Understanding regional variation in euthanasia using geomedical frameworks: a critical ethical reflection.

Considerable geographical variation in the uptake of euthanasia has been reported: some municipalities in the Netherlands have a 25 times higher euthanasia rate than other municipalities. Current 'geomedical' frameworks for interpreting practice variation in health care utilization seem inadequately tailored to understand regional variation in morally controversial procedures such as euthanasia. The aim of this conceptual article is threefold: i) to add relevant medical ethical principles to current frameworks; ii) to provide a four-step ethical-geomedical model for the interpretation of geographical differences in the utilization of health care in general and for ethically controversial treatments in specific; iii) to gain better understanding of the existing geographical variation in the incidence of euthanasia by using this framework in our analysis.

Zeb1 mediates EMT/plasticity-associated ferroptosis sensitivity in cancer cells by regulating lipogenic enzyme expression and phospholipid composition.

Therapy resistance and metastasis, the most fatal steps in cancer, are often triggered by a (partial) activation of the epithelial-mesenchymal transition (EMT) programme. A mesenchymal phenotype predisposes to ferroptosis, a cell death pathway exerted by an iron and oxygen-radical-mediated peroxidation of phospholipids containing polyunsaturated fatty acids. We here show that various forms of EMT activation, including TGFβ stimulation and acquired therapy resistance, increase ferroptosis susceptibility in cancer cells, which depends on the EMT transcription factor Zeb1.

Virtues in Competency-Based Assessment Frameworks: A Text Analysis.

Introduction: Official documentation of specialty training provides comprehensive and elaborate criteria to assess residents. These criteria are commonly described in terms of competency roles and entrustable professional activities (EPA's), but they may also encompass virtues. Virtues are desirable personal qualities that enable a person, in this case, a medical specialist, to make and act on the right decisions.

Patient-derived zebrafish xenografts of uveal melanoma reveal ferroptosis as a drug target.

Uveal melanoma (UM) has a high risk to progress to metastatic disease with a median survival of 3.9 months after metastases detection, as metastatic UM responds poorly to conventional and targeted chemotherapy and is largely refractory to immunotherapy. Here, we present a patient-derived zebrafish UM xenograft model mimicking metastatic UM.

Zebrafish Patient-Derived Xenograft Model as a Preclinical Platform for Uveal Melanoma Drug Discovery.

Uveal melanoma (UM) is a rare malignant cancer of the eye, with up to 50% of patients dying from metastasis, for which no effective treatment is available. Due to the rarity of the disease, there is a great need to harness the limited material available from primary tumors and metastases for advanced research and preclinical drug screening. We established a platform to isolate, preserve, and transiently recover viable tissues, followed by the generation of spheroid cultures derived from primary UM.

Challenges in pastoral care practice in euthanasia: A concept mapping study among Dutch protestant pastors.

This study explores the various difficulties that protestant pastors experience in the context of care for parishioners with a wish for euthanasia. In a reproducible and non-subjective way, using the concept mapping method, we cluster and rank-order 600 elements that pastors had mentioned as "difficult in caring for parishioners with a death wish" in an earlier survey study. The three clusters of items ranked as most difficult are connected with inappropriate care, doubts whether euthanasia in specific circumstances is justified, and disagreements between pastor and parishioner, including the emotional burden arising from those disagreements.

The EMT transcription factor ZEB1 governs a fitness-promoting but vulnerable DNA replication stress response.

The DNA damage response (DDR) and epithelial-to-mesenchymal transition (EMT) are two crucial cellular programs in cancer biology. While the DDR orchestrates cell-cycle progression, DNA repair, and cell death, EMT promotes invasiveness, cellular plasticity, and intratumor heterogeneity. Therapeutic targeting of EMT transcription factors, such as ZEB1, remains challenging, but tumor-promoting DDR alterations elicit specific vulnerabilities.

Actual timing versus GPs' perceptions of optimal timing of advance care planning: a mixed-methods health record-based study.

Background: Timely initiation of advance care planning (ACP) in general practice is challenging, especially in patients with non-malignant conditions. Our aim was to investigate how perceived optimal timing of ACP initiation and its triggers relate to recorded actual timing in patients with cancer, organ failure, or multimorbidity.

Methods: In this mixed-methods study in the Netherlands, we analysed health records selected from a database with primary care routine data and with a recorded ACP conversation in the last two years before death of patients who died with cancer, organ failure, or multimorbidity.

Novel Treatments of Uveal Melanoma Identified with a Synthetic Lethal CRISPR/Cas9 Screen.

Currently, no systemic treatment is approved as the standard of care for metastatic uveal melanoma (UM). mTOR has been evaluated as a drug target in UM. However, one of the main limitations is dose reduction due to adverse effects.

XePhIR: the zebrafish xenograft phenotype interactive repository.

Zebrafish xenografts are an established model in cancer biology, with a steadily rising number of models and users. However, as of yet, there is no platform dedicated to standardizing protocols and sharing data regarding zebrafish xenograft phenotypes. Here, we present the Xenograft Phenotype Interactive Repository (XePhIR, https://www.

Establishment of Embryonic Zebrafish Xenograft Assays to Investigate TGF-β Family Signaling in Human Breast Cancer Progression.

Transforming growth factor-β (TGF-β) family members have pivotal functions in controlling breast cancer progression, acting not only on cancer cells but also on other cells within the tumor microenvironment. Here we describe embryonic zebrafish xenograft assays to investigate how TGF-β family signaling controls breast cancer cell intravasation, extravasation and regulates tumor angiogenesis. Fluorescently mCherry-labeled breast cancer cells are injected in the perivitelline space or Duct of Cuvier of Tg (fli:EGFP) transgenic Casper zebrafish embryos, in which the zebrafish express enhanced green fluorescent protein in the entire vasculature.

The ethics of euthanasia in dementia: A qualitative content analysis of case summaries (2012-2020).

Background: The practice of euthanasia in dementia has thus far been described both in terms of its empirical patient characteristics and its ethical questions. However, 40 new cases have been published since the last study.

Methods: A qualitative content analysis of all 111 Dutch case summaries of euthanasia in dementia patients between 2012 and 2020, selected from the total of 1117 cases published by the Regional Euthanasia Review Committees (RTE).

Advance care planning in primary care: a retrospective medical record study among patients with different illness trajectories.

Background: Advance Care Planning (ACP) enables physicians to align healthcare with patients' wishes, reduces burdensome life-prolonging medical interventions, and potentially improves the quality of life of patients in the last phase of life. However, little objective information is available about the extent to which structured ACP conversations are held in general practice. Our aim was to examine the documentation of ACP for patients with cancer, organ failure and multimorbidity in medical records (as a proxy for ACP application) in Dutch general practice.

General practitioners' evaluations of optimal timing to initiate advance care planning for patients with cancer, organ failure, or multimorbidity: A health records survey study.

Background: Appropriate timing to initiate advance care planning is difficult, especially for individuals with non-malignant disease in community settings.

Aim: To identify the optimal moment for, and reasons to initiate advance care planning in different illness trajectories.

Design And Methods: A health records survey study; health records were presented to 83 GPs with request to indicate and substantiate what they considered optimal advance care planning timing within the 2 years before death.

Ortho- and Ectopic Zebrafish Xeno-Engraftment of Ocular Melanoma to Recapitulate Primary Tumor and Experimental Metastasis Development.

There are currently no animal models for metastatic ocular melanoma. The lack of metastatic disease models has greatly hampered the research and development of novel strategies for the treatment of metastatic ocular melanoma. In this protocol we delineate a quick and efficient way to generate embryonic zebrafish models for both the primary and disseminated stage of ocular melanoma, using retro-orbital orthotopic and intravascular ectopic cell engraftment, respectively.

Uniform criteria for total hip replacement surgery in patients with hip osteoarthritis: a decision tool to guide treatment decisions.

Background: Uniform criteria for performing hip replacement surgery in hip osteoarthritis patients are currently lacking. As a result, variation in surgery and inappropriateness of care may occur. The aim of this study was to develop a consensus-based decision tool to support the decision-making process for hip replacement surgery.

Euthanasia in the Netherlands: a claims data cross-sectional study of geographical variation.

Background: The annual incidence of euthanasia in the Netherlands as a percentage of all deaths rose from 1.9% in 1990 to 4.4% in 2017.

Effects of an Integrated Palliative Care Pathway: More Proactive GPs, Well Timed, and Less Acute Care: A Clustered, Partially Controlled Before-After Study.

Objectives: This study presents the design of an integrated, proactive palliative care pathway covering the full care cycle and evaluates its effects using 3 types of outcomes: (1) physician-reported outcomes, (2) outcomes reported by family, and (3) (utilization of) health care outcomes.

Design: A clustered, partially controlled before-after study with a multidisciplinary integrated palliative care pathway as its main intervention.

Setting And Participants: after assessment in hospital departments of oncology, and geriatrics, and in 13 primary care facilities, terminally ill patients were proactively included into the pathway.

Preferences in end of life care substantially differ between the Netherlands and Japan: Results from a cross-sectional survey study.

Strategies to increase appropriateness of EoL care, such as shared decision making (SDM), and advance care planning (ACP) are internationally embraced, especially since the COVID-19 pandemic. However, individuals preferences regarding EoL care may differ internationally. Current literature lacks insight in how preferences in EoL care differ between countries and continents.

Selecting interventions to improve patient-relevant outcomes in health care for aortic valve disease - the Intervention Selection Toolbox.

Background: Measuring and improving outcomes is a central element of value-based health care. However, selecting improvement interventions based on outcome measures is complex and tools to support the selection process are lacking. The goal was to present strategies for the systematic identification and selection of improvement interventions applied to the case of aortic valve disease and to combine various methods of process and outcome assessment into one integrated approach for quality improvement.

TLD1433 Photosensitizer Inhibits Conjunctival Melanoma Cells in Zebrafish Ectopic and Orthotopic Tumour Models.

The ruthenium-based photosensitizer (PS) TLD1433 has completed a phase I clinical trial for photodynamic therapy (PDT) treatment of bladder cancer. Here, we investigated a possible repurposing of this drug for treatment of conjunctival melanoma (CM). CM is a rare but often deadly ocular cancer.

Is there a volume-quality relationship within the independent treatment centre sector? A longitudinal analysis.

Background: The number of independent treatment centres (ITCs) has grown substantially. However, little is known as to whether the volume-quality relationship exists within this sector and whether other possible organisational factors mediate this relationship. The aim of this study is to gain a better understanding of such possible relationships.