Leiden University Scholary Publications
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Associations between common genetic variants and income provide insights about the socio-economic health gradient
Get PDFWe conducted a genome-wide association study on income among individuals of European descent (N = 668,288) to investigate the relationship between socio-economic status and health disparities. We identified 162 genomic loci associated with a common genetic factor underlying various income measures, all with small effect sizes (the Income Factor). Our polygenic index captures 1–5% of income variance, with only one fourth due to direct genetic effects. A phenome-wide association study using this index showed reduced risks for diseases including hypertension, obesity, type 2 diabetes, depression, asthma and back pain. The Income Factor had a substantial genetic correlation (0.92, s.e. = 0.006) with educational attainment. Accounting for the genetic overlap of educational attainment with income revealed that the remaining genetic signal was linked to better mental health but reduced physical health and increased risky behaviours such as drinking and smoking. These findings highlight the complex genetic influences on income and health.Public Health and primary carePrevention, Population and Disease management (PrePoD
Primary and secondary resistance mechanisms in EGFR mutated non-small cell lung cancer
Get PDFThe primary goals of this thesis were to gain insights in primary and secondary resistance mechanisms in patients with EGFR mutated NSCLC and to develop new treatment strategies. The first part focuses on a specific subgroup of patients with an EGFR exon 20 insertion mutation. We reptrospectively and prospectively analyzed the activity of two different treatment regimens: (high dose) osimertinib and afatinib in combination with cetuximab, respectively. Osimertinib 80 mg once daily was not effective with a response rate of 5%. High dose osimertinib resulted in an overall response rate of 28%, however, this study did not meet its primary endpoint. The combination of afatinib and cetuximab was promising in a retrospective series of four patients. Three of four patients showed a partial repsonse. These results led to dedicated trial in which 37 patients were treated with this combination with modest activity. The second part focusses on genomic profiling of resistance mechanisms after treatment with a third generation EGFR TKI. In addition, we investigated the activity of combination treatment after cMET driven resistance. The addition of crizotinib to a third generation EGFR TKI proved effective with a response rate of 50%; however, responses were short-lasting and often heterogeneous.LUMC / Geneeskund
Intelligence for a complex environment: transforming traditional intelligence with insights from complexity science and field research on NATO
Get PDFThis study asserts that complexity science, the study of systems that are complex and adaptive, holds many promises for examining the threats in the operational environment as well as intelligence organisations themselves. While this may seem a logical deduction, the study of intelligence has yet to adopt the ideas and methods of complexity science. Therefore this study aims to seek insights from complexity science and to apply these to intelligence. In doing so it strives for a theoretical and also an empirical contribution to the study of intelligence. The latter is formed by case study research into how NATO’s Multinational Corps Northeast (MNC NE) organises its intelligence. This is guided with the research question How can complexity science advance intelligence transformation?The research shows that complexity science offers alternative insights, tested in broader military sciences and other related fields, to improve intelligence performance. With complexity, a new intelligence paradigm is formulated, and contrasted to the traditional intelligence paradigm. To apply this, three design properties (requisite variety, sensemaking, and organisational learning) show how concepts from complexity can help to move from the traditional to the new, complex intelligence paradigm.Koninklijke Landmacht/Ministerie van DefensieSecurity and Global Affair
Why you should not use CI to evaluate socially disruptive technology
Get PDFContextual Integrity (CI) is built to assess potential privacy violations of new sociotechnical systems and practices. It does so by evaluating their respect for the context-relative informational norms at play in a given context. But can CI evaluate new sociotechnical systems that severely disrupt established social practices? In this paper, I argue that, while CI claims to be able to assess privacy violations of all sociotechnical systems and practices, it cannot assess the ones that cause severe changes and disruptions in the norms and values of a given context. These types of technology are known as socially disruptive technologies (SDTs) and this paper argues that they are beyond CI’s scope. It follows that at best, a privacy assessment of those technologies by CI would be useless and, at worst, lead to potential harm, including failure to identify privacy violations and unwarranted legitimisation of privacy-threatening technology. Government actors, policymakers, and academics should refrain from relying on CI to assess this type of technology.Political Philosophy and Ethic
Parenthood, gender and turning points to crime for young people in Latin America
Get PDFSecurity and Global Affair
Daad en discussie: links geweld: de invloed van interne discussie en overheidsrespons
Get PDFDit proefschrift betreft een historiografie van drie categorieën radicaal-linkse actievoerders in de periode 1965-2015: de marxistisch-leninistische Rode Jeugd, Rode Hulp en Rood Verzetsfront (tot eind jaren tachtig); de anti-imperialistische 'oude' Beweging (jaren tachtig en negentig) en de 'nieuwe' single issue Beweging sinds circa 2000). Het proefschrift betreft de in feite eerste beschrijving van de zich illegaal manifesterende linkse extremisten, die zich door hun geweld onderscheiden van de brede gematigde Beweging. Deze radicale personen en groepen zijn zichtbaar gemaakt door gebruik van een groot aantal inlichtingenbronnen, die via de Wob zijn verkregen. Via deze humint en techint is de drempel van de omerta - extremisten weigeren te spreken met wetenschappers uit angst dat hun informatie zo bij inlichtingendiensten en opsporingsinstanties terechtkomt - omzeild. Naast de belangrijke bewegingsinterne discussie over de onwenselijkheid van geweldsgebruik is aandacht besteed aan de 'Dutch Approach', de aanpak van de autoriteiten, die werd gekenmerkt door een zo lang mogelijk coulante houding ten opzichte van ook extremisten. Buitensporige repressie, zoals bijvoorbeeld in Duitsland jegens de Rote Armee Fraktion en haar sympathisanten, is hier achterwege gebleven. Het onderzoek heeft tevens nader zicht geboden op de werkelijke intenties van diverse (zich geweldloos noemende) actievoerders, maar bijvoorbeeld ook de criminele activiteiten van RaRa ten behoeve van terroristische bewegingen in Zuid-Amerika blootgelegd. Dit alles dank zij de van inlichtingendiensten verkregen informatie. Security and Global Affair
T-cell gene therapy for low mutational burden cancer
Get PDFT-cell gene therapy is a relatively new immunotherapeutic strategy to treat cancer. Where immune checkpoint inhibition demonstrates promising results in cancer with a high mutational burden, cancers with a low mutational burden respond less well. For these cancers, T-cell gene therapy might be an attractive alternative. In this thesis, uveal melanoma and synovial sarcoma are described as favorable targets for T-cell gene therapy targeting PRAME. Furthermore, the immune tumor microenvironment of synovial sarcoma is studied in depth.LUMC / Geneeskund
Do P-glycoprotein-mediated drug-drug interactions at the blood-brain barrier impact morphine brain distribution?
Get PDFP-glycoprotein (P-gp) is a key efflux transporter and may be involved in drug-drug interactions (DDIs) at the blood-brain barrier (BBB), which could lead to changes in central nervous system (CNS) drug exposure. Morphine is a P-gp substrate and therefore a potential victim drug for P-gp mediated DDIs. It is however unclear if P-gp inhibitors can induce clinically relevant changes in morphine CNS exposure. Here, we used a physiologically-based pharmacokinetic (PBPK) model-based approach to evaluate the potential impact of DDIs on BBB transport of morphine by clinically relevant P-gp inhibitor drugs.The LeiCNS-PK3.0 PBPK model was used to simulate morphine distribution at the brain extracellular fluid (brainECF) for different clinical intravenous dosing regimens of morphine, alone or in combination with a P-gp inhibitor. We included 34 commonly used P-gp inhibitor drugs, with inhibitory constants and expected clinical P-gp inhibitor concentrations derived from literature. The DDI impact was evaluated by the change in brainECF exposure for morphine alone or in combination with different inhibitors. Our analysis demonstrated that P-gp inhibitors had a negligible effect on morphine brainECF exposure in the majority of simulated population, caused by low P-gp inhibition. Sensitivity analyses showed neither major effects of increasing the inhibitory concentration nor changing the inhibitory constant on morphine brainECF exposure. In conclusion, P-gp mediated DDIs on morphine BBB transport for the evaluated P-gp inhibitors are unlikely to induce meaningful changes in clinically relevant morphine CNS exposure. The developed CNS PBPK modeling approach provides a general approach for evaluating BBB transporter DDIs in humans.Horizon 2020(H2020)Pharmacolog
Advancing waste valorization and end-of-life strategies in the bioeconomy through multi-criteria approaches and the safe and sustainable by design framework
Get PDFProper waste management is a key element in the transition to a sustainable bioeconomy. Population growth and the demand for food and services have led to an ever-increasing production of biotic waste whose disposal in landfills is no longer considered a sustainable option. For this reason, efforts are being made to find an appropriate management strategy for biotic waste, whose organic content allows it to be considered as a resource for the development of biotechnological and/or biorefinery processes. Assessing the sustainability of alternative options is of paramount importance. To this end, this systematic review researches trends in waste management in terms of technology and sustainability profile according to the life-cycle approach and multi-criteria analysis. The aim is to provide insights into potential resource recovery and waste valorization schemes towards high-value-added products in the marketplace, beyond their direct energy recovery. Our results show that future studies should focus on the development of multi-criteria analysis from an SSbD perspective, so that all pillars of sustainability and risk assessment are properly assessed from an early design stage.Industrial Ecolog