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Background Investigating the causes of stillbirth is crucial for both parents and healthcare providers as it helps explain why the baby died, guides clinical care in future pregnancies, and aids in developing strategies to prevent stillbirth. The usefulness or utility of investigations for stillbirth is poorly defined and unclear. As a result, protocols for investigating the causes of stillbirth are currently based on clinical consensus and fail to prioritise investigative approaches that are most effective at determining a cause of death. Objectives The objectives of this scoping review were to identify the available evidence, key characteristics, and knowledge gaps regarding the utility of stillbirth investigations. Search strategy An a priori protocol was implemented and included a systematic search in MEDLINE, CINAHL, EMBASE, Scopus, and Cochrane from inception until 28 May 2024. Selection criteria Studies examining stillbirth investigations, yield, and value were included. Data collection and analysis Data were collected using a purpose-built data extraction tool and an analysis was undertaken. Results 57 potentially eligible studies were identified, and 34 studies (with 11,410 stillbirths) were included. Three studies examined clinical utility using a comprehensive testing protocol. Definition of utility or value of investigations varied across the studies, classification system for cause of death and investigation protocols varied. Placental pathology was reported as the most useful investigation in 65%–96% of cases, identified a cause of death in 61–71% of cases and impacting the medical management in 36% of cases (13 studies, 5,169 stillbirths). Autopsy can identify the cause of death in 36–77% of cases and provided new information in 17–26% of cases (17 studies, 4,336 stillbirths). Genetic analysis was useful in 29% of cases (seven studies, 1,886 stillbirths). One study (512 stillbirths) examined the value of investigation by presenting clinical scenario. Conclusions This review indicates that Investigation protocols for stillbirth should include placental pathology, autopsy, and genetic testing. Future studies should address the value of tests by presenting clinical scenarios, use of a consistent definition of stillbirth, classification system and measurement of investigation value.

Hemolytic uremic syndrome (HUS) is a potentially life-threatening condition. It often occurs after gastrointestinal infection with E. coli O157:H7, which produces Shiga toxins (Stx) that cause hemolytic anemia, thrombocytopenia, and renal injury. Stx-mediated changes in endothelial phenotype have been linked to the pathogenesis of HUS. Here we report our studies investigating Stx-induced changes in gene expression and their contribution to the pathogenesis of HUS. Stx function by inactivating host ribosomes but can also alter gene expression at concentrations that minimally affect global protein synthesis. Gene expression profiling of human microvascular endothelium treated with Stx implicated a role for activation of CXCR4 and CXCR7 by their shared cognate chemokine ligand (stromal cell-derived factor-1 [SDF-1]) in Stx-mediated pathophysiology. The changes in gene expression required a catalytically active Stx A subunit and were mediated by enhanced transcription and mRNA stability. Stx also enhanced the association of CXCR4, CXCR7, and SDF1 mRNAs with ribosomes. In a mouse model of Stx-mediated pathology, we noted changes in plasma and tissue content of CXCR4, CXCR7, and SDF-1 after Stx exposure. Furthermore, inhibition of the CXCR4/SDF-1 interaction decreased endothelial activation and organ injury and improved animal survival. Finally, in children infected with E. coli O157:H7, plasma SDF-1 levels were elevated in individuals who progressed to HUS. Collectively, these data implicate the CXCR4/CXCR7/SDF-1 pathway in Stx-mediated pathogenesis and suggest novel therapeutic strategies for prevention and/or treatment of complications associated with E. coli O157:H7 infection.

Escherichia coli O157:H7-associated hemolytic-uremic syndrome (HUS) is characterized by profound prothrombotic abnormalities. Endothelial dysfunction, manifested as dysregulation of angiopoietins 1 and 2 (Ang-1/2), could underlie HUS pathophysiology. We measured Ang-1/2 in 77 children with E. coli O157:H7 infection. Ang-1, Ang-2, and the Ang-2/Ang-1 ratio were significantly different in HUS vs the pre-HUS phase of illness or uncomplicated infection. Angiopoietin dysregulation preceded HUS and worsened as HUS developed. In vitro exposure of human microvascular endothelial cells to Shiga toxin recapitulated the in vivo observations. Angiopoietin regulation is profoundly affected before and during HUS, reflecting that subdinical endothelial dysfunction precedes overt microangiopathy.

Escherichia coli-derived verotoxins (VTs) play a critical role in the pathogenesis of hemolytic uremic syndrome (HUS) in major part due to vascular endothelial damage. Perturbations in endothelial phenotype account for many of the clinical features observed in patients. VTs inactivate host cell ribosomes and prevent protein synthesis. Interestingly, however, they also dramatically alter gene expression at concentrations that have only minor effects on overall mRNA translation. Using endothelin-1 as a model, we describe the molecular mechanisms by which VT alters the endothelial cell phenotype in HUS. RNA metabolism pathways and effects on translation may play central roles in the molecular events operative in vascular injury mediated by these potent bacteria-derived exotoxins.

Melanoma of the skin is an increasingly common tumour, which often has a slow early growth rate during which curable lesions may be detected and removed. Physicians therefore have the potential to reduce mortality and this guideline is intended to promote early diagnosis of melanoma. The majority of melanomas occur in white-skinned people. The most common risk factors are pale sun-sensitive skin and the presence of increased numbers of melanocytic naevi (moles). Melanoma is more common in women than men; the mean age of onset is 50 years; and a fifth of cases occur in young adults. In the UK population the most common sites are on the lower leg in women, and on the back in men. The predictors of melanoma are progressive change in the shape, size and colour of moles. This guideline provides a series of photographs of moles, melanomas and other skin lesions, which may resemble melanomas.

The EU ruling bans the import or manufacture of vacuum cleaners over 1,600 watts from today, although stores will still be able to sell their remaining stock.

The EU ruling bans the import or manufacture of vacuum cleaners over 1,600 watts from today, although stores will still be able to sell their remaining stock.

The EU ruling bans the import or manufacture of vacuum cleaners over 1,600 watts from today, although stores will still be able to sell their remaining stock.

The militia leader who shot the film, named only as 'Zhuk', tried to justify his men's actions.