Defining and Assessing the Syndrome of Moral Injury:Initial Findings of the Moral Injury Outcome Scale Consortium

Potentially morally injurious events (PMIEs) entail acts of commission (e.g., cruelty, proscribed or prescribed violence) or omission (e.g., high stakes failure to protect others) and bearing witness (e.g., to grave inhumanity, to the gruesome aftermath of violence), or being the victim of others' acts of commission (e.g., high stakes trust violations) or omission (e.g., being the victim of grave individual or systemic failures to protect) that transgress deeply held beliefs and expectations about right and wrong. Although there is a proliferation of interest in moral injury (the outcome associated with exposure to PMIEs), there has been no operational definition of the putative syndrome and no standard assessment scheme or measure, which has hampered research and care in this area. We describe an international effort to define the syndrome of moral injury and develop and validate the Moral Injury Outcome Scale (MIOS) in three stages. To ensure content validity, in Stage I, we conducted interviews with service members, Veterans, and clinicians/Chaplains in each country, inquiring about the lasting impact of PMIEs. Qualitative analysis yielded six operational definitions of domains of impact of PMIEs and components within domains that establish the parameters of the moral injury syndrome. From the domain definitions, we derived an initial pool of scale items. Stage II entailed scale refinement using factor analytic methods, cross-national invariance testing, and internal consistency reliability analyses of an initial 34-item MIOS. A 14-item MIOS was invariant and reliable across countries and had two factors: Shame-Related (SR) and Trust-Violation-Related (TVR) Outcomes. In Stage III, MIOS total and subscale scores had strong convergent validity, and PMIE-endorsers had substantially higher MIOS scores vs. non-endorsers. We discuss and contextualize the results and describe research that is needed to substantiate these inaugural findings to further explore the validity of the MIOS and moral injury, in particular to examine discriminant and incremental validity.</p

Defining and Assessing the Syndrome of Moral Injury:Initial Findings of the Moral Injury Outcome Scale Consortium

Potentially morally injurious events (PMIEs) entail acts of commission (e.g., cruelty, proscribed or prescribed violence) or omission (e.g., high stakes failure to protect others) and bearing witness (e.g., to grave inhumanity, to the gruesome aftermath of violence), or being the victim of others' acts of commission (e.g., high stakes trust violations) or omission (e.g., being the victim of grave individual or systemic failures to protect) that transgress deeply held beliefs and expectations about right and wrong. Although there is a proliferation of interest in moral injury (the outcome associated with exposure to PMIEs), there has been no operational definition of the putative syndrome and no standard assessment scheme or measure, which has hampered research and care in this area. We describe an international effort to define the syndrome of moral injury and develop and validate the Moral Injury Outcome Scale (MIOS) in three stages. To ensure content validity, in Stage I, we conducted interviews with service members, Veterans, and clinicians/Chaplains in each country, inquiring about the lasting impact of PMIEs. Qualitative analysis yielded six operational definitions of domains of impact of PMIEs and components within domains that establish the parameters of the moral injury syndrome. From the domain definitions, we derived an initial pool of scale items. Stage II entailed scale refinement using factor analytic methods, cross-national invariance testing, and internal consistency reliability analyses of an initial 34-item MIOS. A 14-item MIOS was invariant and reliable across countries and had two factors: Shame-Related (SR) and Trust-Violation-Related (TVR) Outcomes. In Stage III, MIOS total and subscale scores had strong convergent validity, and PMIE-endorsers had substantially higher MIOS scores vs. non-endorsers. We discuss and contextualize the results and describe research that is needed to substantiate these inaugural findings to further explore the validity of the MIOS and moral injury, in particular to examine discriminant and incremental validity.</p

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2015)

The EURL ECVAM status report provides an update on the progress made in the development, validation and regulatory acceptance of alternative methods and approaches and their dissemination since the last report published in June 2014. It is informing on ongoing research and development activities, validation studies, peer reviews, recommendations, strategies and regulatory/international acceptance of alternative methods and approaches and dissemination activities. R&D activities within large European or International consortia continued in toxicity areas where 3Rs solutions are more difficult to find due to the underlying complexity of the area. On the other hand, toxicity areas where promising non-animal approaches have been developed, their validation and regulatory acceptance/international adoption could be progressed. Particular emphasis was given to the best and most intelligent combination and integration of these different non-animal approaches to ultimately obtain the required information without resorting to animal testing.JRC.I.5-Systems Toxicolog

EURL ECVAM Status Report on the Development, Validation and Regulatory Acceptance of Alternative Methods and Approaches (2016)

Replacement, Reduction and Refinement of animal testing is anchored in EU legislation. Alternative non-animal approaches facilitate a shift away from animal testing. Cell-based methods and computational technologies are integrated to translate molecular mechanistic understanding of toxicity into safety testing strategies.JRC.F.3-Chemicals Safety and Alternative Method

The immunological functions of the Appendix: an example of redundancy?

Biological redundancy ensures robustness in living organisms at several levels, from genes to organs. In this review, we explore the concept of redundancy and robustness through an analysis of the caecal appendix, an organ that is often considered to be a redundant remnant of evolution. However, phylogenic data show that the Appendix was selected during evolution and is unlikely to disappear once it appeared. In humans, it is highly conserved and malformations are extremely rare, suggesting a role for that structure. The Appendix could perform a dual role. First, it is a concentrate of lymphoid tissue resembling Peyer's patches and is the primary site for immunoglobulin A production which is crucial to regulate the density and quality of the intestinal flora. Second, given its shape and position, the Appendix could be a unique niche for commensal bacteria in the body. It is extremely rich in biofilms that continuously shed bacteria into the intestinal lumen. The Appendix contains a microbiota as diverse as that found in the colon and could replenish the large intestine with healthy flora after a diarrhea episode. In conditions of modern medicine hygiene, and people live healthy without their appendix. However, several reports suggest that the effects of appendectomy could be subtler and associated with the development of inflammatory conditions such as inflammatory bowel disease (IBD), heart disease but also in less expected disorders such as Parkinson's disease. Lack of an Appendix also predicts a worsen outcome for recurrent Clostridium difficile infection, which is the first nosocomial infection in hospitals. Here, we review the literature and in combination with our own data, we suggest that the Appendix might be redundant in its immunological function but unique as a reservoir of microbiota

The immunological functions of the Appendix: An example of redundancy?

Biological redundancy ensures robustness in living organisms at several levels, from genes to organs. In this review, we explore the concept of redundancy and robustness through an analysis of the caecal appendix, an organ that is often considered to be a redundant remnant of evolution. However, phylogenic data show that the Appendix was selected during evolution and is unlikely to disappear once it appeared. In humans, it is highly conserved and malformations are extremely rare, suggesting a role for that structure. The Appendix could perform a dual role. First, it is a concentrate of lymphoid tissue resembling Peyer's patches and is the primary site for immunoglobulin A production which is crucial to regulate the density and quality of the intestinal flora. Second, given its shape and position, the Appendix could be a unique niche for commensal bacteria in the body. It is extremely rich in biofilms that continuously shed bacteria into the intestinal lumen. The Appendix contains a microbiota as diverse as that found in the colon and could replenish the large intestine with healthy flora after a diarrhea episode. In conditions of modern medicine hygiene, and people live healthy without their appendix. However, several reports suggest that the effects of appendectomy could be subtler and associated with the development of inflammatory conditions such as inflammatory bowel disease (IBD), heart disease but also in less expected disorders such as Parkinson's disease. Lack of an Appendix also predicts a worsen outcome for recurrent Clostridium difficile infection, which is the first nosocomial infection in hospitals. Here, we review the literature and in combination with our own data, we suggest that the Appendix might be redundant in its immunological function but unique as a reservoir of microbiota

Membrane-bound Fas ligand only is essential for Fas-induced apoptosis

Fas ligand (FasL), an apoptosis-inducing member of the TNF cytokine family, and its receptor Fas are critical for the shutdown of chronic immune responses and prevention of autoimmunity. Accordingly, mutations in their genes cause severe lymphadenopathy and autoimmune disease in mice and humans. FasL function is regulated by deposition in the plasma membrane and metalloprotease-mediated shedding. Here we generated gene-targeted mice that selectively lack either secreted FasL (sFasL) or membrane-bound FasL (mFasL) to resolve which of these forms is required for cell killing and to explore their hypothesized non-apoptotic activities. Mice lacking sFasL (FasL Δs/Δs) appeared normal and their T cells readily killed target cells, whereas T cells lacking mFasL (FasL Δm/Δm) could not kill cells through Fas activation. FasL Δm/Δm mice developed lymphadenopathy and hyper-gammaglobulinaemia, similar to FasL gld/gld mice, which express a mutant form of FasL that cannot bind Fas, but surprisingly, FasL Δm/Δm mice (on a C57BL/6 background) succumbed to systemic lupus erythematosus (SLE)-like autoimmune kidney destruction and histiocytic sarcoma, diseases that occur only rarely and much later in FasL gld/gld mice. These results demonstrate that mFasL is essential for cytotoxic activity and constitutes the guardian against lymphadenopathy, autoimmunity and cancer, whereas excess sFasL appears to promote autoimmunity and tumorigenesis through non-apoptotic activities

NFIL3 mutations alter immune homeostasis and sensitise for arthritis pathology

OBJECTIVES: NFIL3 is a key immunological transcription factor, with knockout mice studies identifying functional roles in multiple immune cell types. Despite the importance of NFIL3, little is known about its function in humans. METHODS: Here, we characterised a kindred of two monozygotic twin girls with juvenile idiopathic arthritis at the genetic and immunological level, using whole exome sequencing, single cell sequencing and flow cytometry. Parallel studies were performed in a mouse model. RESULTS: The patients inherited a novel p.M170I in NFIL3 from each of the parents. The mutant form of NFIL3 demonstrated reduced stability in vitro. The potential contribution of this mutation to arthritis susceptibility was demonstrated through a preclinical model, where Nfil3-deficient mice upregulated IL-1β production, with more severe arthritis symptoms on disease induction. Single cell sequencing of patient blood quantified the transcriptional dysfunctions present across the peripheral immune system, converging on IL-1β as a pivotal cytokine. CONCLUSIONS: NFIL3 mutation can sensitise for arthritis development, in mice and humans, and rewires the innate immune system for IL-1β over-production.status: publishe