The Linear Ubiquitin chain Assembly Complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR11. Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, due to deregulation of TNFR1-mediated cell death2–8. In humans, deficiency in the third LUBAC component, HOIL-1, causes autoimmunity and inflammatory disease, similar to HOIP deficiency, whereas HOIL-1 deficiency in mice was reported to cause no overt phenotype9–11. By creating HOIL-1-deficient mice, we here show that HOIL-1 is, however, as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is LUBAC’s catalytically active component, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1-signalling complex (TNFR1-SC), thereby preventing aberrant cell death. Both, HOIL-1 and HOIP prevent embryonic lethality at mid-gestation by interfering with aberrant TNFR1-mediated endothelial cell death, which only partially depends on RIPK1 kinase activity. Co-deletion of Caspase-8 with RIPK3 or MLKL prevents cell death in Hoil-1-/- embryos, yet only combined loss of Caspase-8 with MLKL results in viable HOIL-1-deficient mice. Interestingly, Ripk3-/-Caspase-8-/-Hoil-1-/- embryos die at late-gestation due to haematopoietic defects that are rescued by co-deletion of RIPK1 but not MLKL. Collectively, these results demonstrate that both, HOIP and HOIL-1 are essential LUBAC components and are required for embryogenesis by preventing aberrant cell death. Furthermore, they unveil that, when LUBAC and Caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in foetal haematopoiesis.

BackgroundPostmortem examination is the single most useful investigation in providing information to parents about why their baby or child died. Despite this, uptake remains well below the recommended 75%.ObjectiveTo address the question ‘what are the barriers and motivators to perinatal, prenatal and paediatric PM examination?’Search strategyKey databases including Pubmed and CINAHL; Cochrane library, websites of relevant patient organisations, hand search of key journals, first and last authors and references.Selection criteriaPeer‐reviewed qualitative, quantitative or mixed methods research examining factors affecting uptake or decline of perinatal or paediatric postmortem examination.Data collection and analysisNarrative synthesis; findings were compared across studies to examine interrelations.Main resultsSeven major themes describing barriers to postmortem uptake were identified: dislike of invasiveness, practicalities of the procedure, organ retention issues, protective parenting, communication and understanding, religion and culture and professional or organisational barriers. Six major themes related to factors which facilitated parental consent were identified: desire for information, contributing to research, coping and well‐being, respectful care, minimally invasive options, and policy and practice. There were a number of themes in the literature that reflected best practice.ConclusionFindings highlight the need for better health professional education and the fact some concerns may be mitigated if less invasive methods of postmortem were routinely available. New consent packages and codes of practice may have a positive impact on perception of examination after death. The landscape is changing; further research is necessary to assess the impact on postmortem uptake rates.Tweetable abstractSystematic review to explore the barriers and motivators to perinatal, prenatal and paediatric postmortem examination.

Postmortem whole-body fetal microfocus computed tomography gives noninvasive, detailed anatomic examinations that are achieved in minutes at high resolution. Microfocus computed tomography may be preferable to magnetic resonance imaging in early gestation fetuses and may offer an acceptable method of examination after fetal loss for parents who decline invasive autopsy. This will facilitate autopsy and subsequent discussions between medical professionals who are involved in patient care and counselling for future pregnancies.

+A: AbstractObjectives There have been many attempts to classify cause of death in stillbirth, all such systems being subjective, allowing for significant observer bias, making accurate comparisons between systems challenging. The aim of this study was to examine factors relating to determination of cause of death by using a large dataset from two specialist centres, in which observer bias has been reduced by objectively classifying findings and assigning causes of death based on predetermined criteria.Methods Detailed autopsy reports from intrauterine fetal deaths (IUFD) during [2005][2006][2007][2008][2009][2010][2011][2012][2013] in the second and third trimesters were reviewed and findings entered into a specially designed database, in which cause of death (CoD) was assigned using predefined objective criteria. Data regarding CoD categories and factors affecting determination of CoD were analysed through queries and statistical tests run using Microsoft Access, Excel, Graph Pad Prism and StatsDirect, with Mann-Whitney U-test and comparison of proportions testing as appropriate.Results There were 1,064 IUFDs, including 639 stillbirths at >23 weeks' gestation.Overall, around 40% (412 (39%)), had a definite or highly likely cause of death identified, whilst 60% (652) were classified as 'unexplained'. Of these, around half had identified risk factors, or lesions of uncertain significance present, whilst the remaining half (292 (45%)) were entirely unexplained. A stepwise increase in the proportion of unexplained deaths was observed with increasing severity of maceration. Black and Asian women had significantly greater proportions of deaths due to ascending infection whilst women aged over 40 had significantly increased placental-related causes of death. There was no significant difference in cause of death distribution by maternal 3 body mass index or with increasing post-mortem interval. Almost 20% of definitive or likely causes of death could be identified from clinical review or external examination / imaging of the fetus, with most of the remainder being determined following placental examination.Conclusions Based on objective criteria, most IUFDs across gestation remain unexplained despite autopsy examination. The rate of unexplained death varies between 30 and 60% depending on interpretation of the significance of features. The cause of death provided across studies is variable and dependent on both the classification system used and subjective interpretation such that reduction in the proportion of 'unexplained' cases across studies is largely based on speculation around mechanism of death. Novel methods to determine objectively the mechanism of death at postmortem examination are required. 4 +A: IntroductionThe primary aim of postmortem investigation of intrauterine death is determination of cause and mechanism of death, to facilitate counseling of parents, management of subsequent pregnancies and future interventions [1][2][3][4] . Over the last 50 years there have been many attempts to classify cause o...

Placental pathologies represent the largest category of cause of intrauterine death. Placental histological examination is the single most useful component of the autopsy process in this clinical setting. A minority of cases are associated with specific placental pathologies, often with high recurrence rates, that can be diagnosed only on microscopic examination of the placenta. Many deaths remain unexplained, although placental histological lesions may be present which are of uncertain significance. A rigorous, systematic approach to placental pathology research and classification may yield better understanding of the significance of placental findings and reduce the rate of unexplained intrauterine deaths. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

Objectives

The thymus is a primary lymphoid organ, essential for T cell maturation and selection. There has been long-standing interest in processes underpinning thymus generation and the potential to manipulate it clinically, because alterations of thymus development or function can result in severe immunodeficiency and autoimmunity. Here, we identify epithelial-mesenchymal hybrid cells, capable of long-term expansion in vitro, and able to reconstitute an anatomic phenocopy of the native thymus, when combined with thymic interstitial cells and a natural decellularised extracellular matrix (ECM) obtained by whole thymus perfusion. This anatomical human thymus reconstruction is functional, as judged by its capacity to support mature T cell development in vivo after transplantation into humanised immunodeficient mice. These findings establish a basis for dissecting the cellular and molecular crosstalk between stroma, ECM and thymocytes, and offer practical prospects for treating congenital and acquired immunological diseases.

Although maceration may lead to failure in some cases, postmortem ultrasound reaches diagnostically acceptable levels for brain and abdominal organs, compared with conventional autopsy. It may therefore play a role as a first-line examination before other virtual autopsy techniques are indicated.