Search

We propose a method for optimizing the geometry of a freeform lens to redirect the light emitted from an extended source into a desired irradiance distribution. We utilize a gradient-based optimization approach with MITSUBA 3, an algorithmic differentiable non-sequential ray tracer that allows us to obtain the gradients of the freeform surface parameters with respect to the produced irradiance distribution. To prevent the optimizer from getting trapped in local minima, we gradually increase the number of degrees of freedom of the surface by using Truncated Hierarchical B-splines (THB-splines) during optimization. The refinement locations are determined by analyzing the gradients of the surface vertices. We first design a freeform using a collimated beam (zero-etendue source) for a complex target distribution to demonstrate the method’s effectiveness. Then, we demonstrate the ability of this approach to create a freeform that can project the light of an extended Lambertian source into a prescribed target distribution., ImPhys/Adam group, Numerical Analysis

Algorithmic differentiable ray tracing is a new paradigm that allows one to solve the forward problem of how light propagates through an optical system while obtaining gradients of the simulation results with respect to parameters specifying the optical system. Specifically, the use of algorithmically differentiable non-sequential ray tracing provides an opportunity in the field of illumination engineering to design complex optical system. We demonstrate its potential by designing freeform lenses that project a prescribed irradiance distribution onto a plane. The challenge consists in finding a suitable surface geometry of the lens so that the light emitted by a light source is redistributed into a desired irradiance distribution. We discuss the crucial steps allowing the non-sequential ray tracer to be differentiable. The obtained gradients are used to optimize the geometry of the freeform, and we investigate the effectiveness of adding a multi-layer perceptron neural network to the optimization that outputs parameters defining the freeform lens. Lenses are designed for various sources such as collimated beams or point sources, and finally, a grid of point sources approximating an extended source. The obtained lens designs are finally validated using the commercial non-sequential ray tracer LightTools., ImPhys/Adam group, Numerical Analysis

Excluding oligo-, di-, monosaccharides and polyols (FODMAPs) from the diet is increasingly being used to treat children with gastrointestinal complaints. The aim of this position paper is to review the available evidence on the safety and efficacy of its use in children and provide expert guidance regarding practical aspects in case its use is considered . Members of the Gastroenterology Committee, the Nutrition Committee and the Allied Health Professionals Committee of the European Society for Pediatric Gastroenterology Hepatology and Nutrition contributed to this position paper. Clinical questions regarding initiation, introduction, duration, weaning, monitoring, professional guidance, safety and risks of the diet are addressed. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. The systematic literature search revealed that the low-FODMAP diet has not been comprehensively studied in children. Indications and contraindications of the use of the diet in different pediatric gastroenterological conditions are discussed and practical recommendations are formulated. There is scarce evidence to support the use of a low-FODMAP diet in children with Irritable Bowel Syndrome and no evidence to recommend its use in other gastrointestinal diseases and complaints in children. Awareness of how and when to use the diet is crucial, as a restrictive diet may impact nutritional adequacy and/or promote distorted eating in vulnerable subjects. The present article provides practical safety tips to be applied when the low-FODMAP diet is considered in children.

Excluding oligo-, di-, monosaccharides and polyols (FODMAPs) from the diet is increasingly being used to treat children with gastrointestinal complaints. The aim of this position paper is to review the available evidence on the safety and efficacy of its use in children and provide expert guidance regarding practical aspects in case its use is considered . Members of the Gastroenterology Committee, the Nutrition Committee and the Allied Health Professionals Committee of the European Society for Pediatric Gastroenterology Hepatology and Nutrition contributed to this position paper. Clinical questions regarding initiation, introduction, duration, weaning, monitoring, professional guidance, safety and risks of the diet are addressed. A systematic literature search was performed from 2005 to May 2021 using PubMed, MEDLINE and Cochrane Database of Systematic Reviews. In the absence of evidence, recommendations reflect the expert opinion of the authors. The systematic literature search revealed that the low-FODMAP diet has not been comprehensively studied in children. Indications and contraindications of the use of the diet in different pediatric gastroenterological conditions are discussed and practical recommendations are formulated. There is scarce evidence to support the use of a low-FODMAP diet in children with Irritable Bowel Syndrome and no evidence to recommend its use in other gastrointestinal diseases and complaints in children. Awareness of how and when to use the diet is crucial, as a restrictive diet may impact nutritional adequacy and/or promote distorted eating in vulnerable subjects. The present article provides practical safety tips to be applied when the low-FODMAP diet is considered in children.Copyright © 2022 by European Society for European Society for P

[EN] Background Despite treatment with pancreatic enzyme replacement therapy (PERT), patients with cystic fibrosis (CF) can still suffer from fat malabsorption. A cause could be low intestinal pH disabling PERT. The aim of this study was to assess the association between faecal pH (as intestinal pH surrogate) and coefficient of fat absorption (CFA). Additionally, faecal free fatty acids (FFAs) were quantified to determine the amount of digested, but unabsorbed fat. Methods In a 24-h pilot study, CF patients followed a standardised diet with fixed PERT doses, corresponding to theoretical optimal doses determined by an in vitro digestion model. Study variables were faecal pH, fat and FFA excretion, CFA and transit time. Linear mixed regression models were applied to explore associations. Results In 43 patients, median (1st, 3rd quartile) faecal pH and CFA were 6.1% (5.8, 6.4) and 90% (84, 94), and they were positively associated (p < 0.001). An inverse relationship was found between faecal pH and total fat excretion (p < 0.01), as well as total FFA (p = 0.048). Higher faecal pH was associated with longer intestinal transit time (p = 0.049) and the use of proton pump inhibitors (p = 0.009). Conclusions Although the clinical significance of faecal pH is not fully defined, its usefulness as a surrogate biomarker for intestinal pH should be further explored. Impact Faecal pH is a physiological parameter that may be related to intestinal pH and may provide important physiopathological information on CF-related pancreatic insufficiency. Faecal pH is correlated with fat absorption, and this may explain why pancreatic enzyme replacement therapy is not effective in all patients with malabsorption related to CF. Use of proton pump inhibitors is associated to higher values of faecal pH. Faecal pH could be used as a surrogate biomarker to routinely monitor the efficacy of pancreatic enzyme replacement therapy in clinical practice. Strategies to increase intestinal pH in children

Dynamic visualizations are particularly helpful for learning procedural tasks. This study investigates whether observing hand actions in dynamic visualizations from an egocentric versus an altercentric perspective is helpful for learning hand-manipulative tasks in terms of knot tying. During learning to tie two knots participants viewed dynamic visualizations with or without hands either filmed from an egocentric or an altercentric perspective (visibility of hands and perspective in a 2x2-between-subjects-design). Moreover, learners’ visuospatial ability was measured as a potential moderator during learning with different types of visualizations. Participants performed a motor skills task (knot tying performance) and a cognitive task (reasoning about the knot tying process). Results on motor skills indicated that in the egocentric perspective observing hands is helpful, whereas if no hands are shown, the allocentric perspective was beneficial. Results on cognitive reasoning showed a main effect regarding the altercentric perspective. Learners’ visuospatial ability was beneficial for both tasks (motor skills and cognitive reasoning) but did not interact with visibility of hands or perspective. In sum, the effectiveness of dynamic visualizations depends on an interplay between visibility of hands and depicted perspective: Observing hands is only beneficial in the egocentric perspective, whereas the allocentric perspective might have some advantages when no hands are shown.

Background & aims: In the absence of methodologically sound randomized controlled trials (RCTs), current recommendations for timing and amount of enteral nutrition (EN) in critically ill children are based on observational studies. These studies have associated achievement of a higher EN intake in critically ill children with improved outcome. Inherent to the observational design of these underlying studies, thorough insight in possible confounding factors to correct for is essential. We evaluated the associations between EN intake and 1) patient and daily clinical characteristics and 2) clinical outcomes adjusted for these patient and clinical characteristics during the first week of critical illness with a multivariable mixed model. Methods: This secondary analysis of the multicentre PEPaNIC RCT investigated a subgroup of critically ill children with daily prospectively recorded gastrointestinal symptoms and EN intake during the first week with multivariable analyses using two-part mixed effect models, including multiple testing corrections using Holm's method. These models combined a mixed-effects logistic regression for the dichotomous outcome EN versus no EN, and a linear mixed-effects model for the patients who received any EN intake. EN intake per patient was expressed as mean daily EN as % of predicted resting energy expenditure (% of EN/REE). Model 1 included 40 fixed effect baseline patient characteristics, and daily parameters of illness severity, feeding, medication and gastrointestinal symptoms. Model 2 included these patient and daily variables as well as clinical outcomes. Results: Complete data were available for 690 children. EN was provided in 503 (73%) patients with a start after a median of 2 (IQR 2–3) days and a median % of EN/REE of 38.8 (IQR 14.1–79.5) over the first week. Multivariable mixed model analyses including all patients showed that admission after gastrointestinal surgery (−49%EN/REE; p = 0.002), gastric feeding (−31% EN/REE

This study investigates whether observing hand actions in dynamic and static visualizations is helpful for learning hand-manipulative tasks in terms of knot tying. Functional near-infrared spectroscopy (fNIRS) was used to address whether dynamic visualizations or/and observing hands in the visualizations activate the human mirror-neuron-system and whether its activation mediates the facilitation of learning. During learning to tie two knots (Trucker’s Hitch and Bowline) participants viewed either dynamic or static visualizations with or without hands (2x2-between-subjects-design). Moreover, learners’ spatial ability was measured as a potential moderator during learning with different types of visualizations. Participants performed a motor skills task (knot tying performance) and a cognitive task (reasoning about the knot tying process). Results differed in dependence of the task, the to-be-tied knot, and learners’ spatial ability. Higher-spatial-ability learners showed better motor skill performance from viewing dynamic visualizations (Bowline knot) and visualizations with hands (Trucker’s Hitch knot). Lower-spatial-ability learners showed lower cognitive task performance from viewing the dynamic visualizations (Bowline knot) and visualizations with hands (Trucker’s Hitch and Bowline knot). The fNIRS data are currently analyzed. In sum, the effectiveness of different types of visualizations in terms of their dynamism (dynamic or static) and hand visibility (with or without) depends on the to-be-tied knot, the to-be-accomplished task (motor skills performance vs. cognitive reasoning) as well as spatial ability. Whereas higher-spatial-ability learners acquire better motor skills from learning with dynamic visualizations and observing hands in visualizations, lower-spatial-ability learners suffer from the same instructional formats on cognitive reasoning tasks.

The study of learning is grounded in theories and research. Since learning is complex and not directly observable, it is often inferred by collecting and analysing data based on the things learners do or say. By virtue, theories are developed from the analyses of data collected. With the proliferation of technology, large amounts of data are generated when students learn online. Therefore, researchers not only have data on students’ learning performance, but they also have data on the actions students take to achieve the desired learning outcomes. These data could help researchers to understand how students learn and the conditions needed for successful learning. In turn, the information can be translated to instructional and learning design to support students. The aim of the chapter is to discuss how learning theories and learning analytics are important components of educational research. To achieve this aim, studies employing learning analytics are qualitatively reviewed to examine which theories have been used and how the theories have been investigated. The results of the review show that self-regulated learning, motivation, and social constructivism theories were used in studies employing learning analytics. However, the studies at present are mostly correlational. Therefore, experimental studies are needed to examine how theory-informed practices can be implemented so that students can be better supported in online learning environments. The chapter concludes by proposing an iterative loop for educational research employing learning analytics in which learning theories guide data collection and analyses. To convert data into knowledge, it is important to recognize what we already know and what we want to examine., Green Open Access added to TU Delft Institutional Repository ‘You share, we take care!’ – Taverne project https://www.openaccess.nl/en/you-share-we-take-care Otherwise as indicated in the copyright section: the publisher is the copyright holder of this work and the author uses the Dutch legislation to make this work public., Web Information Systems

Research shows that instructional animations yield better learning outcomes than static graphics when learning about human motor skills, especially for learning hand-manipulation tasks such as origami folding. The present study investigates whether this superiority of instructional animations is caused by the hands that are shown during learning. In a between-participants design, participants (n = 100) studied a visualization (static graphics vs. animation) that did or did not show hand actions when learning how to tie two nautical knots. Subsequently they performed a motor skills task, a cognitive task and indicated cognitive load. Additionally, spatial skills were measured. Results showed that animations were superior to static graphics and that showing the hands negatively affected learning from static graphics.

Mitochondrial disorders, characterized by clinical symptoms and/or OXPHOS deficiencies, are caused by pathogenic variants in mitochondrial genes. However, pathogenic variants in some of these genes can lead to clinical manifestations which overlap with other neuromuscular diseases, which can be caused by pathogenic variants in non-mitochondrial genes as well. Mitochondrial pathogenic variants can be found in the mitochondrial DNA (mtDNA) or in any of the 1,500 nuclear genes with a mitochondrial function. We have performed a two-step next-generation sequencing approach in a cohort of 117 patients, mostly children, in whom a mitochondrial disease-cause could likely or possibly explain the phenotype. A total of 86 patients had a mitochondrial disorder, according to established clinical and biochemical criteria. The other 31 patients had neuromuscular symptoms, where in a minority a mitochondrial genetic cause is present, but a non-mitochondrial genetic cause is more likely. All patients were screened for pathogenic variants in the mtDNA and, if excluded, analyzed by whole exome sequencing (WES). Variants were filtered for being pathogenic and compatible with an autosomal or X-linked recessive mode of inheritance in families with multiple affected siblings and/or consanguineous parents. Non-consanguineous families with a single patient were additionally screened for autosomal and X-linked dominant mutations in a predefined gene-set. We identified causative pathogenic variants in the mtDNA in 20% of the patient-cohort, and in nuclear genes in 49%, implying an overall yield of 68%. We identified pathogenic variants in mitochondrial and non-mitochondrial genes in both groups with, obviously, a higher number of mitochondrial genes affected in mitochondrial disease patients. Furthermore, we show that 31% of the disease-causing genes in the mitochondrial patient group were not included in the MitoCarta database, and therefore would have been missed with MitoCarta based gene-p

Multimedia learning research has shown that presenting the same words as spoken text and as written text to accompany graphical information hinders learning (i.e., redundancy effect). However, recent work showed that a “condensed” form of written text (i.e., on-screen labels) that overlaps with the spoken text, and thus is only partially redundant, can actually foster learning. This study extends this line of research by focusing on the usefulness of on-screen labels in an animation explaining a procedural task (i.e., first-aid procedure). The experiment had a 2 × 2 × 2 between-subject design (N = 129) with the factors spoken text (yes vs. no), written text (yes vs. no), and on-screen labels (yes vs. no). Learning outcomes were measured as retention accuracy and behavioral performance accuracy. Results showed that on-screen labels improved retention accuracy (but not behavioral performance accuracy) of the procedure, especially when presented together with spoken text. So, on-screen labels appear to be promising for learning from procedural animations.

Autosomal recessive cerebellar ataxia (ARCA) is a group of neurological disorders characterized by degeneration or abnormal development of the cerebellum and spinal cord. ARCA is clinically and genetically highly heterogeneous, with over 20 genes involved. Exome sequencing of a girl with ARCA from non-consanguineous Dutch parents revealed two pathogenic variants c.37G>C; p.D13H and c.946A>T; p.K316∗ in CWF19L1, a gene with an unknown function, recently reported to cause ARCA in a Turkish family. Sanger sequencing showed that the c.37G>C variant was inherited from the father and the c.946A>T variant from the mother. Pathogenicity was based on the damaging effect on protein function as the c.37G>C variant changed the highly conserved, negatively charged aspartic acid to the positively charged histidine and the c.946A>T variant introduced a premature stop codon. In addition, 27 patients with ARCA were tested for pathogenic variants in CWF19L1, however, no pathogenic variants were identified. Our data confirm CWF19L1 as a novel but rare gene causing ARCA.

In establishing a genetic diagnosis in heterogeneous neurological disease, clinical characterization and whole exome sequencing (WES) go hand-in-hand. Clinical data are essential, not only to guide WES variant selection and define the clinical severity of a genetic defect but also to identify other patients with defects in the same gene. In an infant patient with sensorineural hearing loss, psychomotor retardation, and epilepsy, WES resulted in identification of a novel homozygous CLPP frameshift mutation (c.21delA). Based on the gene defect and clinical symptoms, the diagnosis Perrault syndrome type 3 (PRLTS3) was established. The patient's brain-MRI revealed specific abnormalities of the subcortical and deep cerebral white matter and the middle blade of the corpus callosum, which was used to identify similar patients in the Amsterdam brain-MRI database, containing over 3000 unclassified leukoencephalopathy cases. In three unrelated patients with similar MRI abnormalities the CLPP gene was sequenced, and in two of them novel missense mutations were identified together with a large deletion that covered part of the CLPP gene on the other allele. The severe neurological and MRI abnormalities in these young patients were due to the drastic impact of the CLPP mutations, correlating with the variation in clinical manifestations among previously reported patients. Our data show that similarity in brain-MRI patterns can be used to identify novel PRLTS3 patients, especially during early disease stages, when only part of the disease manifestations are present. This seems especially applicable to the severely affected cases in which CLPP function is drastically affected and MRI abnormalities are pronounced.

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome- and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

Bridging Domains A Comparison between Information Processing in Archaea and Eukarya Studying Information Processing Living cells evolved complex systems to handle the flow of information both accurately and efficiently. These systems are highly comparable between the three domains of life: eukaryotes, bacteria and archaea. The central components of replication, transcription, aminoacylation, and translation are found in every living cell known today, with only relatively small deviations, despite a separation of billions of years of evolution. Archaea are unicellular, do not contain organelles, and have relatively small genomes, so are, at first sight, quite similar to their far better known prokaryotic cousins: the bacteria. Nevertheless, if it comes down to information processing, archaea are, surprisingly, more related to eukaryotes than to bacteria, both at the sequence level of RNA and proteins, and at the architecture level of key complexes as well. This makes them excellent model systems to study eukaryote-like information processing. The absence of cell specialization, less cell organization, less or even no intracellular compartmentalization, and less intensive regulation, have proven to give a clearer picture of the function of conserved key elements within these complex systems. [Chapter 2] In this thesis, we report several attempts to elucidate functional details of some very conserved factors in information processing in S. solfataricus using recently established genetic modification techniques. S. solfataricus is a thermoacidophilic crenarchaeote that grows optimally at temperatures between 70°C and 85°C and at pH values between 2 and 3. Its genome sequence is known since 2001. Best practices have become standardized between laboratories, and the genomic toolbox includes gene knockout, overexpression systems, the availability of reporter genes, and tunable promoters. MBF1, a highly conserved activator MBF1 (multi-protein bridging factor 1) is reported

Implementation of next-generation DNA sequencing (NGS) technology into routine diagnostic genome care requires strategic choices. Instead of theoretical discussions on the consequences of such choices, we compared NGS-based diagnostic practices in eight clinical genetic centers in the Netherlands, based on genetic testing of nine pre-selected patients with cardiomyopathy. We highlight critical implementation choices, including the specific contributions of laboratory and medical specialists, bioinformaticians and researchers to diagnostic genome care, and how these affect interpretation and reporting of variants. Reported pathogenic mutations were consistent for all but one patient. Of the two centers that were inconsistent in their diagnosis, one reported to have found 'no causal variant', thereby underdiagnosing this patient. The other provided an alternative diagnosis, identifying another variant as causal than the other centers. Ethical and legal analysis showed that informed consent procedures in all centers were generally adequate for diagnostic NGS applications that target a limited set of genes, but not for exome-and genome-based diagnosis. We propose changes to further improve and align these procedures, taking into account the blurring boundary between diagnostics and research, and specific counseling options for exome- and genome-based diagnostics. We conclude that alternative diagnoses may infer a certain level of 'greediness' to come to a positive diagnosis in interpreting sequencing results. Moreover, there is an increasing interdependence of clinic, diagnostics and research departments for comprehensive diagnostic genome care. Therefore, we invite clinical geneticists, physicians, researchers, bioinformatics experts and patients to reconsider their role and position in future diagnostic genome care.

A key element during the flow of genetic information in living systems is fidelity. The accuracy of DNA replication influences the genome size as well as the rate of genome evolution. The large amount of energy invested in gene expression implies that fidelity plays a major role in fitness. On the other hand, an increase in fidelity generally coincides with a decrease in velocity. Hence, an important determinant of the evolution of life has been the establishment of a delicate balance between fidelity and variability. This paper reviews the current knowledge on quality control in archaeal information processing. While the majority of these processes are homologous in Archaea, Bacteria, and Eukaryotes, examples are provided of nonorthologous factors and processes operating in the archaeal domain. In some instances, evidence for the existence of certain fidelity mechanisms has been provided, but the factors involved still remain to be identified