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Item does not contain fulltext, Background and objectives: In standard practice, sleep is classified into distinct stages by human observers according to specific rules as for instance specified in the AASM manual. We here show proof of principle for a conceptualization of sleep stages as attractor states in a nonlinear dynamical system in order to develop new empirical criteria for sleep stages. Methods: EEG (single channel) of two healthy sleeping participants was used to demonstrate this conceptualization. Firstly, distinct EEG epochs were selected, both detected by a MLR classifier and through manual scoring. Secondly, change point analysis was used to identify abrupt changes in the EEG signal. Thirdly, these detected change points were evaluated on whether they were preceded by early warning signals. Results: Multiple change points were identified in the EEG signal, mostly in interplay with N2. The dynamics before these changes revealed, for a part of the change points, indicators of generic early warning signals, characteristic of complex systems (e.g., ecosystems, climate, epileptic seizures, global finance systems). Conclusions :The sketched new framework for studying critical transitions in sleep EEG might benefit the understanding of individual and pathological differences in the dynamics of sleep stage transitions. Formalising sleep as a nonlinear dynamical system can be useful for definitions of sleep quality, i.e. stability and accessibility of an equilibrium state, and disrupted sleep, i.e. constant shifting between instable sleep states.

Item does not contain fulltext, Online learning environments are well-suited for tailoring the learning experience of children individually and on a large scale. An environment such as Math Garden allows children to practice exercises adapted to their specific mathematical ability; this is thought to maximize their mathematical skills. In the current experiment, we investigated whether learning environments should also consider the differential impact of cognitive load on children's math performance depending on their individual verbal working memory (WM) and inhibitory control (IC) capacity. A total of 39 children (8-11 years old) performed a multiple-choice computerized arithmetic game. Participants were randomly assigned to two conditions where the visibility of time pressure, a key feature in most gamified learning environments, was manipulated. Results showed that verbal WM was positively associated with arithmetic performance in general but that higher IC predicted better performance only when the time pressure was not visible. This effect was mostly driven by the younger children. Exploratory analyses of eye-tracking data (N = 36) showed that when time pressure was visible, children attended more often to the question (e.g., 6 × 8). In addition, when time pressure was visible, children with lower IC, in particular younger children, attended more often to answer options representing operant confusion (e.g., 9 × 4 = 13) and visited more answer options before responding. These findings suggest that tailoring the visibility of time pressure, based on a child’s individual cognitive profile, could improve arithmetic performance and may in turn improve learning in online learning environments.

Biologische actiefkoolfiltratie met zuurstofdosering (BODAC) blijkt medicijnen effectief te verwijderen uit rwzi-effluent. Het werkingsmechanisme en de praktische toepassingsmogelijkheden (processtappen, rendement, schaalgrootte en financiële en milieukosten) worden op dit moment nader onderzocht.

Sinds 2010 produceert NieuWater ultrapuur water uit effluent van de RWZI Emmen. Dit water wordt als proceswater geleverd aan de NAM in Schoonebeek. De biologische actieve koolfiltratie met zuurstofdosering (BODAC), die als voorzuivering gebruikt wordt, lijkt ook een veelbelovende techniek om geneesmiddelen te verwijderen.

Contains fulltext : 205471.pdf (publisher's version ) (Open Access), BACKGROUND: Anti-tumour necrosis factor (TNF) agents are effective in treating people with rheumatoid arthritis (RA), but are associated with (dose-dependent) adverse effects and high costs. To prevent overtreatment, several trials have assessed the effectiveness of down-titration compared with continuation of the standard dose. This is an update of a Cochrane Review published in 2014. OBJECTIVES: To evaluate the benefits and harms of down-titration (dose reduction, discontinuation, or disease activity-guided dose tapering) of anti-TNF agents on disease activity, functioning, costs, safety, and radiographic damage compared with usual care in people with RA and low disease activity. SEARCH METHODS: We searched MEDLINE, Embase, Web of Science and CENTRAL (29 March 2018) and four trial registries (11 April 2018) together with reference checking, citation searching, and contact with study authors to identify additional studies. We screened conference proceedings (American College of Rheumatology and European League Against Rheumatism 2005-2017). SELECTION CRITERIA: Randomised controlled trials (RCTs) and controlled clinical trials (CCTs) comparing down-titration (dose reduction, discontinuation, disease activity-guided dose tapering) of anti-TNF agents (adalimumab, certolizumab pegol, etanercept, golimumab, infliximab) to usual care/no down-titration in people with RA and low disease activity. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodology. MAIN RESULTS: One previously included trial was excluded retrospectively in this update because it was not an RCT/CCT. We included eight additional trials, for a total of 14 studies (13 RCTs and one CCT, 3315 participants in total) reporting anti-TNF down-titration. Six studies (1148 participants) reported anti-TNF dose reduction compared with anti-TNF continuation. Eight studies (2111 participants) reported anti-TNF discontinuation compared with anti-TNF continuation (three studies assessed both anti-TNF discont

Contains fulltext : 203210.pdf (publisher's version ) (Closed access)

Contains fulltext : 206732.pdf (publisher's version ) (Open Access)

Inaugurele rede uitgesproken bij de aanvaarding van het ambt van lector Duurzame Watersystemen aan hogeschool Van Hall Larenstein op vrijdag 1 november 2019. Voldoende en schoon zoetwater is van levensbelang. Toch is het niet vanzelfsprekend. Door intensivering landbouw, groei van bevolking en welvaart, neemt het gebruik van schoon zoetwater toe. Tegelijkertijd komen grond- en oppervlaktewater meer onder druk te staan van vervuiling, zoals nutriënten, gewasbeschermingsmiddelen, geneesmiddelen en andere microverontreinigingen. Bovendien leidt klimaatverandering tot een nieuwe dynamiek in verdamping en neerslag. Dit spanningsveld is het werkveld van het lectoraat Sustainable water systems. Via toegepast onderzoek draagt het lectoraat bij aan het veiligstellen van voldoende schoon zoetwater voor drinkwater, natuur, landbouw, recreatie en industrie.

Rioolwaterzuiveringen zijn de belangrijkste bron van geneesmiddelen en kunstmatige zoetstoffen in oppervlaktewater. De mate waarin rwzi’s deze organische microverontreinigingen verwijderen, lijkt te variëren van locatie tot locatie en/of in de tijd. Oriënterend onderzoek bij zeven rwzi’s in Groningen en Drenthe toonde aan dat de verwijdering van de zoetstof acesulfaam varieerde: van volledige verwijdering (>99%) op de rwzi in Assen tot minder dan 40 procent op de rwzi in Gieten. Bovendien bleek dat de verwijdering van acesulfaam volledig is gebaseerd op biologische afbraak. Duits onderzoek heeft aangetoond dat de afbraak van acesulfaam sterk kan variëren in de tijd, maar dat er geen verband bestaat met de nitrificatiesnelheid en temperatuur.

Lozingen van gezuiverd industrieel afvalwater kunnen soms een bedreiging vormen voor de kwaliteit van het ontvangende oppervlaktewater. Online bewaking met biologische meetsystemen (biomonitoring) kan helpen bij het vroegtijdig detecteren van veranderingen in de effluentkwaliteit die mogelijk leiden tot verhoogde toxiciteitsdruk op het ontvangende oppervlaktewater. Onderzoek door het Centre of Expertise Water Technology (CEW) en WLN heeft duidelijk gemaakt dat de selectie en implementatie van online biomonitoren ten behoeve van waterkwaliteitsbewaking maatwerk is. Dit artikel gaat in op de praktische toepasbaarheid van biologische bewakingssystemen op het effluent van de Integrale Afvalwater Zuiveringsinstallatie (IAZI) van Sitech in Geleen.

Sinds 2010 produceert Nieuwater ultrapuur water uit effluent van de RWZI Emmen. Dit water wordt als proceswater geleverd aan de NAM in Schoonebeek. Op basis van bijna 10 jaar ervaring kan worden geconcludeerd dat RWZI-effluent een prima bron is voor industriewater, zeker wanneer grond- en oppervlaktewater relatief schaars zijn.

Radboud University, 29 mei 2018, Promotor : Hoogen, F.H.J. van den Co-promotores : Maas, A. van der, Broeder, A.A. den, Contains fulltext : 190671.pdf (publisher's version ) (Open Access)

Contains fulltext : 246750.pdf (Publisher’s version ) (Open Access), Molenaar's manifesto on psychology as idiographic science (Molenaar, 2004) brought the N=1 times series perspective firmly to the attention of developmental scientists. The rich intraindividual variation in complex developmental processes requires the study of these processes at the level of the individual. Yet, the idiographic approach is all but easy in practical research. One major limitation is the collection of short interval times series of high quality data on developmental processes. In this paper, we present a novel measurement approach to this problem. We developed an online practice and monitoring system which is now used by thousands of Dutch primary school children on a daily or weekly basis, providing a new window on cognitive development. We will introduce the origin of this new instrument, called Math Garden, explain its setup, and present and discuss ways to analyze children’s individual developmental pathways.

Er is een groeiend besef dat geneesmiddelen een probleem (kunnen) vormen voor de oppervlaktewater- en grondwaterkwaliteit. Mede in dit kader is er behoefte aan kwantitatieve tracers waarmee de belasting van watersystemen met huishoudelijk afvalwater c.q. RWZI effluent bepaald kan worden. Daarnaast is in 2016 het RIVM rapport ‘Geneesmiddelen en Waterkwaliteit’ verschenen. Naar aanleiding van dit rapport is de vraag gerezen wat de omvang van het probleem van geneesmiddelen in de praktijk is en hoe zich dat verhoudt tot een andere groep organische microverontreinigingen: gewasbeschermingsmiddelen. Daarom is in de samenwerking Waterketen Onderzoek Noord verkennend onderzoek uitgevoerd naar geneesmiddelen en zoetstoffen in grond- en oppervlaktewater in Noord Nederland. De centrale onderzoeksvragen: 1. Wat is het aandeel RWZI effluent op verschillende locaties in het watersysteem en kunnen we dit goed meten met bepaalde tracers? 2. Hoe verhouden de concentraties geneesmiddelen zich tot de concentraties gewasbeschermingsmiddelen in grond- en oppervlaktewater?

Het doel van het onderzoek is het verkrijgen van een eerste indruk van de kwaliteit van drainagewater van kunstgrasvelden, om op basis daarvan te kunnen besluiten of aanvullend onderzoek gewenst is en hoe het aanvullend onderzoek vorm zou moeten krijgen. De kwaliteit van drainagewater van een aantal kunstgrasvelden is vergeleken met run-off water van wegen. Dit run-off water is als referentie gebruikt omdat logischerwijs mag worden verwacht dat dit water ook vervuild is als gevolg van slijtage van autobanden, d.w.z. de grondstof voor rubbergranulaat.

In Leeuwarden, Groningen en Assen is de toepasbaarheid van sensortechnologie voor het sturen van rioolwater op basis van waterkwaliteit onderzocht. Dit met het oog op optimalisering van de hydraulische capaciteit van gemengde rioolstelsels en de ontvangende RWZI’s. De centrale vragen: (1) bieden eenvoudige waterkwaliteitssensoren voldoende informatie om (in hevige regenweersituaties) sterk verdund rioolwater gecontroleerd te lozen op oppervlaktewater en (2) onder welke condities biedt deze Real Time Control substantiële winst op de afvoercapaciteit van gemengde stelsels? Uit de resultaten blijkt dat het real-time sturen van rioolwater in gemengde stelsels op basis van waterkwaliteit kansen biedt in specifieke situaties.

Systeeminnovatie leidt tot sterk verminderde afhankelijkheid van chemische gewasbescherming, mét behoud van marktpositie voor de teler.

Contains fulltext : 174699.pdf (publisher's version ) (Open Access), OBJECTIVE: In a randomised controlled trial investigating tapering of TNF inhibitors (TNFi) compared with usual care (UC) in rheumatoid arthritis patients, minimal radiographic progression was more frequent in patients who attempted tapering. Possible explanations include higher incidence of flaring, higher mean disease activity or lower TNFi use. METHODS: 18 months data from the DRESS study were used. Change in Sharp-van der Heijde (DeltaSvdH) score (linear regression) and proportion of patients with >0.5 DeltaSvdH (logistic regression) were used as outcomes. The cumulative incidence and number of short-lived and major flares per patient, mean time-weighted disease activity (MTW-DAS28-CRP) and TNFi use were used as independent variables. Regression models were performed stratified per study group and corrected for possible confounders. RESULTS: 175 of 180 patients had 18-month data available. The mean DeltaSvdH were 0.75 and 0.15 units with 37 of 116 (32%) and 9 of 59 (15%) patients exceeding 0.5 points in the tapering and UC group, respectively (both p<0.05). MTW-DAS28-CRP, but not incidence or number of short-lived or major flares, or TNFi use, was independently associated with the mean progression score, but only in the tapering group. Additional analyses on DAS28-CRP subcomponents showed that this was mainly caused by MTW swollen joint count. No confounders were identified. CONCLUSIONS: Radiographic progression was associated with higher MTW-DAS28-CRP (and especially swollen joint count), but only in patients who tapered TNFi. This finding stresses the importance of maintaining disease activity as low as possible in patients in whom TNFi is tapered and to check for radiographic progression regularly. TRIAL REGISTRATION NUMBER: NTR 3216; Post-results.

Item does not contain fulltext, BACKGROUND: To evaluate if TNF inhibitor serum drug levels (DL) or anti-drug antibodies (ADAb) can predict successful dose reduction (in patients with high DL) or discontinuation (in patients with no/low DL or ADAb) in rheumatoid arthritis (RA) patients. RESEARCH DESIGN AND METHODS: RA patients that were using adalimumab (n = 42), etanercept (n = 76) or infliximab (n = 51) and were doing well, were tapered until discontinuation or flare (1-1.5 year follow up). Random timed DL for adalimumab and etanercept and trough DL for infliximab were measured before dose reduction: Receiver-Operator-Curves (ROC) analyses with optimal cut-off DL were determined. RESULTS: No predictive value of adalimumab and infliximab DL for all outcomes were found, except for an inverse association of lower etanercept DL and higher chance for successful dose reduction (Area Under the Curve (AUC) 0.36, 95% CI 0.23-0.49; cut-off <2.6 mg/l). In sub analyses, higher adalimumab trough DL predicted successful dose reduction (AUC 0.86, 0.58-1.00; cut-off >7.8). ADAb were infrequent and not predictive of successful discontinuation. CONCLUSIONS: No predictive value of baseline adalimumab, etanercept and infliximab DL or ADAb for successful dose reduction or discontinuation in RA was found in this context, with the possible exception of high adalimumab trough levels for successful dose reduction.

Item does not contain fulltext, AIMS: The morphometry of the distal femur was largely studied to improve bone-implant fit in total knee arthroplasty (TKA), but little is known about the asymmetry of the posterior condyles. This study aimed to investigate the dimensions of the posterior condyles and the influence of externally rotating the femoral component on potential prosthetic overhang or under-coverage. PATIENTS AND METHODS: We analysed the shape of 110 arthritic knees at the time of primary TKA using pre-operative CT scans. The height and width of each condyle were measured at the posterior femoral cut in neutral position, and in 3 masculine and 5 masculine of external rotation, using both central and medial referencing systems. We compared the morphological characteristics with those of 14 TKA models. RESULTS: In the neutral position, the dimensions of the condyles were nearly equal. Externally rotating the femoral cut by 3 masculine and 5 masculine with 'central referencing' induced width asymmetry > 3 mm in 23 (21%) and 33 (30%) knees respectively, while with 'medial referencing' it induced width asymmetry > 3 mm in 43 (39%) and 75 (68%) knees respectively. The asymmetries induced by rotations were not associated with gender, aetiology or varus-valgus alignment. CONCLUSION: External rotation may amplify the asymmetry between the medial and lateral condyles, and exacerbate prosthetic overhang, particularly in the superolateral zone. 'Central referencing' guides result in less potential prosthetic overhang than 'medial referencing' guides. Cite this article: Bone Joint J 2017;99-B:894-903.

Contains fulltext : 175617.pdf (publisher's version ) (Closed access), BACKGROUND: Both cervical esophagogastric anastomosis (CEA) and intrathoracic esophagogastric anastomosis (IEA) are used to restore gastrointestinal integrity following minimally invasive esophagectomy (MIE). No prospective randomized data on functional outcome, postoperative morbidity, and mortality between these techniques are currently available. METHODS: A comparison was conducted including all consecutive patients with esophageal carcinoma of the distal esophagus or gastroesophageal junction undergoing MIE with CEA or MIE with IEA from October 2009 to July 2014 in 3 high-volume esophageal cancer centers. Functional outcome, postoperative morbidity, and mortality were analyzed. RESULTS: MIE with CEA was performed in 146 patients and MIE with IEA in 210 patients. The incidence of recurrent laryngeal nerve palsy was 14.4% after CEA and 0% after IEA (p < 0.001). Dysphagia, dumping, and regurgitation were reported less frequently after IEA compared with CEA (p < 0.05). Dilatation of benign strictures occurred in 43.8% after CEA and this was 6.2% after IEA (p < 0.001). If a benign stricture was identified, it was dilated a median of 4 times in the CEA group and only once in the IEA group (p < 0.001). Anastomotic leakage for which reoperation was required occurred in 8.2% after CEA and in 11.4% after IEA (not significant). Median ICU stay, hospital stay, in-hospital mortality, 30-day mortality, and 90-day mortality were similar between the groups (not significant). CONCLUSIONS: MIE with IEA was associated with better functional results than MIE with CEA with less dysphagia, less benign anastomotic strictures requiring fewer dilatations, and a lower incidence of recurrent laryngeal nerve palsy. Other postoperative morbidity and mortality did not differ between the groups.

Item does not contain fulltext, Objective.: The aim was to evaluate the predictive value of the baseline multi-biomarker disease activity (MBDA) score in long-standing RA patients with low disease activity tapering TNF inhibitors (TNFi) for successful tapering or discontinuation, occurrence of flare and major flare, and radiographic progression. Methods.: Dose REduction Strategies of Subcutaneous TNF inhibitors (Dutch Trial Register, NTR 3216) is an 18-month non-inferiority randomized controlled trial comparing tapering of TNFi until discontinuation or flaring with usual care (UC) in long-standing RA patients with stable low disease activity. Flare was defined as DAS28-CRP increase >1.2 or >0.6 if current DAS 3.2; major flare was a flare lasting >3 months, despite treatment intervention. MBDA scores were measured at baseline. Radiographs were scored at baseline and 18 months using the Sharp-van der Heijde score. The area under the receiver operating characteristic (AUROC) curve was used to analyse the capability of baseline MBDA score to predict the above-mentioned outcomes. Results.: Serum samples and outcomes were available for 171 of 180 patients from Dose REduction Strategies of Subcutaneous TNF inhibitors (115 tapering; 56 UC). AUROC analyses showed that baseline MBDA score was not predictive for the above-mentioned clinical outcomes in the taper group, but did predict major flare in the UC group (AUROC = 0.72, 95% CI: 0.56, 0.88). Radiographic progression was minimal and was not predicted by MDBA score. Conclusion.: In this disease activity-guided strategy study of TNFi tapering in RA patients with low disease activity, baseline MBDA score was not predictive for successful tapering, discontinuation, flare, major flare or radiographic progression in patients who tapered TNFi.

In dit onderzoek wordt ingegaan op vroegchristelijke identiteitsconstructie, aan de hand van de tweede- of derde eeuwse tekst Octavius, geschreven door Marcus Minucius Felix. Door gebruik van sociaalpsychologisch onderzoek naar intergroup relations – oftewel: de manieren waarop relaties tussen maatschappelijke groepen werken – is een bijdrage getracht te leveren aan het debat omtrent de vraag in hoeverre binnen vroegchristelijke teksten sprake is van identiteitsconstructie in overeenstemming met de realiteit. Hieruit zal blijken dat zowel mentale processen als de apologetische traditie waarbinnen Minucius schreef van invloed waren op zijn constructie van een christelijke identiteit.

In dit project is de potentie van sensortechnologie voor het actief sturen van rioolwater in gemengde stelsels op basis van waterkwaliteit oriënterend onderzocht. De gedachte is dat, in geval van hevige neerslag, het rioolwater zover wordt verdund met (schoon) regenwater, dat het via Real Time Control (RTC) kan worden geloosd op (ruim) oppervlaktewater zonder dat dit leidt tot waterkwaliteitsproblemen. Hiermee wordt zowel het rioolstelsel als de RWZI ontlast. De potentiële winst zit dan in (1) het voorkomen van overstorten op kritische locaties, (2) het verminderen van de netto vuilemissie naar het oppervlaktewater en (3) het verminderen van pomp- en beluchtingsenergie voor zuivering en transport van rioolwater.

Kunstmatige zoetstoffen als acesulfaam komen via urine in huishoudelijk afvalwater terecht. Acesulfaam stond tot voor kort te boek als persistente stof. Onderzoek van noordelijke waterschappen en waterbedrijven laat echter zien dat de stof wel degelijk afgebroken wordt in RWZI’s, maar ook dat de mate van verwijdering sterk varieert tussen RWZI’s. De biologische afbraak van de zoetstof is blijkbaar afhankelijk van lokale factoren. De resultaten werpen een nieuw licht op de verwijdering van microverontreinigingen in RWZI’s.

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Contains fulltext : 172326.pdf (publisher's version ) (Closed access), BACKGROUND: A disease activity-guided dose optimisation strategy of adalimumab or etanercept (TNFi (tumour necrosis factor inhibitors)) has shown to be non-inferior in maintaining disease control in patients with rheumatoid arthritis (RA) compared with usual care. However, the cost-effectiveness of this strategy is still unknown. METHOD: This is a preplanned cost-effectiveness analysis of the Dose REduction Strategy of Subcutaneous TNF inhibitors (DRESS) study, a randomised controlled, open-label, non-inferiority trial performed in two Dutch rheumatology outpatient clinics. Patients with low disease activity using TNF inhibitors were included. Total healthcare costs were measured and quality adjusted life years (QALY) were based on EQ5D utility scores. Decremental cost-effectiveness analyses were performed using bootstrap analyses; incremental net monetary benefit (iNMB) was used to express cost-effectiveness. RESULTS: 180 patients were included, and 121 were allocated to the dose optimisation strategy and 59 to control. The dose optimisation strategy resulted in a mean cost saving of -euro12 280 (95 percentile -euro10 502; -euro14 104) per patient per 18 months. There is an 84% chance that the dose optimisation strategy results in a QALY loss with a mean QALY loss of -0.02 (-0.07 to 0.02). The decremental cost-effectiveness ratio (DCER) was euro390 493 (euro5 085 184; dominant) of savings per QALY lost. The mean iNMB was euro10 467 (euro6553-euro14 037). Sensitivity analyses using 30% and 50% lower prices for TNFi remained cost-effective. CONCLUSIONS: Disease activity-guided dose optimisation of TNFi results in considerable cost savings while no relevant loss of quality of life was observed. When the minimal QALY loss is compensated with the upper limit of what society is willing to pay or accept in the Netherlands, the net savings are still high. TRIAL REGISTRATION NUMBER: NTR3216; Post-results.

Although in the past decennium much research has been conducted in the field of software ecosystems, still little is known about how such ecosystems evolve. In existing literature, software ecosystems are often analyzed from a single point of time, without regard for their dynamic history. We study an aspect of the evolution of open source software ecosystems: collaboration. In this thesis, we present a method to identify and analyze collaboration networks in software ecosystems, based on historical data from the online source code hosting service GitHub. We apply this method to analyze the evolution of collaboration within the well-established open source ecosystem around the Ruby programming language. Our method can be used to identify and visualize collaboration networks around a given actor or software component over the course of time. This is done using statistical analysis techniques, without requiring subjective input. Our study analyzes over 200 collaboration networks to identify typical life cycle shapes and gives insight in the evolution an open source software ecosystem. Awareness of such collaboration networks and how they evolve is beneficial for actors in software ecosystems and for external stakeholders.