Risk factors for intensive care admission in children with severe acute asthma in the Netherlands:a prospective multicentre study

Rationale: Severe acute asthma (SAA) can be fatal, but is often preventable. We previously observed in a retrospective cohort study, a three-fold increase in SAA paediatric intensive care (PICU) admissions between 2003 and 2013 in the Netherlands, with a significant increase during those years of numbers of children without treatment of inhaled corticosteroids (ICS). Objectives: To determine whether steroid-naïve children are at higher risk of PICU admission among those hospitalised for SAA. Furthermore, we included the secondary risk factors tobacco smoke exposure, allergic sensitisation, previous admissions and viral infections. Methods: A prospective, nationwide multicentre study of children with SAA (2-18 years) admitted to all Dutch PICUs and four general wards between 2016 and 2018. Potential risk factors for PICU admission were assessed using logistic regression analyses. Measurements and main results: 110 PICU and 111 general ward patients were included. The proportion of steroid-naïve children did not differ significantly between PICU and ward patients. PICU children were significantly older and more exposed to tobacco smoke, with symptoms >1 week prior to admission. Viral susceptibility was not a significant risk factor for PICU admission. Conclusions: Children with SAA admitted to a PICU were comparable to those admitted to a general ward with respect to ICS treatment prior to admission. Preventable risk factors for PICU admission were >7 days of symptoms without adjustment of therapy and exposure to tobacco smoke. Physicians who treat children with asthma must be aware of these risk factors

Novel Blood Pressure Locus and Gene Discovery Using Genome-Wide Association Study and Expression Data Sets From Blood and the Kidney.

Elevated blood pressure is a major risk factor for cardiovascular disease and has a substantial genetic contribution. Genetic variation influencing blood pressure has the potential to identify new pharmacological targets for the treatment of hypertension. To discover additional novel blood pressure loci, we used 1000 Genomes Project-based imputation in 150 134 European ancestry individuals and sought significant evidence for independent replication in a further 228 245 individuals. We report 6 new signals of association in or near HSPB7, TNXB, LRP12, LOC283335, SEPT9, and AKT2, and provide new replication evidence for a further 2 signals in EBF2 and NFKBIA Combining large whole-blood gene expression resources totaling 12 607 individuals, we investigated all novel and previously reported signals and identified 48 genes with evidence for involvement in blood pressure regulation that are significant in multiple resources. Three novel kidney-specific signals were also detected. These robustly implicated genes may provide new leads for therapeutic innovation

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Dosimetric feasibility of MRI-guided proton therapy

The goal of radiotherapy is to deliver a high conformal radiation dose to a target, while sparing healthy surrounding tissue. Proton therapy, where protons are used to deliver the dose, promises higher dose conformality in comparison with photon-based radiotherapy. This is due to the existence of the Bragg Peak, a point where a large amount of the dose is delivered and after which the protons stop in the body. This leads to a sharp dose fall-off, potentially sparing tissue beyond the target. Because of these properties, up-to-date knowledge of the location of the target and the surrounding anatomy is crucial. Similar to the development in photon therapy, image-guided radiotherapy (IGRT) is emerging as well in proton therapy and in the recent years, an increasing number of studies have been performed on the development of image-guided proton therapy (IGPT). Various imaging modalities are available to deliver the necessary imaging in IGPT. One of those modalities is Magnetic Resonance Imaging (MRI). MRI has several benefits, such as the fact that no ionizing radiation is used and the superior soft-tissue contrast, which can lead to better tissue classification. Therefore an ideal solution for IGPT would be a hybrid MRI-proton therapy system, similar to the already existing MR-linac in photon therapy. As a step towards the development of such a system, the dosimetric feasibility of proton therapy inside the strong magnetic fields of an MRI is addressed in this thesis. For this purpose, Monte Carlo (MC) simulations are used. First, an MC model of the MD Anderson Cancer Center Proton Therapy Center clinical scanning proton beam is created using the TOol for PArticle Simulations (TOPAS), an MC toolkit based on Geant4 and specifically tailored for medical particle simulations. This beam model is then used for the simulation of a quality assurance phantom measurement and is the basis for the further simulation studies in this thesis. To account for inter-fraction and intrafraction motion during treatment, an adaptive planning workflow is presented. As in proton therapy anatomical changes can introduce profound dose changes, adaptive planning could significantly improve proton dose delivery. It is shown that for IMPT, the deterioration in target coverage is mostly restored with the adaptive plan. Next, a study on the dosimetric feasibility of Intensity Modulated Proton Therapy (IMPT) in a transverse magnetic field of 1.5T is presented. It Is shown that the impact of the magnetic field is small and, when taken into account into the planning, the resulting dose distributions are equivalent for 0T and 1.5T, concluding that IMPT in a 1.5T transverse magnetic field is dosimetrically feasible. Finally, the implementation of proton transport inside a magnetic field in the commercial treatment planning system RayStation is validated. This validation paves the way for broad clinical planning studies, which is necessary to build the clinical rationale for the development of MRI-guided proton therapy. In conclusion, this thesis lays the foundation for future dosimetric and clinical studies for the further development and, finally, the implementation of MRI-guided proton therapy

Dosimetric feasibility of MRI-guided proton therapy

The goal of radiotherapy is to deliver a high conformal radiation dose to a target, while sparing healthy surrounding tissue. Proton therapy, where protons are used to deliver the dose, promises higher dose conformality in comparison with photon-based radiotherapy. This is due to the existence of the Bragg Peak, a point where a large amount of the dose is delivered and after which the protons stop in the body. This leads to a sharp dose fall-off, potentially sparing tissue beyond the target. Because of these properties, up-to-date knowledge of the location of the target and the surrounding anatomy is crucial. Similar to the development in photon therapy, image-guided radiotherapy (IGRT) is emerging as well in proton therapy and in the recent years, an increasing number of studies have been performed on the development of image-guided proton therapy (IGPT). Various imaging modalities are available to deliver the necessary imaging in IGPT. One of those modalities is Magnetic Resonance Imaging (MRI). MRI has several benefits, such as the fact that no ionizing radiation is used and the superior soft-tissue contrast, which can lead to better tissue classification. Therefore an ideal solution for IGPT would be a hybrid MRI-proton therapy system, similar to the already existing MR-linac in photon therapy. As a step towards the development of such a system, the dosimetric feasibility of proton therapy inside the strong magnetic fields of an MRI is addressed in this thesis. For this purpose, Monte Carlo (MC) simulations are used. First, an MC model of the MD Anderson Cancer Center Proton Therapy Center clinical scanning proton beam is created using the TOol for PArticle Simulations (TOPAS), an MC toolkit based on Geant4 and specifically tailored for medical particle simulations. This beam model is then used for the simulation of a quality assurance phantom measurement and is the basis for the further simulation studies in this thesis. To account for inter-fraction and intrafraction motion during treatment, an adaptive planning workflow is presented. As in proton therapy anatomical changes can introduce profound dose changes, adaptive planning could significantly improve proton dose delivery. It is shown that for IMPT, the deterioration in target coverage is mostly restored with the adaptive plan. Next, a study on the dosimetric feasibility of Intensity Modulated Proton Therapy (IMPT) in a transverse magnetic field of 1.5T is presented. It Is shown that the impact of the magnetic field is small and, when taken into account into the planning, the resulting dose distributions are equivalent for 0T and 1.5T, concluding that IMPT in a 1.5T transverse magnetic field is dosimetrically feasible. Finally, the implementation of proton transport inside a magnetic field in the commercial treatment planning system RayStation is validated. This validation paves the way for broad clinical planning studies, which is necessary to build the clinical rationale for the development of MRI-guided proton therapy. In conclusion, this thesis lays the foundation for future dosimetric and clinical studies for the further development and, finally, the implementation of MRI-guided proton therapy

Operando Shell-Isolated Nanoparticle-Enhanced Raman Spectroscopy of the NO Reduction Reaction over Rhodium-Based Catalysts

Operando shell-isolated nanoparticle-enhanced Raman spectroscopy (SHINERS) with on-line mass spectrometry (MS) has been used to investigate the surface species, such as NO, NOH, NO2, N2O, and reaction products of the NO reduction reaction with CO and H2 over supported Rh-based catalysts in the form of catalyst extrudates. By correlating surface intermediates and reaction products, new insights in the reaction mechanism could be obtained. Upon applying different reaction conditions (i. e., H2 or CO), the selectivity of the catalytic reaction could be tuned towards the formation of N2. Furthermore, in the absence of Rh, no reaction products were detected. The importance of the operando SHINERS as a surface-sensitive characterization technique in the field of heterogeneous catalysis provides routes towards a better understanding of catalytic performance