Advanced tool and methods for modeling cardiovascular disease using human pluripotent stem cells

To advance drug discovery for cardiovascular patients, new pre-clinical models and quantification methods are needed to improve clinical predictivity. This thesis aims to explore several approaches to bringing new solutions for disease modeling which reflect the human heart. Firstly, we review the current status of the Heart-on-chip (HoC) field and the cutting edge (bio)materials which enable more physiologically relevant culture methods for stem cell-derived cardiomyocytes (hiPSC-CMs). Then, we use a polydimethylsiloxane chip to culture hiPSC-CM, hiPSC-endothelial cells and hiPSC-cardiac fibroblasts combined with a microfluidic flow-channel to mimic physiological blood flow. Subsequently, we fabricated and tested a platform for 3D-culture of heart tissues designed ultimately for medium- to high-throughput drug screening. Moreover, we create a stand-alone software application for automated and robust analysis of in vitro models of striated muscle. We have used a previously published mathematical tool and applied it to static, live, 2D, 3D, hiPSC-CM, primary CM and skeletal muscle, providing evidence of its versatility. This was successfully applied to study hiPSC-CMs from patients with hypertrophic cardiomyopathy and carrying a heterozygous mutation in the MYBPC3 gene. Finally, we discuss the results and conclusions presented in this thesis, and provide an outlook of future research directions in this exciting field. Netherlands Organ on Chip Initiative (NWO)LUMC / Geneeskund

Re-evaluating genetic models for porphyry Mo mineralization at Questa, New Mexico: Implications for ore deposition following silicic ignimbrite eruption

The Questa porphyry Mo deposit in New Mexico provides a unique opportunity to study the relationship between pluton assembly and mineralization in a long-lived volcanic field. Magmatism along the caldera margin initiated at ∼ 25.20 Ma and continued for ∼ 770 ka. During this time, the emplacement of mineralizing intrusions progressed westward and culminated in the assembly of the Questa Mo deposit between 24.76 Ma and 24.50 Ma. Molybdenite Re/Os geochronology shows that mineralization occurred in multiple pulses without thermal resetting of the chronometer. Because most of the molybdenite samples used in this study are from previous fluid inclusion studies, we treat Re/Os molybdenite as a new thermochronometer. Molybdenite Re/Os ages are integrated with zircon U/Pb ages to evaluate the cooling histories within the Mo deposit. This study suggests that individual cycles of magma emplacement and mineralization cooled rapidly. In contrast to prior genetic models for the Questa Mo deposit, these data show that the mineralizing intrusions were generated via rapid melt generation, separation, and intrusion into the shallow crust without involvement in a long-lived magma chamber. It is proposed that the anomalously high magma flux event associated with ignimbrite eruption transferred materials (Mo, volatiles) from the upper mantle necessary for immediately subsequent mineralization. Partial melting and scavenging within a deep-crustal hybridized zone generated Mo-rich magma that ascended to form the Questa deposit. Moreover, this hypothesis predicts an important connection between caldera-forming systems and porphyry-style mineralization that could be incorporated into future exploration models

Can sand dunes be used to study historic storm events?

Knowing the long-term frequency of high magnitude storm events that cause coastal inundation is critical for present coastal management, especially in the context of rising sea levels and potentially increasing frequency and severity of storm events. Coastal sand dunes may provide a sedimentary archive of past storm events from which long-term frequencies of large storms can be reconstructed. This study uses novel portable optically stimulated luminescence (POSL) profiles from coastal dunes to reconstruct the sedimentary archive of storm and surge activity for Norfolk, UK. Application of POSL profiling with supporting luminescence ages and particle size analysis to coastal dunes provides not only information of dunefield evolution but also on past coastal storms. In this study, seven storm events, two major, were identified from the dune archive spanning the last 140 years. These appear to correspond to historical reports of major storm surges. Dunes appear to be only recording (at least at the sampling resolution used here) the highest storm levels that were associated with significant flooding. As such the approach seems to hold promise to obtain a better understanding of the frequency of large storms by extending the dune archive records further back to times when documentation of storm surges was sparse

Slicing Sets and Measures, and the Dimension of Exceptional Parameters

We consider the problem of slicing a compact metric space \Omega with sets of the form \pi_{\lambda}^{-1}\{t\}, where the mappings \pi_{\lambda} \colon \Omega \to \R, \lambda \in \R, are \emph{generalized projections}, introduced by Yuval Peres and Wilhelm Schlag in 2000. The basic question is: assuming that \Omega has Hausdorff dimension strictly greater than one, what is the dimension of the 'typical' slice \pi_{\lambda}^{-1}{t}, as the parameters \lambda and t vary. In the special case of the mappings \pi_{\lambda} being orthogonal projections restricted to a compact set \Omega \subset \R^{2}, the problem dates back to a 1954 paper by Marstrand: he proved that for almost every \lambda there exist positively many $t \in \R$ such that \dim \pi_{\lambda}^{-1}{t} = \dim \Omega - 1. For generalized projections, the same result was obtained 50 years later by J\"arvenp\"a\"a, J\"arvenp\"a\"a and Niemel\"a. In this paper, we improve the previously existing estimates by replacing the phrase 'almost all \lambda' with a sharp bound for the dimension of the exceptional parameters.Comment: 31 pages, three figures; several typos corrected and large parts of the third section rewritten in v3; to appear in J. Geom. Ana

On thin plate spline interpolation

We present a simple, PDE-based proof of the result [M. Johnson, 2001] that the error estimates of [J. Duchon, 1978] for thin plate spline interpolation can be improved by $h^{1/2}$. We illustrate that ${\mathcal H}$-matrix techniques can successfully be employed to solve very large thin plate spline interpolation problem

Zinc-enriched fertilisers as a potential public health intervention in Africa

Background In this review, we examine the potential of Zn-enriched fertilisers to alleviate human dietary Zn deficiency. The focus is on ten African countries where dietary Zn supply is low and where fertiliser subsidies are routinely deployed on cereal crops. Scope Dietary Zn supply and deficiency prevalence were quantified from food supply and composition data. Typical effects of soil (granular) and foliar Zn applications on Zn concentrations in maize (Zea mays L.), rice (Oryza sativa L.) and wheat (Triticum aestivum L.) grains were based on a systematic literature review. Reductions in disease burdens attributable to Zn deficiency and cost-effectiveness were estimated using a disability-adjusted life years (DALYs) approach. Conclusions Baseline Zn supply in 2009 ranged from 7.1 (Zambia) to 11.9 (Mali) mg capita−1 day−1; prevalence of Zn deficiency ranged from 24 (Nigeria) to 66 % (Zambia). In reviewed studies, soil Zn application led to an increase in median Zn concentration in maize, rice and wheat grains of 23, 7 and 19 %; foliar application led to increases of 30, 25 and 63 %. Enriching granular fertilisers within current subsidy schemes would be most effective in Malawi, reducing DALYs lost due to Zn deficiency by 10 %. The cost per DALY saved ranged from US$624 to 5893 via granular fertilisers and from US$ 46 to 347 via foliar fertilisers. Foliar applications are likely to be more cost effective than soil applications due to fixation of Zn in the soil but may be more difficult to deploy. Zinc fertilisation is likely to be less cost-effective than breeding in the longer term although other micronutrients such as selenium could be incorporated

European Association of Urology and European Society for Paediatric Urology Guidelines on Paediatric Urinary Stone Disease

Context: Paediatric stone disease is an important clinically entity and management is often challenging. Although it is known that the condition is endemic in some geographic regions of the world, the global incidence is also increasing. Patient age and sex; the number, size, location, and composition of the stone; and the anatomy of the urinary tract are factors that need to be taken into consideration when choosing a treatment modality. Objective: To provide a general insight into the evaluation and management of urolithiasis in the paediatric population in the era of minimally invasive surgery. Evidence acquisition: A nonsystematic review of the literature on management of paediatric urolithiasis was conducted with the aim of presenting the most suitable treatment modality for different scenarios. Evidence synthesis: Because of high recurrence rates, open surgical intervention is not the first option for paediatric stone disease, except for very young patients with very large stones in association with congenital abnormalities. Minimally invasive surgeries have become the first option with the availability of appropriately sized instruments and accumulating experience. Extracorporeal shockwave lithotripsy (SWL) is noninvasive and can be carried out as an outpatient procedure under sedation, and is the initial choice for management of smaller stones. However, for larger stones, SWL has lower stone-free rates and higher retreatment rates, so minimally invasive endourology procedures such as percutaneous nephrolithotomy and retrograde intrarenal surgery are preferred treatment options. Conclusions: Contemporary surgical treatment for paediatric urolithiasis typically uses minimally invasive modalities. Open surgery is very rarely indicated. Patient summary: Cases of urinary stones in children are increasing. Minimally invasive surgery can achieve high stone-free rates with low complication rates. After stone removal, metabolic evaluation is strongly recommended so that medical treatment for any underlying metabolic abnormality can be given. Regular follow-up with imaging such as ultrasound is required because of the high recurrence rates

Eyes on CVI:Eye movements unveil distinct visual search patterns in Cerebral Visual Impairment compared to ADHD, dyslexia, and neurotypical children

Visual search problems are often reported in children with Cerebral Visual Impairment (CVI). To tackle the clinical challenge of objectively differentiating CVI from other neurodevelopmental disorders, we developed a novel test battery. Visual search tasks were coupled with verbal and gaze-based measurements. Two search tasks were performed by children with CVI (n: 22; mean age (SD): 9.63 (.46) years) ADHD (n: 32; mean age (SD): 10.51 (.25) years), dyslexia (n: 28; mean age (SD): 10.29 (.20) years) and neurotypical development (n: 44; mean age (SD): 9.30 (.30) years). Children with CVI had more impaired search performance compared to all other groups, especially in crowded and unstructured displays and even when they had normal visual acuity. In-depth gaze-based analyses revealed that this group searched in overall larger areas and needed more time to recognize a target, particularly after their initial fixation on the target. Our gaze-based approach to visual search offers new insights into the distinct search patterns and behaviours of children with CVI. Their tendency to overlook targets whilst fixating on it, point towards higher-order visual function (HOVF) deficits. The novel method is feasible, valid, and promising for clinical differential-diagnostic evaluation between CVI, ADHD and dyslexia, and for informing individualized training.</p

Eyes on CVI:Eye movements unveil distinct visual search patterns in Cerebral Visual Impairment compared to ADHD, dyslexia, and neurotypical children

Visual search problems are often reported in children with Cerebral Visual Impairment (CVI). To tackle the clinical challenge of objectively differentiating CVI from other neurodevelopmental disorders, we developed a novel test battery. Visual search tasks were coupled with verbal and gaze-based measurements. Two search tasks were performed by children with CVI (n: 22; mean age (SD): 9.63 (.46) years) ADHD (n: 32; mean age (SD): 10.51 (.25) years), dyslexia (n: 28; mean age (SD): 10.29 (.20) years) and neurotypical development (n: 44; mean age (SD): 9.30 (.30) years). Children with CVI had more impaired search performance compared to all other groups, especially in crowded and unstructured displays and even when they had normal visual acuity. In-depth gaze-based analyses revealed that this group searched in overall larger areas and needed more time to recognize a target, particularly after their initial fixation on the target. Our gaze-based approach to visual search offers new insights into the distinct search patterns and behaviours of children with CVI. Their tendency to overlook targets whilst fixating on it, point towards higher-order visual function (HOVF) deficits. The novel method is feasible, valid, and promising for clinical differential-diagnostic evaluation between CVI, ADHD and dyslexia, and for informing individualized training.</p