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Contains fulltext : 241557.pdf (Publisher’s version ) (Open Access) Radboud University, 27 januari 2022 Promotor : Hoogen, F.H.J. van den Co-promotores : Maas, A. van der, Broeder, A.A. den 152 p.

Antimicrobial resistance (AMR) has been considered one of the major challenges to global public health, and it is now seen as a One Health concept, under which people’s health is connected to the health of animals and their shared environment. Agriculture contributes to the emergence and spread of antibiotic resistance genes (ARGs) and antibiotic residues in the environment as manure from (intensive) livestock production is widely used as fertilizer. Despite being a nutrient-rich and stable organic carbon source, the application of animal manure also results in the introduction of manure-derived bacteria and their ARGs into the soil, enriching the already occurring set of ARGs. The fate of ARGs in the environment, particularly in farmlands, is not yet clear, and this thesis set out to investigate ARG proliferation in microbial communities in the agricultural chain, from the animal gut to water (manure, soil, and water), and the extent of ARG transfer potential. Understanding the main factors driving ARG dissemination in farmlands will help define concrete points of action that aim to mitigate the spread of AMR at the farm level. Chapter 2 evaluated the soil texture’s role on ARG dynamics in manured soils and surrounding surface waters. It was demonstrated that rather than showing similar decay dynamics, factors such as the type of ARG and soil texture drive the ARG persistence in the environment. Chapter 3 explored the dynamics of bacteria and ARGs introduced by manuring to soils and adjacent water ditches, both at the community and individual scale, over three weeks. It showed that the bacteriome and resistome structures are shaped by different factors, where the bacterial community composition could not explain the changes in ARG diversity or abundances. Additionally, it also highlighted the potential of applying targeted metagenomic techniques, such as ResCap, to study the fate of AMR in the environment. Chapter 4 examined the ARG removal potential of a manure treatment process using a newly designed up-flow anaerobic sludge bed reactor operating at thermophilic conditions. It indicated that this treatment successfully removes some, but not all, bacterial groups. It also showed that the abundance of the selected ARGs was not reduced. Chapter 5 assessed how conjugation frequencies between E. coli strains in filter matings differ based on the temperature and nutrient availability. It showed that, despite less favorable conditions, plasmid transfer can occur in the environment. Therefore, fecal microorganisms in manure can be a source of AMR transmission. Chapter 6 investigated the fate of plasmids in manured soil microcosms introduced by fecal microorganisms over time. While being a laboratory simulation, it provided realistic quantifications of conjugation frequencies, and it identified the new hosts of the transferred plasmids. In the end, the findings reported throughout the thesis were discussed and the implications of research outcomes were contextualized. Action points to reduce the farm burden in environmental AMR spread were suggested.

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

In the treatment of rheumatoid arthritis (RA), optimal individual dosing of biologic disease modifying antirheumatic drugs (bDMARDs) is warranted, because of their increased risk of (dose dependent) adverse effects and high costs. The bDMARDs available for RA have their own pharmacological characteristics and subsequently need different strategies to reach the lowest effective dose. Different rituximab retreatment strategies are being used in clinical practice.We investigated another possible rituximab treatment strategy; retreatment when there is loss of response, and thereafter using a fixed interval based on the first response duration, in seventy RA patients treated with at least three rituximab courses. Limits of agreement between intervals were large, therefore we concluded that duration of response after the first rituximab course is not a useful parameter in timing of retreatment. Only limited data exists on dose reduction of tocilizumab in patients with RA and low disease activity. We investigated the feasibility of reducing the dose of tocilizumab in 22 patients with RA and low disease activity from 8mg/kg to 4mg/kg every 4 weeks. After 6 months, 55% of patients had successfully reduced the dose without losing disease control. All patients who experienced worsening of disease activity after dose reduction regained low disease activity after dose escalation. Disease activity guided dose reduction of tocilizumab thus seems to be feasible in a relevant proportion of patients. To summarise the research previously performed on dose reduction and discontinuation of anti-TNF agents, we conducted a systematic literature review of randomised controlled trials and controlled clinical trials comparing down titration of anti-TNF agents to usual care/no down titration in RA patients and a low disease activity state.Based on the results of this systematic review, we designed and conducted a pragmatic, non-inferiority, randomised controlled trial on tapering and discontinuation of the subcutaneous anti-TNF agents adalimumab and etanercept in RA patients with low disease activity (the DRESS study). 180 RA patients in low disease activity using adalimumab or etanercept were randomised to a disease activity guided tapering strategy or usual care. Dose reduction consisted of stepwise increases of injection intervals 3 monthly until flare in disease activity or discontinuation, with the possibility to escalate or restart in case of flare of disease activity. The primary outcome was the difference in proportions of patients with major flare (flare > 3 months) between the two groups at 18 months. Dose reduction was shown to be non-inferior to usual care, with the difference in major flare being 2% (95% CI -12% to 12%). Anti-TNF agent could successfully be stopped in 20% of patients, the interval successfully increased in 43%. Functional status, quality of life and clinically relevant radiographic progression were not different between the groups. Mean costs were €9,038 lower per patient in the dose reduction group. A disease activity guided tapering strategy of adalimumab and etanercept is therefore non-inferior to usual care for major flare and other clinical outcomes, while being clearly superior in cost-effectiveness. No predictors for successful tapering were found, including (anti) drug levels.

The fight against an untimely death is an element of medical science which comes to the fore especially with cardiopulmonary resuscitation. A successful resuscitation constitutes a victory over death. Hence modem resuscitation techniques are considered one of the breakthroughs which advanced medical science has offered humanity. The importance of resuscitation is reinforeed by the fact that everyone eventually dies. For everyone there is the moment when heartbeat and/or respiration fails. Thus all humanity is a possible candidate for resuscitation. However, resuscitation has its drawbacks. Resuscitation is more often than not unsuccessful and practising it involves some technical violence. When the resuscitation attempt is not successful, than the process of dying can be severely disturbed while nothing positive can be attributed to the intervention. Moreover, not for all people death needs to be fought with all possible force. In short, somelimes it is better not to resuscitate at all. The question which then needs to be faced is 'when not to resuscitate?'. This question is the subject of the present dissertation. An added problem is the fact that the decision to resuscitate needs to be taken quickly. Hence the question 'should this patient be resuscitated or not?' must be answered when there is time to think it over. When this kind of decision-making process leads to the decision not to intervene, a DO NOT RESUSCITATE-decision has been taken. The central issue of this thesis is: Which grounds allow a DNR-decision to be taken. This matter derives its moral importance from the fact that by taking a DNR-decision one takes the responsibility that the decision may shorten a patient's life. The objective of this study is not limited to a norrnalive analysis of the reasons not to resuscitate. The aim is to offer some considerations with which to fonnulate a DNR-policy as well. In another aspect the study is limited: the answers to the questions poscd are aimed at taking DNR-decisions in hospitals and for patients who have reached majority.