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The full text of this thesis is not available due to privacy or embargo reasons.

Background: In several settings, a shorter time to diagnosis has been shown to lead to improved clinical outcomes. The implementation of a rapid laboratory testing allows for a pre-visit testing in the outpatient clinic, meaning that test results are available during the first outpatient visit. Objective: To determine whether the pre-visit laboratory testing leads to a shorter time to diagnosis in the general internal medicine outpatient clinic. Design: An “on-off” trial, allocating subjects to one of two treatment arms in consecutive alternating blocks. Participants: All new referrals to the internal medicine outpatient clinic of a university hospital were included, excluding second opinions. A total of 595 patients were eligible; one person declined to participate, leaving data from 594 patients for analysis. Intervention: In the intervention group, patients had a standardized pre-visit laboratory testing before the first visit. Main Measures: The primary outcome was the time to diagnosis. Secondary outcomes were the correctness of the preliminary diagnosis on the first day, health care utilization, and patient and physician satisfaction. Key Results: There was no difference in time to diagnosis between the two groups (median 35 days vs 35 days; hazard ratio 1.03 [0.87–1.22]; p =.71). The pre-visit testing group had higher proportions of both correct preliminary diagnoses on day 1 (24% vs 14%; p =.003) and diagnostic workups being completed on day 1 (10% vs 3%; p <.001). The intervention group had more laboratory tests done (50.0 [interquartile range (IQR) 39.0–69.0] vs 43.0 [IQR 31.0–68.5]; p <.001). Otherwise, there were no differences between the groups. Conclusions: Pre-visit testing did not lead to a shorter overall time to diagnosis. However, a greater proportion of patients had a correct diagnosis on the first day. Further studies should focus on customizing pre-visit laboratory panels, to improve their efficacy. Trial Registration: NL5009

Cryptosporidiosis is a major cause of diarrhoeal illness among African children, and is associated with childhood mortality, malnutrition, cognitive development and growth retardation. Cryptosporidium hominis is the dominant pathogen in Africa, and genotyping at the glycoprotein 60 (gp60) gene has revealed a complex distribution of different subtypes across this continent. However, a comprehensive exploration of the metapopulation structure and evolution based on whole-genome data has yet to be performed. Here, we sequenced and analysed the genomes of 26 C. hominis isolates, representing different gp60 subtypes, collected at rural sites in Gabon, Ghana, Madagascar and Tanzania. Phylogenetic and cluster analyses based on single-nucleotide polymorphisms showed that isolates predominantly clustered by their country of origin, irrespective of their gp60 subtype. We found a significant isolation-by-distance signature that shows the importance of local transmission, but we also detected evidence of hybridization between isolates of different geographical regions. We identified 37 outlier genes with exceptionally high nucleotide diversity, and this group is significantly enriched for genes encoding extracellular proteins and signal peptides. Furthermore, these genes are found more often than expected in recombinant regions, and they show a distinct signature of positive or balancing selection. We conclude that: (1) the metapopulation structure of C. hominis can only be accurately captured by whole-genome analyses; (2) local anthroponotic transmission underpins the spread of this pathogen in Africa; (3) hybridization occurs between distinct geographical lineages; and (4) genetic introgression provides novel substrate for positive or balancing selection in genes involved in host-parasite coevolution.

Background: In several settings, a shorter time to diagnosis has been shown to lead to improved clinical outcomes. The implementation of a rapid laboratory testing allows for a pre-visit testing in the outpatient clinic, meaning that test results are available during the first outpatient visit. Objective: To determine whether the pre-visit laboratory testing leads to a shorter time to diagnosis in the general internal medicine outpatient clinic. Design: An “on-off” trial, allocating subjects to one of two treatment arms in consecutive alternating blocks. Participants: All new referrals to the internal medicine outpatient clinic of a university hospital were included, excluding second opinions. A total of 595 patients were eligible; one person declined to participate, leaving data from 594 patients for analysis. Intervention: In the intervention group, patients had a standardized pre-visit laboratory testing before the first visit. Main Measures: The primary outcome was the time to diagnosis. Secondary outcomes were the correctness of the preliminary diagnosis on the first day, health care utilization, and patient and physician satisfaction. Key Results: There was no difference in time to diagnosis between the two groups (median 35 days vs 35 days; hazard ratio 1.03 [0.87–1.22]; p =.71). The pre-visit testing group had higher proportions of both correct preliminary diagnoses on day 1 (24% vs 14%; p =.003) and diagnostic workups being completed on day 1 (10% vs 3%; p <.001). The intervention group had more laboratory tests done (50.0 [interquartile range (IQR) 39.0–69.0] vs 43.0 [IQR 31.0–68.5]; p <.001). Otherwise, there were no differences between the groups. Conclusions: Pre-visit testing did not lead to a shorter overall time to diagnosis. However, a greater proportion of patients had a correct diagnosis on the first day. Further studies should focus on customizing pre-visit laboratory panels, to improve their efficacy. Trial Registration: NL5009.

In 2018 is in samenwerking met varkenshouder Dirk Dekker het project Startersboerderij gestart. Dekker maakt zich - als ondernemer zonder opvolger - hard voor nieuwkomers in de agrarische sector. Steeds meer burgers hebben de ambitie om een agrarisch bedrijf te runnen. Ze zijn innovatief, hebben een frisse blik en zorgen voor bedrijvigheid en werkgelegenheid op het platteland. De weg ernaartoe is er echter één van puzzelen en uitdagingen aangaan. Want boer of tuinder worden: hoe pak je dat aan? Gedurende het project Startersboerderij is gewerkt aan een verkenning van deze uitdagingen. Waarom is het zo lastig om als nieuwe boer toe te treden tot de agrarische sector? Wat hebben starters nodig om succesvol te kunnen starten? Welke oplossingen dragen zij zelf aan en wat is hiervoor nodig? Welke rol kunnen huidige boeren zonder opvolgers hierin spelen?

Radboud University, 16 januari 2019, Promotores : Smits, P., Russel, F.G.M. Co-promotor : Wagener, F.A.D.T.G., Contains fulltext : 199081.pdf (publisher's version ) (Open Access)

Item does not contain fulltext, RATIONALE: COMMD (copper metabolism MURR1 domain)-containing proteins are a part of the CCC (COMMD-CCDC22 [coiled-coil domain containing 22]-CCDC93 [coiled-coil domain containing 93]) complex facilitating endosomal trafficking of cell surface receptors. Hepatic COMMD1 inactivation decreases CCDC22 and CCDC93 protein levels, impairs the recycling of the LDLR (low-density lipoprotein receptor), and increases plasma low-density lipoprotein cholesterol levels in mice. However, whether any of the other COMMD members function similarly as COMMD1 and whether perturbation in the CCC complex promotes atherogenesis remain unclear. OBJECTIVE: The main aim of this study is to unravel the contribution of evolutionarily conserved COMMD proteins to plasma lipoprotein levels and atherogenesis. METHODS AND RESULTS: Using liver-specific Commd1, Commd6, or Commd9 knockout mice, we investigated the relation between the COMMD proteins in the regulation of plasma cholesterol levels. Combining biochemical and quantitative targeted proteomic approaches, we found that hepatic COMMD1, COMMD6, or COMMD9 deficiency resulted in massive reduction in the protein levels of all 10 COMMDs. This decrease in COMMD protein levels coincided with destabilizing of the core (CCDC22, CCDC93, and chromosome 16 open reading frame 62 [C16orf62]) of the CCC complex, reduced cell surface levels of LDLR and LRP1 (LDLR-related protein 1), followed by increased plasma low-density lipoprotein cholesterol levels. To assess the direct contribution of the CCC core in the regulation of plasma cholesterol levels, Ccdc22 was deleted in mouse livers via CRISPR/Cas9-mediated somatic gene editing. CCDC22 deficiency also destabilized the complete CCC complex and resulted in elevated plasma low-density lipoprotein cholesterol levels. Finally, we found that hepatic disruption of the CCC complex exacerbates dyslipidemia and atherosclerosis in ApoE3*Leiden mice. CONCLUSIONS: Collectively, these findings demonstrate a strong inter

Item does not contain fulltext, The NF-kappaB family of transcription factors is essential for an effective immune response, but also controls cell metabolism, proliferation and apoptosis. Its broad relevance and the high connectivity to diverse signaling pathways require a tight control of NF-kappaB activity. To investigate the control of NF-kappaB activity by phosphorylation of the NF-kappaB p65 subunit, we generated a knock-in mouse model in which serine 467 (the mouse homolog of human p65 serine 468) was replaced with a non-phosphorylatable alanine (S467A). This substitution caused reduced p65 protein synthesis and diminished TNFalpha-induced expression of a selected group of NF-kappaB-dependent genes. Intriguingly, high-fat fed S467A mice displayed increased locomotor activity and energy expenditure, which coincided with a reduced body weight gain. Although glucose metabolism or insulin sensitivity was not improved, diet-induced liver inflammation was diminished in S467A mice. Altogether, this study demonstrates that phosphorylation of p65 serine 467 augment NF-kappaB activity and exacerbates various deleterious effects of overnutrition in mice.

Om alle bezoekers tegelijkertijd de weg te kunnen wijzen gebruiken vliegvelden pictogrammen, omdat deze niet taal-specifiek zijn. Iemands culturele afkomst kan echter wel een rol spelen bij het begrijpen van pictogrammen, evenals de ontwerpkenmerken ervan. In de literatuur is een debat gaande over de veronderstelde impact van culturele afkomst en mate van eenvoud van een pictogram op de begrijpelijkheid ervan. Dit onderzoek heeft als doelstelling inzicht te krijgen in de invloed van eenvoud op de mate waarop vliegveldpictogrammen begrijpelijk zijn voor Chinezen en Nederlanders. Uit het gedane experimenteel onderzoek, waarbij details toegevoegd zijn aan een set van achttien eenvoudige pictogrammen, is gebleken dat Nederlanders gedetailleerde pictogrammen beter begrijpen dan eenvoudige. Dit is onderzocht door de pictogrammen te verwerken in enquêtes waarbij zowel het objectieve als het subjectieve begrip is bevraagd. Opvallend was daarbij dat de pictogrammen niet als zodanig werden beoordeeld en dat de deelnemers beide pictogrammen ook als even eenvoudig beoordeelden. Over de Chinese deelnemers in dit onderzoek kan geen uitsluitsel gegeven worden, omdat het aantal hiervan te klein was om betrouwbare toetsen te kunnen doen. In vervolgonderzoek kan het interessant zijn om wel te kijken naar Chinese deelnemers en om meerdere pictogrammensets met uiteenlopende aantallen aan details te onderzoeken. Zo kan er onderzocht worden wat een groter aantal aan details voor impact heeft op de begrijpelijkheid.

Het Rotterdamse programma Rivier als Getijdenpark heeft twee doelstellingen: vergroten van de natuurlijke en recreatieve waarde van de Maasoevers en een toekomstbestendige inrichting van onze delta in relatie tot klimaatverandering. Twee potentiële locaties die in aanmerking komen zijn polder de Esch en het Eiland van Brienenoord. De potentiële natuurwinst van de mogelijke ingrepen en daarmee het belang van de verschillende inrichtingsscenario’s is nog niet voldoende in kaart gebracht. Dit rapport heeft als doel de potentiële biotische omstandigheden in relatie tot de verschillende scenario’s in beeld te brengen. Ook wordt bekeken hoe ingrepen kunnen bijdragen een verbetering van de ecologische waterkwaliteit voor de Kaderrichtlijn Water (KRW).