Contrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken... Show moreContrary to common belief, sign languages are distinct across different communities and cultures, evolving organically through interactions among deaf people, rather than being based on spoken languages. Each sign language has its own grammar, vocabulary, and cultural nuances, with variations even within a single country, showcasing the diverse communication methods within the deaf community. Deaf individuals often face encouragement to use spoken language techniques like lipreading or text communication, highlighting a bias towards spoken languages. This is compounded by the lack of sign languages in linguistic technologies, emphasizing the need for more inclusive research and development. This dissertation aims to address this gap using machine and deep learning to improve sign language processing and recognition. It covers six chapters, introducing methods for video-based sign annotation, webcam-based sign language dictionary search, and ranking systems for sign suggestions. It also explores tools for visualizing and comparing sign language variation, contributing valuable resources to linguistic research. Show less
Palliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of... Show morePalliative care is care improving the quality of life of patients and their families, who are facing a life-threatening condition or frailty, through prevention and relief of suffering by means of early identification and careful assessment, and treatment of problems of a physical, psychological, social, and spiritual nature. This thesis describes five studies that evaluated the support of clinicians not specialized in palliative care, or generalists in palliative care. The results show that generalists need education on basic palliative care principles and need support with the initiation of a palliative care approach on time, especially when they care for patients with life-limiting illness other than cancer. To have mor attention for alle problems in the physical, psychological, social and spiritual dimension of care, they can be supported with a more structured approach to the total burden of symptoms and problems. This could be achieved by supporting them with a clinical decision support system for symptom management in palliative care. Such a system can be used for every individual patient, includes a symptom predictor, and provides recommendations on treatment and referral possibilities. Show less
Rede uitgesproken door Prof. dr. Pieter ter Keurs ter gelegenheid van zijn afscheid als Hoogleraar Museums, Collections and Society aan de Universiteit Leiden op maandag 8 april 2024
In Noord-Holland zijn zeer gevaarlijke en verboden stoffen aangetroffen in het water. Het gaat om het onkruidbestrijdingsmiddel dinoterb en de insecticide fenchloorfos. Op de vergadering van het... Show moreIn Noord-Holland zijn zeer gevaarlijke en verboden stoffen aangetroffen in het water. Het gaat om het onkruidbestrijdingsmiddel dinoterb en de insecticide fenchloorfos. Op de vergadering van het waterschap spraken heel veel geschrokken burgers hun zorgen uit. Over gif in de regenton, of ze nog wel kunnen zwemmen in openbaar water en of het drinkwater wel veilig is. Een verslag van de insprekers Een verslag van de insprekers, de eerste reactie van de GGD Hollands Noorden en de visie van ecotoxicoloog Martina Vijver. Show less
Sluiskes, M.; Goeman, J.; Beekman, M.; Slagboom, E.; Akker, E. van den; Putter, H.; Rodríguez-Girondo, M. 2024
Aging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While... Show moreAging is a multifaceted and intricate physiological process characterized by a gradual decline in functional capacity, leading to increased susceptibility to diseases and mortality. While chronological age serves as a strong risk factor for age-related health conditions, considerable heterogeneity exists in the aging trajectories of individuals, suggesting that biological age may provide a more nuanced understanding of the aging process. However, the concept of biological age lacks a clear operationalization, leading to the development of various biological age predictors without a solid statistical foundation. This paper addresses these limitations by proposing a comprehensive operationalization of biological age, introducing the “AccelerAge” framework for predicting biological age, and introducing previously underutilized evaluation measures for assessing the performance of biological age predictors. The AccelerAge framework, based on Accelerated Failure Time (AFT) models, directly models the effect of candidate predictors of aging on an individual’s survival time, aligning with the prevalent metaphor of aging as a clock. We compare predictors based on the AccelerAge framework to a predictor based on the GrimAge predictor, which is considered one of the best-performing biological age predictors, using simulated data as well as data from the UK Biobank and the Leiden Longevity Study. Our approach seeks to establish a robust statistical foundation for biological age clocks, enabling a more accurate and interpretable assessment of an individual’s aging status. Show less
This thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods... Show moreThis thesis investigates the contribution of quantum computers to machine learning, a field called Quantum Machine Learning. Quantum Machine Learning promises innovative perspectives and methods for solving complex problems in machine learning, leveraging the unique capabilities of quantum computers. These computers differ fundamentally from classical computers by exploiting certain quantum mechanical phenomena. The thesis explores various proposals within quantum machine learning, such as the application of quantum algorithms in topological data analysis. With respect to topological data analysis, results demonstrate that quantum algorithms solve problems considered inefficient in classical settings. The thesis also explores structural risk minimization in quantum machine learning models, identifying crucial design choices for new quantum machine learning models. Additionally, it introduces quantum models in reinforcement learning, which deliver comparable performance to traditional models and are superior in certain scenarios. The final part identifies learning tasks in computational learning theory where quantum learning algorithms have exponential advantages. In summary, this thesis contributes to understanding how quantum computers can address complex machine learning problems, from topological data analysis to reinforcement learning and computational learning tasks. Show less
The dissertation explores the relationship between online and offline anti-corruption activism in Banten, Indonesia. It examines the historical background of anti-corruption activism in Indonesia,... Show moreThe dissertation explores the relationship between online and offline anti-corruption activism in Banten, Indonesia. It examines the historical background of anti-corruption activism in Indonesia, the comparison of online discourse of corruption framed by national civil society organizations (CSOs) and local activists, the impact of online activism on citizenship characteristics, and its potential transformation into strong or weak offline mobilization. The study uses social media ethnography to examine the materiality of being online and its relation to corruption and anti-corruption campaigns. The research reveals that corruption is primarily constructed as a legal discourse in national anti-corruption campaigns, while in Banten, morality and religious discourse are used to frame corruption. Online anti-corruption activism in Banten involves digital acts of reporting and sharing corruption news and flaming to resist corrupt leaders. This approach has led to the development of 'digital affective citizenship', where citizens express anger, hate, passion, and disgust towards corrupt leaders. The dissertation also discusses the characteristic of citizens in Banten that reflects "powerless angry citizens," who desire to influence political outcomes through corruption but feel powerless due to the mismatch between their desire and the limitations of participatory channels and organizations. Show less
The work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related... Show moreThe work described in this thesis had two objectives, specifically focusing on people aged 70 years and older: first, we aimed to investigate the associations between several thrombosis-related risk factors described in young and middle-aged populations and the risk of venous thrombosis (VT) in the elderly; second, we aimed to provide insight into several long-term consequences (i.e., health-related quality of life (HRQoL) and long-term risk of mortality) after a first VT at old age. Show less
Rede uitgesproken door prof. dr. Albert M. van Hemert ter gelegenheid van zijn afscheid als hoogleraar Psychiatrie aan de Universiteit Leiden op donderdag 4 april 2024
Chinese materia medica (CMM), comprising a diverse array of natural substances from plants, animals, and minerals, has been integral to Traditional Chinese Medicine (TCM) throughout history. This... Show moreChinese materia medica (CMM), comprising a diverse array of natural substances from plants, animals, and minerals, has been integral to Traditional Chinese Medicine (TCM) throughout history. This study investigates the dynamic evolution of CMM, noting shifts in species for improved therapeutic effects and the abandonment of those with adverse outcomes. By examining historical CMM specimens, particularly those in Dutch collections, tangible evidence of this evolution emerges.The Westhoff collection, spanning 140 years, reveals significant changes alongside enduring practices. A handwritten catalogue accompanying the collection aligns with modern CMM practices, indicating a remarkable continuity. Comparative analyses of historical collections and contemporary CMM in EU markets over three centuries emphasize the stability of core medicinal plant taxa. Additionally, the study validates the delayed luminescence (DL) technique for discerning CMM storage times, showing promising results.Despite challenges in preservation, historical CMM specimens offer unique insights into medicine's history, underscoring their importance for further research and understanding. Show less
Radiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined... Show moreRadiotherapy is intriguing as it not only eliminates tumor cells but also triggers a response from cytotoxic T cells, which attack the tumor. Thus, radiotherapy and immunotherapy are being combined in clinical studies, although their success has been limited. We used mouse tumor models to understand how radiotherapy induces T cell priming and subsequent anti-tumor immunity. In a model resembling lymphocyte-depleted cancer, we identified obstacles to systemic radiotherapy-induced T cell responses and proposed interventions to overcome them. Additionally, we explored strategies to counter local T cell suppression in the tumor microenvironment. In poorly immunogenic tumors, radiotherapy can provoke a T cell response, but this is counteracted by the generation of immunosuppressive Tregs. Combining radiotherapy with checkpoint immunotherapy, despite its success in humans, unexpectedly amplified the Treg response, further hindering cytotoxic T-cell activity. Our findings suggest this immunotherapy may not benefit these cancers. We discovered that molecules like CD80 and CD86, capable of stimulating T cells via the CD28 receptor, have distinct roles in promoting cytotoxic and Treg cells. Blocking CD86 enhanced cytotoxic T cell responses post-radiotherapy, leading to tumor rejection. Our study elucidates how tumor characteristics shape T-cell responses, how radiotherapy can evoke both favorable and unfavorable responses, and how targeted antibody immunotherapy can influence this interplay. Show less
Dit proefschrift onderzoekt de totstandkoming van geloofwaardigheid in live blogs. Live blogs worden gekenmerkt door hun onmiddellijkheid en onzekerheid. Het is taak voor journalisten het publiek... Show moreDit proefschrift onderzoekt de totstandkoming van geloofwaardigheid in live blogs. Live blogs worden gekenmerkt door hun onmiddellijkheid en onzekerheid. Het is taak voor journalisten het publiek te overtuigen de beste versie van de werkelijkheid te presenteren. In drie studies (inhoudsanalyse, interviews met makers en focusgroepen met gebruikers) onderzoekt dit proefschrift hoe geloofwaardigheid wordt betracht en geëvalueerd. Show less
Observations of low-lying dark states in several photosynthetic complexes challenge our understanding of the mechanisms behind their efficient energy transfer processes. Computational models are... Show moreObservations of low-lying dark states in several photosynthetic complexes challenge our understanding of the mechanisms behind their efficient energy transfer processes. Computational models are necessary for providing novel insights into the nature and function of dark states, especially since these are not directly accessible in spectroscopy experiments. Here, we will focus on signatures of dark-type states in chlorosomes, a light-harvesting complex from green sulfur bacteria well-known for uniting a broad absorption band with very efficient energy transfer. In agreement with experiments, our simulations of two-dimensional electronic spectra capture the ultrafast exciton transfer occurring in 100s of femtoseconds within a single chlorosome cylinder. The sub-100 fs process corresponds to relaxation within the single-excitation manifold in a single chlorosome tube, where all initially created populations in the bright exciton states are quickly transferred to dark-type exciton states. Structural inhomogeneities on the local scale cause a redistribution of the oscillator strength, leading to the emergence of these dark-type exciton states, which dominate ultrafast energy transfer. The presence of the dark-type exciton states suppresses energy loss from an isolated chlorosome via fluorescence quenching, as observed experimentally. Our results further question whether relaxation to dark-exciton states is a leading process or merely competes with transfer to the baseplate within the photosynthetic apparatus of green sulfur bacteria. Show less
Mental health problems among children and youths are common and have numerous negative consequences for young people and their social network. Therewith, these problems pose a social issue. GPs... Show moreMental health problems among children and youths are common and have numerous negative consequences for young people and their social network. Therewith, these problems pose a social issue. GPs play an important role in early detection and management of these problems. Insight into their clinical decision- making and, as a result, way of working would be helpful to develop methods for providing children and youths with the help they need. Previous literature suggest many doctors(-to-be), of whom some are or will become GPs, have (lived) experience related to mental health problems themselves. Previous studies also suggest having (lived) experience influences GPs’ clinical decision-making, and consequently their way of working. It would have clinical benefits for GPs and patients to explore this process. This thesis is constructed of four different articles, each contributing to answering the main question: ‘How do GPs decide on child and youth mental health problems and what is the influence of their(lived) experience regarding these problems on this decision?’ Article 1: How do GPs make decisions regarding mental health problems in children and youths? For answering this subquestion, a mixed methods design was used: interviews among 14 and an online survey among 15 GPs. GPs were asked about their clinical decision-making process on children and youths with mental health problems using three vignettes describing children and youths with mental health problems representative of clinical practice. The findings suggest GPs differ with regards to their decision- making regarding child and youth mental health problems, and that their decision-making is influenced by factors related to 1) the GP, for example if the GP approaches the problem somatically or psychosocially, if the GP considers themself competent enough to solve the problem with regards to their interest in and knowledge about youth mental health care, 2) the child and its social context, for example if the child or youth has psychiatric (co)morbidity, if the problem is likely to solve itself and if the problem could be assessed as being complex and 3) the GPs’ collaboration with other youth care providers, for example if GPs have existing collaboration agreements with these youth care providers and how they view their collaboration. Article 2: Can GPs’ decisions on child and youth mental health problems be supported by means of a decision-support method?For answering this subquestion, a literature search was conducted to retrieve studies that involved clinical decision support methods for GPs’ clinical decision-making related to mental health problems among children and youths. This systematic review yielded 25 studies on 18 clinical decision-support methods, divided into computer-based methods (such as MyGRaCE), telecommunication methods (such as CAP PC) and methods with a combination of components related to computer-based methods and telecommunication methods (such as Collaborative care for depression intervention). The article provides insight into (possible) beneficial clinical implications of clinical decision-support methods. These methods could give more insight into possible mental health problems, they could provide structured information which can be used by the GP and/or parents during their next consultation with the child or youth, and they could also decrease time and costs spent by the primary care practice and the GP. There are also less beneficial clinical implications, such as an inability for some computer-based methods to be used in emergency situations, when time is short, problems for children and youths when using computer-based methods because of their mental status, and impediment to discuss certain topics freely because the decision-support method gives too much direction to the consultation. The article describes certain considerations for GPs when choosing a decision-support method, which may indirectly have a positive impact on the implementation of such methods into general practice. For example, the GP can take into account their way of working, user flexibility of the method for the GP, the child/youth and their parent(s) with regards to understandability and ease of use, if the GP already uses a clinical decision-support method, if the GP already has collaboration agreements with youth care providers, as well as their own attitude and knowledge regarding mental health problems among children and youths.Article 3: Do doctors-to-be, among whom future GPs, have (lived) experience regarding mental health problems? Study focused on preclinical medical students.For answering this subquestion, self-report questionnaires were sent to 1311 preclinical medical students of Leiden University Medical Center to measure burnout-, depression- and anxiety-related symptoms. The article concludes that symptoms related to mental health problems are common among preclinical medical students. Burnout-related symptoms were found in 46%, depression-related symptoms in 27% and anxiety- related symptoms in 29% of preclinical medical students. Burnout-related symptoms among preclinical medical students were correlated with a sleep duration of less than 6 hours per night, low happiness and a high need for recovery after a day of study. Depression- and anxiety-related symptoms were mainly correlated with low optimism, low happiness, and a high need for recovery after a day of study. These findings suggest preclinical medical students are at risk to develop mental health problems, which can inspire universities to come up with preventive interventions.Article 4: Do doctors-to-be, among whom future GPs, have (lived) experience regarding mental health problems? Study focused on medical interns.For answering this subquestion, self-report questionnaires were sent to 709 medical interns of the same institution mentioned in article 3 to measure burnout-related symptoms. Burnout-related symptoms were found in 30% of medical interns. Burnout-related symptoms among medical interns were related to low dedication with regards to work, a high work pace and quantity, a high need for recovery after a day of work and low optimism. These correlates could be used to prevent mental health problems among medical interns by making adjustments to the medical curriculum. The articles of this thesis suggest GPs’ decision-making on mental health problems in children and youths is multifactorial and consists of objective and subjective components. Furthermore, decision-making seems to differ between GPs, which may be an explanation why there are a variety of clinical decision support methods. Some clinical decision support methods have been implemented in the context of research into general practice, like MyGRaCE, CHICA, Mobiletype, Youth StepCare, consultation-liason method(between GPs and psychiatrists), telepsychiatry consultation practice and the MC3 Program. A clinical implication is GPs can choose a decision-support method which match their personal style of clinical decision-making. However, the validity, trustworthiness and usability of available methods need to be further explored. A clinical implication with regards to medical students’ mental health comprises universities provide accessible proactive mental support to preclinical medical interns and medical interns, because many do not seek help themselves. Furthermore, universities could stimulate a stigma-reducing educational environment, for example in collaboration with the department of (Child- and Adolescent) Psychiatry. Therefore, medical students could be equipped with effective strategies to cope with mental health problems. Also, they might be made aware of their vulnerability, so that they may know their subjectivity and use their personal experiences in practice. The results of this thesis invite more (longitudinal) research on the diagnostic precision, predictive value and cost-efficiency of clinical decision-support methods. Furthermore, more research is needed on the prevalence of mental health problems among graduated doctors, like GPs, and possible effects of these problems on their way of working, their decision-making and their contacts with patients. Strengths of this thesis include exploration of a relatively unknown research area, namely GPs’ clinical decision-making regarding mental health problems among children and youths. Therefore, this thesis used multiple research methodologies and it used a practical scope. This thesis also contains several limitations, such as inclusion of a small GP population, as well as self-selection bias in the studies on preclinical medical students, medical interns and GPs. Finally, interpretation of the results of this thesis was impeded because the research has been conducted in one university, because cause and effect of results could not always be disentangled and because of low statistical power. Because having mental health problems may influence GPs’ clinical decision-making, one could explore how (future) doctors work, study and relax. Therefore, it is recommended to strive for educating balanced doctors: persons who, in collaboration with their colleagues, are – through reflection – aware of their needs and wants between professional boundaries. Show less
Cutaneous malignancies are the most frequent human malignancy with an increasing incidence reaching epidemic proportions among Caucasians in Europe, America and Australia. The most common cutaneous... Show moreCutaneous malignancies are the most frequent human malignancy with an increasing incidence reaching epidemic proportions among Caucasians in Europe, America and Australia. The most common cutaneous malignancy is basal cell carcinoma, followed by squamous cell carcinoma (cSCC) and melanoma.(1-3) There are also other, less common cutaneous malignancies which consist of less than 5% of the cutaneous malignancies. Some of these rare cutaneous malignancies are still considered skin cancer such as sebaceous carcinoma,while others are classified as soft tissue sarcoma (DFSP, angiosarcoma). In this thesis, I aimed to analyse outcome after surgical procedures for rare cutaneous malignancies and the rare locally advanced cases of cSCC. Show less
This thesis introduces the concept of "physics-based inverse design", working on the notion that the physical driving forces governing functionality are inherently encoded in independently... Show moreThis thesis introduces the concept of "physics-based inverse design", working on the notion that the physical driving forces governing functionality are inherently encoded in independently parameterized energy functions, which can be resolved through the use of inverse design strategies.The thesis describes the development of EVO-MD, a Python-based implementation of the physics-based inverse design concept. EVO-MD is capable of automatically setting-up, performing, and analyzing molecular dynamics simulations, allowing for the evolutionary optimization of complex and dynamic features in peptides. Examples of such applications include the optimization of lipid composition and curvature sensors, and the development of peptides with antiviral properties. Show less
Mulholland, M.; Depuydt, M.A.C.; Jakobsson, G.; Ljungcrantz, I.; Grentzmann, A.; To, F.; ... ; Engelbertsen, D. 2024
The interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we... Show moreThe interleukin-1 receptor accessory protein (IL1RAP) is a co-receptor required for signalling through the IL-1, IL-33, and IL-36 receptors. Using a novel anti-IL1RAP-blocking antibody, we investigated the role of IL1RAP in atherosclerosis.Single-cell RNA sequencing data from human atherosclerotic plaques revealed the expression of IL1RAP and several IL1RAP-related cytokines and receptors, including IL1B and IL33. Histological analysis showed the presence of IL1RAP in both the plaque and adventitia, and flow cytometry of murine atherosclerotic aortas revealed IL1RAP expression on plaque leucocytes, including neutrophils and macrophages. High-cholesterol diet fed apolipoprotein E-deficient (Apoe-/-) mice were treated with a novel non-depleting IL1RAP-blocking antibody or isotype control for the last 6 weeks of diet. IL1RAP blockade in mice resulted in a 20% reduction in subvalvular plaque size and limited the accumulation of neutrophils and monocytes/macrophages in plaques and of T cells in adventitia, compared with control mice. Indicative of reduced plaque inflammation, the expression of several genes related to leucocyte recruitment, including Cxcl1 and Cxcl2, was reduced in brachiocephalic arteries of anti-IL1RAP-treated mice, and the expression of these chemokines in human plaques was mainly restricted to CD68+ myeloid cells. Furthermore, in vitro studies demonstrated that IL-1, IL-33, and IL-36 induced CXCL1 release from both macrophages and fibroblasts, which could be mitigated by IL1RAP blockade.Limiting IL1RAP-dependent cytokine signalling pathways in atherosclerotic mice reduces plaque burden and plaque inflammation, potentially by limiting plaque chemokine production. Show less
