LUBAC is essential for embryogenesis by preventing cell death and enabling haematopoiesis.

The linear ubiquitin chain assembly complex (LUBAC) is required for optimal gene activation and prevention of cell death upon activation of immune receptors, including TNFR1 1 . Deficiency in the LUBAC components SHARPIN or HOIP in mice results in severe inflammation in adulthood or embryonic lethality, respectively, owing 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. Here we show, by creating HOIL-1-deficient mice, that HOIL-1 is as essential for LUBAC function as HOIP, albeit for different reasons: whereas HOIP is the catalytically active component of LUBAC, HOIL-1 is required for LUBAC assembly, stability and optimal retention in the TNFR1 signalling complex, 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-/- (also known as Rbck1-/-) embryos, yet only the combined loss of caspase-8 with MLKL results in viable HOIL-1-deficient mice. Notably, triple-knockout Ripk3-/-Casp8-/-Hoil-1-/- embryos die at late gestation owing 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 reveal that when LUBAC and caspase-8 are absent, RIPK3 prevents RIPK1 from inducing embryonic lethality by causing defects in fetal haematopoiesis.

Alpha-protein kinase 3 (ALPK3) truncating variants are a cause of autosomal dominant hypertrophic cardiomyopathy.

AIMS: The aim of this study was to determine the frequency of heterozygous truncating ALPK3 variants (ALPK3tv) in patients with hypertrophic cardiomyopathy (HCM) and confirm their pathogenicity using burden testing in independent cohorts and family co-segregation studies. METHODS AND RESULTS: In a discovery cohort of 770 index patients with HCM, 12 (1.56%) were heterozygous for ALPK3tv [odds ratio(OR) 16.11, 95% confidence interval (CI) 7.94-30.02, P = 8.05e-11] compared to the Genome Aggregation Database (gnomAD) population. In a validation cohort of 2047 HCM probands, 32 (1.56%) carried heterozygous ALPK3tv (OR 16.17, 95% CI 10.31-24.87, P < 2.2e-16, compared to gnomAD). Combined logarithm of odds score in seven families with ALPK3tv was 2.99. In comparison with a cohort of genotyped patients with HCM (n = 1679) with and without pathogenic sarcomere gene variants (SP+ and SP-), ALPK3tv carriers had a higher prevalence of apical/concentric patterns of hypertrophy (60%, P < 0.001) and of a short PR interval (10%, P = 0.009). Age at diagnosis and maximum left ventricular wall thickness were similar to SP- and left ventricular systolic impairment (6%) and non-sustained ventricular tachycardia (31%) at baseline similar to SP+. After 5.3 ± 5.7 years, 4 (9%) patients with ALPK3tv died of heart failure or had cardiac transplantation (log-rank P = 0.012 vs. SP- and P = 0.425 vs. SP+). Imaging and histopathology showed extensive myocardial fibrosis and myocyte vacuolation. CONCLUSIONS: Heterozygous ALPK3tv are pathogenic and segregate with a characteristic HCM phenotype.

Postmortem microfocus computed tomography for noninvasive autopsies: experience in >250 human fetuses.

BACKGROUND: Noninvasive imaging autopsy alternatives for fetuses weighing <500 grams are limited. Microfocus computed tomography has been reported as a viable option in small case series with the potential to avoid an invasive autopsy. Implementation of postmortem microfocus computed tomography in a large cohort as part of routine clinical service has yet been unreported, and realistic "autopsy prevention rates" are unknown. OBJECTIVE: This study aimed to describe the range of abnormalities detectable on fetal microfocus computed tomography in a clinical setting and additional findings identified on the antenatal ultrasound and to estimate the invasive autopsy avoidance rate (ie, cases in which imaging was sufficient to deem autopsy unnecessary). STUDY DESIGN: A prospective observational case series of all fetuses referred for microfocus computed tomography imaging at a single institution was conducted for 3 years (2016-2019). Imaging was reported by 2 pediatric radiologists before autopsy, with "decision to proceed" based on the specialist perinatal pathologists' judgment and parental consent. Agreement rates between microfocus computed tomography and antenatal ultrasound were evaluated, and where feasible, diagnostic accuracy for microfocus computed tomography was calculated using autopsy as a reference standard. RESULTS: A total of 268 fetuses were included (2-350 grams body weight; 11-24 weeks' gestation), with cause for demise in 122 of 268 (45.5%). Of the 122 fetuses, 64 (52.5%) exhibited fetal anomalies. Although 221 of 268 (82.5%) fetuses had consent for invasive autopsy, only 29 of the 221 (13.1%) underwent this procedure, which implied an autopsy avoidance rate of 192 of 221 (86.9%). Complete agreement was present for all brain, thoracic, and abdominal pathologies, whereas sensitivity and specificity for cardiac anomalies were 66.7% and 91.7%, respectively. Microfocus computed tomography and antenatal ultrasound agreement was found in 219 of 266 cases (81.9%), with partial agreement in 21 of 266 (7.9%) and disagreement in 26 of 266 (10.5%), mostly because of additional cardiac, soft tissue, or genitourinary findings by microfocus computed tomography, which were not seen on the ultrasound. CONCLUSION: Fetal microfocus computed tomography imaging is a viable and useful tool for imaging early gestational fetuses and can avoid the need for invasive autopsy. Confirmation of antenatal diagnoses is achieved in most cases, and additional anomalies may also be detected.

Assessing the Capability and Potential of LiDAR for Weed Detection.

Conventional methods of uniformly spraying fields to combat weeds, requires large herbicide inputs at significant cost with impacts on the environment. More focused weed control methods such as site-specific weed management (SSWM) have become popular but require methods to identify weed locations. Advances in technology allows the potential for automated methods such as drone, but also ground-based sensors for detecting and mapping weeds. In this study, the capability of Light Detection and Ranging (LiDAR) sensors were assessed to detect and locate weeds. For this purpose, two trials were performed using artificial targets (representing weeds) at different heights and diameter to understand the detection limits of a LiDAR. The results showed the detectability of the target at different scanning distances from the LiDAR was directly influenced by the size of the target and its orientation toward the LiDAR. A third trial was performed in a wheat plot where the LiDAR was used to scan different weed species at various heights above the crop canopy, to verify the capacity of the stationary LiDAR to detect weeds in a field situation. The results showed that 100% of weeds in the wheat plot were detected by the LiDAR, based on their height differences with the crop canopy.

Legalities of Healing: Handling Alterities at the Edge of Medicine in France, 1980s-2010s.

The practice of healing by anyone other than qualified doctors or pharmacists has been allegedly illegal in France since the nineteenth century. In this judicial order, the state delegated the power to oversee the boundaries of medicine to doctors and pharmacists, allowing them, with support from criminal courts, to determine which therapeutic techniques should remain their exclusive right. In practice, this apparently neat legal system was never clear-cut; therapists without medical qualifications continued to infringe upon spaces that doctors and pharmacists saw as their preserve, often carving out zones of juridical tolerance. In the 1980s and 1990s, negotiations over the legality or illegality of different kinds of healing intensified. Alternative therapies, such as acupuncture and herbalism, had gained in popularity and their practitioners were keen to negotiate a legal position that would make their work licit. While some succeeded, others got entangled in a new governmental framework that characterized alternative medicines as gateways to "sects." This article examines these developments and explains how new juridical techniques to govern certaintherapies arose in the 1990s. These operated through decentralized surveillance systems that enrolled new actors. These included agencies dedicated to monitoring sects; associations of victims; and individuals such as users, their families, or health professionals. Together, they aimed to "prevent" deviant behavior, thereby fostering what is today one of the most peculiar features of the way the French state regulates alternative healing, which it considers potentially "cult-like."

One-year outcomes in a multicentre cohort study of incident rare diffuse parenchymal lung disease in children (ChILD).

We performed a prospective, observational, cohort study of children newly diagnosed with children's interstitial lung disease (ChILD), with structured follow-up at 4, 8, 12 weeks and 6 and 12 months. 127 children, median age 0.9 (IQR 0.3-7.9) years had dyspnoea (68%, 69/102), tachypnoea (75%, 77/103) and low oxygen saturation (SpO2) median 92% (IQR 88-96). Death (n=20, 16%) was the most common in those <6 months of age with SpO2<94% and developmental/surfactant disorders. We report for the first time that ChILD survivors improved multiple clinical parameters within 8-12 weeks of diagnosis. These data can inform family discussions and support clinical trial measurements.

RBCK1-related disease: A rare multisystem disorder with polyglucosan storage, auto-inflammation, recurrent infections, skeletal, and cardiac myopathy-Four additional patients and a review of the current literature.

In this article, we report four new patients, from three kindreds, with pathogenic variants in RBCK1 and a multisystem disorder characterised by widespread polyglucosan storage. We describe the clinical presentation of progressive skeletal and cardiac myopathy, combined immunodeficiencies and auto-inflammation, illustrate in detail the histopathological findings in multiple tissue types, and report muscle MRI findings.

Chondroid and Osseous Metaplasia of the Central Fibrous Body in Adolescent Hearts with Mutations in TNNI3 and TNNT2 genes.

The histological spectrum of the central fibrous body (CFB) of the heart, particularly in humans, is not fully characterized. Herein, we describe the presence of cartilage and bone within the CFB of 2 explanted heart specimens from patients with known mutation-driven cardiomyopathy involving the TNNI3 and TNNT2 genes, review the existing literature on the identified variants particularly TNNI3 (p.Asn185Thrfs*14) and TNNT2 (p.Arg141Trp), and provide insights into the plausible nature of such histopathological observation based on animal studies and the few reported cases in humans.

Reappraising myocardial fibrosis in severe aortic stenosis: an invasive and non-invasive study in 133 patients.

Aims: To investigate myocardial fibrosis (MF) in a large series of severe aortic stenosis (AS) patients using invasive biopsy and non-invasive imaging. Methods and results: One hundred thirty-three patients with severe, symptomatic AS accepted for surgical aortic valve replacement underwent cardiovascular magnetic resonance (CMR) with late gadolinium enhancement (LGE) and extracellular volume fraction (ECV) quantification. Intra-operative left ventricular (LV) biopsies were performed by needle or scalpel, yielding tissue with (n = 53) and without endocardium (n = 80), and compared with 10 controls. Myocardial fibrosis occurred in three patterns: (i) thickened endocardium with a fibrotic layer; (ii) microscopic scars, with a subendomyocardial predominance; and (iii) diffuse interstitial fibrosis. Collagen volume fraction (CVF) was elevated (P < 0.001) compared with controls, and higher (P < 0.001) in endocardium-containing samples with a decreasing CVF gradient from the subendocardium (P = 0.001). Late gadolinium enhancement correlated with CVF (P < 0.001) but not ECV. Both LGE and ECV correlated independently (P < 0.001) with N-terminal pro-brain natriuretic peptide and high-sensitivity-troponin T. High ECV was also associated with worse LV remodelling, left ventricular ejection fraction and functional capacity. Combining high ECV and LGE better identified patients with more adverse LV remodelling, blood biomarkers and histological parameters, and worse functional capacity than each parameter alone. Conclusion: Myocardial fibrosis in severe AS is complex, but three main patterns exist: endocardial fibrosis, microscars (mainly in the subendomyocardium), and diffuse interstitial fibrosis. Neither histological CVF nor the CMR parameters ECV and LGE capture fibrosis in its totality. A combined, multi-parametric approach with ECV and LGE allows best stratification of AS patients according to the response of the myocardial collagen matrix.

International management platform for children's interstitial lung disease (chILD-EU).

BACKGROUND: Children's interstitial lung diseases (chILD) cover many rare entities, frequently not diagnosed or studied in detail. There is a great need for specialised advice and for internationally agreed subclassification of entities collected in a register.Our objective was to implement an international management platform with independent multidisciplinary review of cases at presentation for long-term follow-up and to test if this would allow for more accurate diagnosis. Also, quality and reproducibility of a diagnostic subclassification system were assessed using a collection of 25 complex chILD cases. METHODS: A web-based chILD management platform with a registry and biobank was successfully designed and implemented. RESULTS: Over a 3-year period, 575 patients were included for observation spanning a wide spectrum of chILD. In 346 patients, multidisciplinary reviews were completed by teams at five international sites (Munich 51%, London 12%, Hannover 31%, Ankara 1% and Paris 5%). In 13%, the diagnosis reached by the referring team was not confirmed by peer review. Among these, the diagnosis initially given was wrong (27%), imprecise (50%) or significant information was added (23%).The ability of nine expert clinicians to subcategorise the final diagnosis into the chILD-EU register classification had an overall exact inter-rater agreement of 59% on first assessment and after training, 64%. Only 10% of the 'wrong' answers resulted in allocation to an incorrect category. Subcategorisation proved useful but training is needed for optimal implementation. CONCLUSIONS: We have shown that chILD-EU has generated a platform to help the clinical assessment of chILD. TRIAL REGISTRATION NUMBER: Results, NCT02852928.

Sirolimus therapy in infants with severe hyperinsulinemic hypoglycemia.

Hyperinsulinemic hypoglycemia is the most common cause of severe, persistent neonatal hypoglycemia. The treatment of hyperinsulinemic hypoglycemia that is unresponsive to diazoxide is subtotal pancreatectomy. We examined the effectiveness of the mammalian target of rapamycin (mTOR) inhibitor sirolimus in four infants with severe hyperinsulinemic hypoglycemia that had been unresponsive to maximal doses of diazoxide (20 mg per kilogram of body weight per day) and octreotide (35 µg per kilogram per day). All the patients had a clear glycemic response to sirolimus, although one patient required a small dose of octreotide to maintain normoglycemia. There were no major adverse events during 1 year of follow-up.

Childhood neoplasms presenting at autopsy: A 20-year experience.

OBJECTIVE: The aims of the review are to establish the number of undiagnosed neoplasms presenting at autopsy in a single centre and to determine the incidence and most common causes of sudden unexpected death due to neoplasia in infancy and childhood (SUDNIC). DESIGN: Retrospective observational study of paediatric autopsies performed on behalf of Her Majesty's Coroner over a 20-year period (1996-2015; n = 2,432). Neoplasms first diagnosed at autopsy were identified from an established database and cases meeting the criteria for sudden unexpected death were further categorised. RESULTS: Thirteen previously undiagnosed neoplasms were identified, including five haematological malignancies, two medulloblastomas, two neuroblastomas, two cardiac tumours and two malignancies of renal origin. Eight cases met the criteria for SUDNIC (0.33% of autopsies), the commonest group of which were haematological malignancies (n = 3). CONCLUSIONS: Neoplasms presenting as unexpected death in infancy and childhood and diagnosed at autopsy are rare. The findings suggest that haematological malignancies are the commonest cause of SUDNIC and highlight the importance of specialist autopsy in cases of sudden unexpected death.

Interstitial Lung Disease in Children Made Easier Well, Almost.

Interstitial lung disease (ILD) in pediatric patients is different from that in adults, with a vast array of pathologic conditions unique to childhood, varied modes of presentation, and a different range of radiologic appearances. Although rare, childhood ILD (chILD) is associated with significant morbidity and mortality, most notably in conditions of disordered surfactant function, with respiratory failure in 100% of neonates with surfactant protein B dysfunction and 100% mortality without lung transplantation. The authors present a summary of lung development and anatomy, followed by an organized approach, using the structure and nomenclature of the 2013 update to the chILD Research Network classification system, to aid radiologic diagnosis of chILD. Index radiologic cases with contemporaneous histopathologic findings illustrate a summary of recent imaging studies covering the full spectrum of chILD. chILD is best grouped by age at presentation from infancy (diffuse developmental disorders, lung growth abnormalities, specific conditions of unknown origin, surfactant dysfunction mutations) to later childhood (disorders of the normal host, disorders related to systemic disease processes, disorders related to immunocompromise). Appreciation of the temporal division of chILD into infant and later childhood onset, along with a sound understanding of pulmonary organogenesis and surfactant homeostasis, will aid in providing useful insight into this important group of pediatric conditions. Application of secondary lobular anatomy to interpretation of thin-section computed tomographic images is pivotal to understanding patterns of ILD and will aid in selecting and narrowing a differential diagnosis. ©RSNA, 2017.

Multiple Cardiac Rhabdomyomas Visualised Using Micro-CT in a Case of Tuberous Sclerosis.

Cardiac rhabdomyoma is the most common tumour of the heart in infancy and childhood, representing approximately 60% of all primary cardiac tumours in these age groups. Though they have a tendency to regress with advancing age and are histologically benign, rhabdomyomas may cause mechanical obstruction to blood flow, arrhythmia, congestive cardiac failure and death and may be associated with underlying genetic syndromes such as tuberous sclerosis. We present the case of a primigravida in her early 20s with no significant medical history who was referred to the Fetal Medicine Unit at 34 weeks' gestation following the detection of an irregular fetal heartbeat. An anomaly scan at 20 weeks had been reported as normal.

Postmortem cardiovascular magnetic resonance imaging in fetuses and children: a masked comparison study with conventional autopsy.

BACKGROUND: Perinatal and pediatric autopsies have declined worldwide in the past decade. We compared the diagnostic accuracy of postmortem, cardiovascular magnetic resonance (CMR) imaging with conventional autopsy and histopathology assessment in fetuses and children. METHODS AND RESULTS: We performed postmortem magnetic resonance imaging in 400 fetuses and children, using a 1.5-T Siemens Avanto magnetic resonance scanner before conventional autopsy. A pediatric CMR imager reported the CMR images, masked to autopsy information. The pathologists were masked to the information from CMR images. The institutional research ethics committee approved the study, and parental consent was obtained. Assuming a diagnostic accuracy of 50%, 400 cases were required for a 5% precision of estimate. Three cases were excluded from analysis, 2 with no conventional autopsy performed and 1 with insufficient CMR sequences performed. Thirty-eight CMR data sets were nondiagnostic (37 in fetuses ≤24 weeks; 1 in a fetus >24 weeks). In the remaining 359 cases, 44 cardiac abnormalities were noted at autopsy. Overall sensitivity and specificity (95% confidence interval) of CMR was 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%) for detecting any cardiac pathology, with positive and negative predictive values of 72.7% (58.2-83.7%) and 96.2% (93.5-97.8%), respectively. Higher sensitivity of 92.6% (76.6-97.9%), specificity of 99.1% (97.4-99.7%), positive predictive value of 89.3% (72.8-96.3%), and negative predictive value of 99.4% (97.8-99.8%) were seen for major structural heart disease. CONCLUSIONS: Postmortem CMR imaging may be a useful alternative to conventional cardiac autopsy in fetuses and children for detecting cardiac abnormalities. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT01417962.

Reference ranges for organ weights of infants at autopsy: results of >1,000 consecutive cases from a single centre.

BACKGROUND: Infancy is the most common period for childhood death, including both neonatal deaths from obstetric or medical complications and sudden unexpected infant deaths. The weighing of organs at autopsy is an established process and is recommended in current protocols. However, minimal contemporary data is available regarding reference ranges for organ weights of infants. METHODS: Organ weight data for consecutive infant autopsies over a 14 year period performed at a single tertiary centre, including >1,000 cases, were examined in order to provide up to date reference ranges across this age range, using linear regression modelling and the standard LMS method. RESULTS: 1,525 infant autopsies were analysed, of which 1,190 were subsequently used in the creation of linear regression models prior to performance of the LMS method. Organ weight charts were produced for the 5th, 25th, 50th, 75th and 95th centiles for the heart, lungs, liver, spleen, kidneys, pancreas, thymus gland and adrenal glands. CONCLUSION: This study provides the largest single centre contemporary dataset of infant autopsies allowing provision of up-to-date 'normal' ranges for all major organ weights across this age range.

Fatal aspiration of foreign bodies in infants and children.

PURPOSE: To investigate the frequency, circumstances, demographics and autopsy findings of infants and children dying as a result of foreign body aspiration. METHODS: Retrospective review of autopsy cases in children aged between seven days and 18 years, at one specialist centre over a 16-year period, in which death was the result of aspiration of a foreign body. RESULTS: Ten cases were identified out of a total autopsy population of 2165. Only one individual had an underlying diagnosis potentially contributing to aspiration. All but one case involved aspiration of food, with grapes being a feature of four cases. In cases with a prolonged survival interval, autopsy demonstrated bronchopneumonia and hypoxic-ischaemic encephalopathy. In the remaining cases autopsy findings were non-specific. CONCLUSIONS: Fatal aspiration of a foreign body is rare in this population. The cases involve normal children who aspirate food, particularly grapes. There are typically minimal, non-specific findings at autopsy.

Immersion-related deaths in infants and children: autopsy experience from a specialist center.

PURPOSE: To investigate the demographics, circumstances and autopsy findings in infants and children dying following immersion. METHODS: A retrospective review of a pediatric autopsy database at a specialist center over a 16-year period (1995-2010) was undertaken to identify deaths between 7 days and 16 years of age in whom death occurred following immersion. RESULTS: 28 infants and children died following immersion during the study period. 82 % were aged <4 years, with peak age of death between 1 and 2 years. Immersion occurred at home in a bath or private pool in 70 % of cases. There was a lack of direct supervision in all but two cases where the information was recorded (91 %); one of these cases occurred in a public swimming lesson, and in the other the carer was incapacitated. Autopsy findings were non-specific. Facial or subconjunctival petechial hemorrhages were a feature of 18 % of cases. There was increased lung weight, or histological pulmonary edema/intra-alveolar hemorrhage in all but one case. CONCLUSIONS: The data suggest that the majority of pediatric immersion-related deaths were potentially preventable with appropriate supervision. The findings strongly support the role of education regarding adequate carer supervision of infants and children while bathing, particularly in children with underlying conditions such as epilepsy. As private pools and "hot tubs" become more common in the UK and other jurisdictions, specific recommendations such as fencing pools will need to be included in advice to carers. So-called 'dry drowning" appears to be an uncommon mechanism of death in this age group.

Sudden unexpected infant deaths associated with car seats.

The purpose of this study was to investigate the frequency, circumstances, demographics, and causes of death of infants dying while seated in car safety seats. A retrospective review of a pediatric autopsy database at a specialist center over a 16-year period was undertaken to identify any infant deaths (aged <1 year), in whom death occurred while seated in a car safety seat. Fourteen car seat-associated deaths were identified from a total of 1,465 coronial infant autopsies (0.96 %). Four involved infants were being appropriately transported in the car seat, all of whom had a medical underlying cause of death (one infection and three congenital heart disease). The majority (10 cases; 70 %) occurred while car seats were being inappropriately used, outside of the car, including as an alternative to a cot or high-chair. Five of these infants died of explained causes, but four deaths remained unexplained after autopsy, and in one no cause of death was available. There were no cases of previously healthy infants dying unexpectedly in a car seat when it was being used appropriately, and in this series there were no cases of traumatic death associated with car seats, either during road traffic accidents, or from falling or being suspended from a car seat. Infant deaths in car seats are rare. These data support the recommendation that car seats be used only for transport and not as alternatives for cots or high-chairs. More research is required to investigate the effect of travel in car seats on infants with underlying conditions. There appears to be no increased risk of unexpected deaths of healthy infants transported appropriately in car seats.