insufficient to achieve the desired performance for very large simulations on computing clusters with many nodes and many cores. In this work we explore a variety of algorithmic techniques for distributed and parallel variations on the Barnes-Hut algorithm to improve parallelism and reduce inter-process communication requirements. Explicit algorithms and details are provided for reproducibility. Our MPI implementation of distributed gravitational N-body simulation, freely available on GitHub, is evaluated on a cluster of 10 nodes, each with two 6-core CPUs, to test the effectiveness and scalability of the aforementioned techniques., 41 pages, 10 figures

BackgroundPatients with anti-aquaporin-4 antibody seropositive (AQP4-IgG+) neuromyelitis optica spectrum disorders (NMOSDs) frequently suffer from optic neuritis (ON) leading to severe retinal neuroaxonal damage. Further, the relationship of this retinal damage to a primary astrocytopathy in NMOSD is uncertain. Primary astrocytopathy has been suggested to cause ON-independent retinal damage and contribute to changes particularly in the outer plexiform layer (OPL) and outer nuclear layer (ONL), as reported in some earlier studies. However, these were limited in their sample size and contradictory as to the localisation. This study assesses outer retinal layer changes using optical coherence tomography (OCT) in a multicentre cross-sectional cohort.Method197 patients who were AQP4-IgG+ and 32 myelin-oligodendrocyte-glycoprotein antibody seropositive (MOG-IgG+) patients were enrolled in this study along with 75 healthy controls. Participants underwent neurological examination and OCT with central postprocessing conducted at a single site.ResultsNo significant thinning of OPL (25.02±2.03 µm) or ONL (61.63±7.04 µm) were observed in patients who were AQP4-IgG+ compared with patients who were MOG-IgG+ with comparable neuroaxonal damage (OPL: 25.10±2.00 µm; ONL: 64.71±7.87 µm) or healthy controls (OPL: 24.58±1.64 µm; ONL: 63.59±5.78 µm). Eyes of patients who were AQP4-IgG+ (19.84±5.09 µm, p=0.027) and MOG-IgG+ (19.82±4.78 µm, p=0.004) with a history of ON showed parafoveal OPL thinning compared with healthy controls (20.99±5.14 µm); this was not observed elsewhere.ConclusionThe results suggest that outer retinal layer loss is not a consistent component of retinal astrocytic damage in AQP4-IgG+ NMOSD. Longitudinal studies are necessary to determine if OPL and ONL are damaged in late disease due to retrograde trans-synaptic axonal degeneration and whether outer retinal dysfunction occurs despite any measurable structural correlates.

Supplemental material, sj-docx-11-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-13-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-12-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-17-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-18-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-19-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-16-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-9-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-12-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-17-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-8-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-14-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-8-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-15-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-18-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-19-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-11-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-1-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-9-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-2-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-1-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-15-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

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Supplemental material, sj-docx-16-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-docx-10-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585221097296 for Serum neurofilament light chain concentration predicts disease worsening in multiple sclerosis by Synne Brune, Einar A Høgestøl, Sigrid A de Rodez Benavent, Pål Berg-Hansen, Mona K Beyer, Ingvild Sørum Leikfoss, Steffan D Bos, Piotr Sowa, Cathrine Brunborg, Magi Andorra, Irene Pulido Valdeolivas, Susanna Asseyer, Alexander Brandt, Claudia Chien, Michael Scheel, Kaj Blennow, Henrik Zetterberg, Nicole Kerlero de Rosbo, Friedemann Paul, Antonio Uccelli, Pablo Villoslada, Tone Berge and Hanne F Harbo in Multiple Sclerosis Journal

Artificial intelligence (AI)-based diagnostic algorithms have achieved ambitious aims through automated image pattern recognition. For neurological disorders, this includes neurodegeneration and inflammation. Scalable imaging technology for big data in neurology is optical coherence tomography (OCT). We highlight that OCT changes observed in the retina, as a window to the brain, are small, requiring rigorous quality control pipelines. There are existing tools for this purpose. Firstly, there are human-led validated consensus quality control criteria (OSCAR-IB) for OCT. Secondly, these criteria are embedded into OCT reporting guidelines (APOSTEL). The use of the described annotation of failed OCT scans advances machine learning. This is illustrated through the present review of the advantages and disadvantages of AI-based applications to OCT data. The neurological conditions reviewed here for the use of big data include Alzheimer disease, stroke, multiple sclerosis (MS), Parkinson disease, and epilepsy. It is noted that while big data is relevant for AI, ownership is complex. For this reason, we also reached out to involve representatives from patient organizations and the public domain in addition to clinical and research centers. The evidence reviewed can be grouped in a five-point expansion of the OSCAR-IB criteria to embrace AI (OSCAR-AI). The review concludes by specific recommendations on how this can be achieved practically and in compliance with existing guidelines.

We present MultivariatePowerSeries, a Maple library introduced in Maple 2021, providing a variety of methods to study formal multivariate power series and univariate polynomials over such series. This library offers a simple and easy-to-use user interface. Its implementation relies on lazy evaluation techniques and takes advantage of Maple's features for object-oriented programming. The exposed methods include Weierstrass Preparation Theorem and factorization via Hensel's lemma. The computational performance is demonstrated by means of an experimental comparison with software counterparts.

Hensel's lemma, combined with repeated applications of Weierstrass preparation theorem, allows for the factorization of polynomials with multivariate power series coefficients. We present a complexity analysis for this method and leverage those results to guide the load-balancing of a parallel implementation to concurrently update all factors. In particular, the factorization creates a pipeline where the terms of degree k of the first factor are computed simultaneously with the terms of degree k-1 of the second factor, etc. An implementation challenge is the inherent irregularity of computational work between factors, as our complexity analysis reveals. Additional resource utilization and load-balancing is achieved through the parallelization of Weierstrass preparation. Experimental results show the efficacy of this mixed parallel scheme, achieving up to 9x parallel speedup on 12 cores., 21 pages, 3 figures, submitted to Computer Algebra in Scientific Computing CASC 2021

OBJECTIVE: To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). METHODS: We enrolled patients with RRMS (aged 18–60 years, Expanded Disability Status Scale [EDSS] score 0–6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. RESULTS: A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. CONCLUSION: In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. TRIAL REGISTRATION INFORMATION: Clinical trial registration number: NCT00525668.

Background: Epigallocatechin gallate (EGCG) is an anti-inflammatory agent and has proven neuroprotective properties in animal models of multiple sclerosis (MS). Optical coherence tomography (OCT) assessed retinal thickness analysis can reflect treatment responses in MS. Objective: To analyze the influence of EGCG treatment on retinal thickness analysis as secondary and exploratory outcomes of the randomized controlled Sunphenon in Progressive Forms of MS trial (SUPREMES, NCT00799890). Methods: SUPREMES patients underwent OCT with the Heidelberg Spectralis device at a subset of visits. We determined peripapillary retinal nerve fiber layer (pRNFL) thickness from a 12. ring scan around the optic nerve head and thickness of the ganglion cell/inner plexiform layer (GCIP) and inner nuclear layer (INL) within a 6 mm diameter grid centered on the fovea from a macular volume scan. Longitudinal OCT data were available for exploratory analysis from 31 SUPREMES participants (12/19 primary/secondary progressive MS (PPMS/SPMS); mean age 51 +/- 7 years; 12 female; mean time since disease onset 16 +/- 11 years). We tested the null hypothesis of no treatment*time interaction using nonparametric analysis of longitudinal data in factorial experiments. Results: After 2 years, there were no significant differences in longitudinal retinal thickness changes between EGCG treated and placebo arms in any OCT parameter Mean change [confidence interval] ECGC vs. Placebo: pRNFL: -0.83 [1.29] mu m vs. -0.64 [1.56] mu m, p = 0.156; GCIP: -0.67 [0.67] mu m vs. -0.14 [0.47] mu m, p = 0.476; INL: -0.06 [0.58] mu m vs. 0.22 [0.41] mu m, p = 0.455). Conclusion: Retinal thickness analysis did not reveal a neuroprotective effect of EGCG. While this is in line with the results of the main SUPREMES trial, our study was probably underpowered to detect an effect. Clinical Trial Registration: www.ClinicalTrials.gov, identifier: NCT00799890.

Background: Clinical outcomes in neuromyelitis optica spectrum disorders (NMOSD) vary across different regions. Objective: To describe clinical profiles in Japanese and German NMOSD patients. Methods: Medical records of aquaporin-4-immunoglobulin G (AQP4-IgG) positive NMOSD patients from Japan (n = 54) and Germany (n = 38) were retrospectively analyzed. Results: The disability status was similar between both cohorts, although Japanese patients had a longer disease duration (13.3 ± 11.1 vs. 8.1 ± 6.9 years, p = 0.018) but similar relapse rates. Optic neuritis and myelitis were the most frequent attacks in both cohorts. Brain attacks occurred more frequently in Japanese patients (40.7% vs. 15.8%, p = 0.020). The time from disease onset (median [interquartile range] 2.3 [0.3-10.1] vs. 0.6 [0.2-1.9] years, p = 0.009) and the number of attacks (2.5 [1-7] vs. 2 [1-3], p = 0.047) until start of the first immunotherapy were higher in the Japanese cohort. Rituximab was the most common drug in the German cohort (52.6%) and not given in the Japanese cohort (p

Objective To assess the safety and efficacy of epigallocatechin-3-gallate (EGCG) add-on to glatiramer acetate (GA) in patients with relapsing-remitting multiple sclerosis (RRMS). Methods We enrolled patients with RRMS (aged 18–60 years, Expanded Disability Status Scale [EDSS] score 0–6.5), receiving stable GA treatment in a multicenter, prospective, double-blind, phase II, randomized controlled trial. Participants received up to 800 mg oral EGCG daily over a period of 18 months. The primary outcome was the proportion of patients without new hyperintense lesions on T2-weighted (T2w) brain MRI within 18 months. Secondary end points included additional MRI and clinical parameters. Immunologic effects of EGCG were investigated in exploratory experiments. Results A total of 122 patients on GA were randomly assigned to EGCG treatment (n = 62) or placebo (n = 60). We could not demonstrate a difference between groups after 18 months for the primary outcome or other radiologic (T2w lesion volume, T1w hypointense lesion number or volume, number of cumulative contrast-enhancing lesions, percent brain volume change), or clinical (EDSS, MS functional composite, and annualized relapse rate) parameter. EGCG treatment did not affect immune response to GA. Pharmacologic analysis revealed wide ranging EGCG plasma levels. The treatment was well tolerated with a similar incidence of mostly mild adverse events similar in both groups. Conclusion In RRMS, oral EGCG add-on to GA was not superior to placebo in influencing MRI and clinical disease activity over 18 months. The treatment was safe at a daily dosage up to 800 mg EGCG. It did not influence immune parameters, despite indication of EGCG being bioavailable in patients. Classification of Evidence This study provides Class II evidence that for patients with RRMS, EGCG added to GA did not significantly affect the development of new hyperintense lesions on T2-weighted brain MRI. Trial Registration Information Clinical trial registration number: NCT00525668.

Objective To examine whether treatment with epigallocatechin gallate (EGCG) influences progression of brain atrophy, reduces clinical and further radiologic disease activity markers, and is safe in patients with progressive multiple sclerosis (PMS). Methods We enrolled 61 patients with primary or secondary PMS in a randomized double-blind, parallel-group, phase II trial on oral EGCG (up to 1,200 mg daily) or placebo for 36 months with an optional open-label EGCG treatment extension (OE) of 12-month duration. The primary end point was the rate of brain atrophy, quantified as brain parenchymal fraction (BPF). The secondary end points were radiologic and clinical disease parameters and safety assessments. Results In our cohort, 30 patients were randomized to EGCG treatment and 31 to placebo. Thirty-eight patients (19 from each group) completed the study. The primary endpoint was not met, as in 36 months the rate of decrease in BPF was 0.0092 ± 0.0152 in the treatment group and −0.0078 ± 0.0159 in placebo-treated patients. None of the secondary MRI and clinical end points revealed group differences. Adverse events of EGCG were mostly mild and occurred with a similar incidence in the placebo group. One patient in the EGCG group had to stop treatment due to elevated aminotransferases (>3.5 times above normal limit). Conclusions In a phase II trial including patients with multiple sclerosis (MS) with progressive disease course, we were unable to demonstrate a treatment effect of EGCG on the primary and secondary radiologic and clinical disease parameters while confirming on overall beneficial safety profile. Clinicaltrial.gov Identifier NCT00799890. Classification of Evidence This phase II trial provides Class II evidence that for patients with PMS, EGCG was safe, well tolerated, and did not significantly reduce the rate of brain atrophy.

Supplemental material, sj-pdf-2-msj-10.1177_13524585211032801 for Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders by Noah Ayadi, Frederike C Oertel, Susanna Asseyer, Rebekka Rust, Ankelien Duchow, Joseph Kuchling, Judith Bellmann-Strobl, Klemens Ruprecht, Alexander Klistorner, Alexander U Brandt, Friedemann Paul and Hanna G Zimmermann in Multiple Sclerosis Journal

Supplemental material, sj-pdf-1-msj-10.1177_13524585211032801 for Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders by Noah Ayadi, Frederike C Oertel, Susanna Asseyer, Rebekka Rust, Ankelien Duchow, Joseph Kuchling, Judith Bellmann-Strobl, Klemens Ruprecht, Alexander Klistorner, Alexander U Brandt, Friedemann Paul and Hanna G Zimmermann in Multiple Sclerosis Journal

Annals of Clinical and Translational Neurology 8(4), 774-789 (2021). doi:10.1002/acn3.51315, Published by Wiley, Chichester [u.a.]

Supplemental material, sj-pdf-2-msj-10.1177_13524585211032801 for Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders by Noah Ayadi, Frederike C Oertel, Susanna Asseyer, Rebekka Rust, Ankelien Duchow, Joseph Kuchling, Judith Bellmann-Strobl, Klemens Ruprecht, Alexander Klistorner, Alexander U Brandt, Friedemann Paul and Hanna G Zimmermann in Multiple Sclerosis Journal

Supplemental material, sj-pdf-4-msj-10.1177_13524585211032801 for Impaired motion perception is associated with functional and structural visual pathway damage in multiple sclerosis and neuromyelitis optica spectrum disorders by Noah Ayadi, Frederike C Oertel, Susanna Asseyer, Rebekka Rust, Ankelien Duchow, Joseph Kuchling, Judith Bellmann-Strobl, Klemens Ruprecht, Alexander Klistorner, Alexander U Brandt, Friedemann Paul and Hanna G Zimmermann in Multiple Sclerosis Journal

Supplemental material, sj-pdf-3-msj-10.1177_13524585211003479 for Longitudinal analysis of T1w/T2w ratio in patients with multiple sclerosis from first clinical presentation by Graham Cooper, Claudia Chien, Hanna Zimmermann, Judith Bellmann-Strobl, Klemens Ruprecht, Joseph Kuchling, Susanna Asseyer, Alexander U Brandt, Michael Scheel, Carsten Finke and Friedemann Paul in Multiple Sclerosis Journal