Targeting HLA class II in allogeneic stem cell transplantation

Allogeneic stem cell transplantation (alloSCT) is a curative treatment for a variety of hematologic diseases. The mechanism of curation by an alloSCT is the induction of an immune response of donor T cells attacking patients hematopoiesis, including the malignant hematopoietic cells. This is called the graft-versus-leukemia (GVL) reactivity. However, donor T cells can also be directed against healthy tissue cells of the recipient, causing graft-versus-host disease (GVHD). In this thesis we focused on targeting HLA class II by donor CD4 T cells to induce GVL without GVHD, because under non-inflammatory conditions, HLA class II is mainly expressed on hematopoietic cells and not on other tissue cells. We showed that CD4 T cells from HLA-identical sibling donors can induce conversion from mixed to full donor chimerism with GVL reactivity, but without GVHD, by targeting HLA class II restricted minor histocompatibility antigens. We also analyzed the immunopeptidome of different HLA-DP alleles. HLA-DP peptide binding motifs showed a clear association with the HLA-DP allele specific sequences of the binding groove. Functional hierarchies among HLA-DP alleles were unravelled, providing new molecular insights into HLA-DP classification. Permissiveness of mismatches between donor and recipient is not a black and white phenomenon, but rather gradual based on similarities and differences in the peptidomes.LUMC / Geneeskund

Noord-Hollands koolbedrijf van 28 ha op kleigrond

Met deze voorbeeldberekening wordt aan de oriënterende ondernemer inzicht gegeven in de financiële verandering tijdens en na het omschakelen naar een biologische bedrijfsvoering. In dit voorbeeld gaat het om een gespecialiseerd (sluit)koolbedrijf met een bedrijfsgrootte van 18 hectare eigen grond en daarnaast nog 10 hectare huurland voor de koolteelt. Door de flexibiliteit van huurland en het hanteren van een 'slim en kort omschakeltraject' komt het bouwplansaldo alleen in het eerste omschakeljaar iets lager uit dan in de gangbare situatie

Technological requirements for solutions in the conservation and protection of historic monuments and archaeological remains

Executive summary: This Study has discovered many achievements associated with European support for scientific and technological research for the protection and conservation of cultural heritage. The achievements to date are: 1. Creation of an active research community 2. A body of research of unparalleled and enviable international quality and character 3. Ongoing effectiveness of research beyond initial funding 4. Substantial rate of publication 5. Imaginative tools of dissemination and publication 6. Clear spin-offs and contribution to European competitiveness often going outside the European cultural heritage area 7. Contribution to emerging European legislation, for example, air quality management. The Study has also uncovered important research gaps associated with this field that have yet to begin to be investigated. It has also discovered the need for continuing fine scale advancement in areas where researchers have been active for a number of years. The overall picture is that European research in the field of cultural heritage protection must be put on a secure footing if it is to maintain its commanding lead over other regions of the world. This Study concludes that: 1. It would be invidious to attempt to separate basic and applied research in this area of research. Like any other scientific endeavour, this field needs to integrate basic and applied research if it is to continue to thrive. 2. Small, flexible, focused interdisciplinary teams responsive to European needs, must be sustained, promoted and celebrated as models of sustainability and that what is proposed under the European Research Area (ERA) for large and complex research projects, could inflict serious damage on this area of research. 3. Resources cannot be delegated to Member States because of the interdisciplinary nature of cultural heritage and the need for a co-ordinated pan-European perspective across this research that helps to define the essential character of European cultural heritage. National programmes only serve local needs, leading to loss of strategic output, lessening of competitiveness and risk of duplication. 4. A mechanism needs to be created to help researchers working in this field to communicate and exchange information with related sectors such as construction, urban regeneration, land reclamation and agriculture. 5. There is overwhelming agreement over the need for sustainable research funding for cultural heritage and for an iterative process of exchange among researchers, decision-makers and end-users in order to maximize benefits from project inception through to dissemination, audit and review. For all the reasons mentioned above, the most significant recommendation in this Report is the identification of the need for a European Panel on the Application of Science for Cultural Heritage (EPASCH)

Strong increases in flood frequency and discharge of the River Meuse over the late Holocene: impacts of long-term anthropogenic land use change and climate variability

International audienceIn recent years the frequency of high-flow events on the Meuse (northwest Europe) has been relatively great, and flooding has become a major research theme. To date, research has focused on observed discharge records of the last century and simulations of the coming century. However, it is difficult to delineate changes caused by human activities (land use change and greenhouse gas emissions) and natural fluctuations on these timescales. To address this problem we coupled a climate model (ECBilt-CLIO-VECODE) and a hydrological model (STREAM) to simulate daily Meuse discharge in two time-slices: 4000?3000 BP (natural situation), and 1000?2000 AD (includes anthropogenic influence). For 4000?3000 BP the basin is assumed to be almost fully forested; for 1000?2000 AD we reconstructed land use based on historical sources. For 1000?2000 AD the simulated mean annual discharge (260.9 m³ s?1) is significantly higher than for 4000?3000 BP (244.8 m³ s?1), and the frequency of large high-flow events (discharge >3000 m³ s?1) is higher (recurrence time decreases from 77 to 65 years). On a millennial timescale almost all of this increase can be ascribed to land use changes (especially deforestation); the effects of climatic change are insignificant. For the 20th Century, the simulated mean discharge (270.0 m³ s?1) is higher than in any other century studied, and is ca. 2.5% higher than in the 19th Century (despite an increase in evapotranspiration). Furthermore, the recurrence time of large high-flow events is almost twice as short as under natural conditions (recurrence time decreases from 77 to 40 years). On this timescale climate change (strong increase in annual and winter precipitation) overwhelmed land use change as the dominant forcing mechanism

Strong increases in flood frequency and discharge of the River Meuse over the late Holocene: impacts of long-term anthropogenic land use change and climate variability

International audienceIn recent years the frequency of high-flow events on the Meuse (northwest Europe) has been relatively great, and flooding has become a major research theme. To date, research has focused on observed discharge records of the last century and simulations of the coming century. However, it is difficult to delineate changes caused by human activities (land use change and greenhouse gas emissions) and natural fluctuations on these timescales. To address this problem we coupled a climate model (ECBilt-CLIO-VECODE) and a hydrological model (STREAM) to simulate daily Meuse discharge in two time-slices: 4000?3000 BP (natural situation), and 1000?2000 AD (includes anthropogenic influence). For 4000?3000 BP the basin is assumed to be almost fully forested; for 1000?2000 AD we reconstructed land use based on historical sources. For 1000?2000 AD the simulated mean annual discharge (260.9 m³ s?1) is significantly higher than for 4000?3000 BP (244.8 m³ s?1), and the frequency of large high-flow events (discharge >3000 m³ s?1) is higher (recurrence time decreases from 77 to 65 years). On a millennial timescale almost all of this increase can be ascribed to land use changes (especially deforestation); the effects of climatic change are insignificant. For the 20th Century, the simulated mean discharge (270.0 m³ s?1) is higher than in any other century studied, and is ca. 2.5% higher than in the 19th Century (despite an increase in evapotranspiration). Furthermore, the recurrence time of large high-flow events is almost twice as short as under natural conditions (recurrence time decreases from 77 to 40 years). On this timescale climate change (strong increase in annual and winter precipitation) overwhelmed land use change as the dominant forcing mechanism

Overcoming the challenges facing Nepal's health system during federalisation: an analysis of health system building blocks.

Nepal's move to a federal system was a major constitutional and political change, with significant devolution of power and resources from the central government to seven newly created provinces and 753 local governments. Nepal's health system is in the process of adapting to federalism, which is a challenging, yet potentially rewarding, task. This research is a part of broader study that aims to explore the opportunities and challenges facing Nepal's health system as it adapts to federalisation. This exploratory qualitative study was conducted across the three tiers of government (federal, provincial, and local) in Nepal. We employed two methods: key informant interviews and participatory policy analysis workshops, to offer an in-depth understanding of stakeholders' practical learnings, experiences, and opinions. Participants included policymakers, health service providers, local elected members, and other local stakeholders. All interviews were audio-recorded, transcribed, translated into English, and analysed thematically using the six WHO (World Health Organization) health system building blocks as a theoretical framework. Participants noted both opportunities and challenges around each building block. Identified opportunities were: (a) tailored local health policies and plans, (b) improved health governance at the municipality level, (c) improved health infrastructure and service capacity, (d) improved outreach services, (e) increased resources (health budgets, staffing, and supplies), and (f) improved real-time data reporting from health facilities. At the same time, several challenges were identified including: (a) poor coordination between the tiers of government, (b) delayed release of funds, (c) maldistribution of staff, (d) problems over procurement, and (e) limited monitoring and supervision of the quality of service delivery and data reporting. Our findings suggest that since federalisation, Nepal's health system performance is improving, although much remains to be accomplished. For Nepal to succeed in its federalisation process, understanding the challenges and opportunities is vital to improving each level of the health system in terms of (a) leadership and governance, (b) service delivery, (c) health financing, (d) health workforce, (e) access to essential medicines and technologies and (f) health information system. [Abstract copyright: © 2023. Crown.

Participatory policy analysis in health policy and systems research: reflections from a study in Nepal.

Background Participatory policy analysis (PPA) as a method in health policy and system research remains underexplored. Using our experiences of conducting PPA workshops in Nepal to explore the impact of the country’s move to federalism on its health system, we reflect on the method’s strengths and challenges. We provide an account of the study context, the design and implementation of the workshops, and our reflections on the approach’s strengths and challenges. Findings on the impact of federalism on the health system are beyond the scope of this manuscript. Main body We conducted PPA workshops with a wide range of health system stakeholders (political, administrative and service-level workforce) at the local and provincial levels in Nepal. The workshops consisted of three activities: river of life, brainstorming and prioritization, and problem-tree analysis. Our experiences show that PPA workshops can be a valuable approach to explore health policy and system issues – especially in a context of widespread systemic change which impacts all stakeholders within the health system. Effective engagement of stakeholders and activities that encourage both individual- and system-level reflections and discussions not only help in generating rich qualitative data, but can also address gaps in participants’ understanding of practical, technical and political aspects of the health system, aid policy dissemination of research findings, and assist in identifying short- and long-term practice and policy issues that need to be addressed for better health system performance and outcomes. Conducting PPA workshops is, however, challenging for a number of reasons, including the influence of gatekeepers and power dynamics between stakeholders/participants. The role and skills of researchers/facilitators in navigating such challenges are vital for success. Although the long-term impact of such workshops needs further research, our study shows the usefulness of PPA workshops for researchers, for participants and for the wider health system. Conclusions PPA workshops can effectively generate and synthesize health policy and system evidence through collaborative engagement of health system stakeholders with varied roles. When designed with careful consideration for context and stakeholders’ needs, it has great potential as a method in health policy and systems research

Overcoming the Challenges Facing Nepal’s Health System During Federalisation: An Analysis of Health System Building Blocks

Introduction Nepal’s move to a federal system was a major constitutional and political change, with significant devolution of power and resources from the central government to seven newly created provinces and 753 local governments. Nepal’s health system is in the process of adapting to federalism, which is a challenging, yet potentially rewarding, task. This research is a part of broader study that aims to explore the opportunities and challenges facing Nepal’s health system as it adapts to federalisation. Methods This exploratory qualitative study was conducted across the three tiers of government (federal, provincial, and local) in Nepal. We employed two methods: key informant interviews and participatory policy analysis workshops, to offer an in-depth understanding of stakeholders’ practical learnings, experiences, and opinions. Participants included policymakers, health service providers, local elected members, and other local stakeholders. All interviews were audio-recorded, transcribed, translated into English, and analysed thematically using the six WHO (World Health Organization) health system building blocks as a theoretical framework. Results Participants noted both opportunities and challenges around each building block. Identified opportunities were: (a) tailored local health policies and plans, (b) improved health governance at the municipality level, (c) improved health infrastructure and service capacity, (d) improved outreach services, (e) increased resources (health budgets, staffing, and supplies), and (f) improved real-time data reporting from health facilities. At the same time, several challenges were identified including: (a) poor coordination between the tiers of government, (b) delayed release of funds, (c) maldistribution of staff, (d) problems over procurement, and (e) limited monitoring and supervision of the quality of service delivery and data reporting. Conclusion Our findings suggest that since federalisation, Nepal’s health system performance is improving, although much remains to be accomplished. For Nepal to succeed in its federalisation process, understanding the challenges and opportunities is vital to improving each level of the health system in terms of (a) leadership and governance, (b) service delivery, (c) health financing, (d) health workforce, (e) access to essential medicines and technologies and (f) health information system