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Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1 High ;CHD7 Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1 High ;CHD7 Low xenograft model. BMI1 and CHD7 are chromatin remodelling genes with a role in medulloblastoma pathogenesis. Here, the authors demonstrate that the BMI1 High /CHD7 Low signature mediates metabolic adaptation in G4 MB and predicts response to inositol treatment either alone or in combination with chemotherapy.

Paediatric brain tumors are becoming well characterized due to large genomic and epigenomic studies. Metabolomics is a powerful analytical approach aiding in the characterization of tumors. This study shows that common cerebellar tumors have metabolite profiles sufficiently different to build accurate, robust diagnostic classifiers, and that the metabolite profiles can be used to assess differences in metabolism between the tumors. Tissue metabolite profiles were obtained from cerebellar ependymoma (n = 18), medulloblastoma (n = 36), pilocytic astrocytoma (n = 24) and atypical teratoid/rhabdoid tumors (n = 5) samples using HR-MAS. Quantified metabolites accurately discriminated the tumors; classification accuracies were 94% for ependymoma and medulloblastoma and 92% for pilocytic astrocytoma. Using current intraoperative examination the diagnostic accuracy was 72% for ependymoma, 90% for medulloblastoma and 89% for pilocytic astrocytoma. Elevated myo -inositol was characteristic of ependymoma whilst high taurine, phosphocholine and glycine distinguished medulloblastoma. Glutamine, hypotaurine and N-acetylaspartate (NAA) were increased in pilocytic astrocytoma. High lipids, phosphocholine and glutathione were important for separating ATRTs from medulloblastomas. This study demonstrates the ability of metabolic profiling by HR-MAS on small biopsy tissue samples to characterize these tumors. Analysis of tissue metabolite profiles has advantages in terms of minimal tissue pre-processing, short data acquisition time giving the potential to be used as part of a rapid diagnostic work-up.

The most common malignant brain tumour in children, medulloblastoma (MB), is subdivided into four clinically relevant molecular subgroups, although targeted therapy options informed by understanding of different cellular features are lacking. Here, by comparing the most aggressive subgroup (Group 3) with the intermediate (SHH) subgroup, we identify crucial differences in tumour heterogeneity, including unique metabolism-driven subpopulations in Group 3 and matrix-producing subpopulations in SHH. To analyse tumour heterogeneity, we profiled individual tumour nodules at the cellular level in 3D MB hydrogel models, which recapitulate subgroup specific phenotypes, by single cell RNA sequencing (scRNAseq) and 3D OrbiTrap Secondary Ion Mass Spectrometry (3D OrbiSIMS) imaging. In addition to identifying known metabolites characteristic of MB, we observed intra- and internodular heterogeneity and identified subgroup-specific tumour subpopulations. We showed that extracellular matrix factors and adhesion pathways defined unique SHH subpopulations, and made up a distinct shell-like structure of sulphur-containing species, comprising a combination of small leucine-rich proteoglycans (SLRPs) including the collagen organiser lumican. In contrast, the Group 3 tumour model was characterized by multiple subpopulations with greatly enhanced oxidative phosphorylation and tricarboxylic acid (TCA) cycle activity. Extensive TCA cycle metabolite measurements revealed very high levels of succinate and fumarate with malate levels almost undetectable particularly in Group 3 tumour models. In patients, high fumarate levels (NMR spectroscopy) alongside activated stress response pathways and high Nuclear Factor Erythroid 2-Related Factor 2 (NRF2; gene expression analyses) were associated with poorer survival. Based on these findings we predicted and confirmed that NRF2 inhibition increased sensitivity to vincristine in a long-term 3D drug treatment assay of Group 3 MB. Thus, by combining scRNAseq and 3D OrbiSIMS in a relevant model system we were able to define MB subgroup heterogeneity at the single cell level and elucidate new druggable biomarkers for aggressive Group 3 and low-risk SHH MB.

Thunderstorm asthma is often characterised by a sudden surge in patients presenting with exacerbated symptoms of asthma linked to thunderstorm activity. Here, we describe a large spike in asthma and difficulty breathing symptoms observed across parts of England on 17 June 2021. The number of healthcare presentations during the asthma event was compared to expected levels for the overall population and across specific regions. Across affected geographical areas, emergency department attendances for asthma increased by 560% on 17 June compared to the average number of weekday daily attendances during the previous 4 weeks. General practitioner out of hours contacts increased by 349%, National Health Service (NHS) 111 calls 193%, NHS 111 online assessments 581% and ambulance call outs 54%. Increases were particularly noted in patient age groups 5–14 and 15–44 years. In non-affected regions, increases were small (<10%) or decreased, except for NHS 111 online assessments where there was an increase of 39%. A review of the meteorological conditions showed several localised, weak, or moderate thunderstorms specifically across parts of Southeast England on the night of June 16. In this unprecedented episode of asthma, the links to meteorologically defined thunderstorm activity were not as clear as previous episodes, with less evidence of ‘severe’ thunderstorm activity in those areas affected, prompting further discussion about the causes of these events and implications for public health management of the risk.

Brain tumours are the most common cause of cancer death in children. Molecular studies have greatly improved our understanding of these tumours but tumour metabolism is underexplored. Metabolites measured in vivo have been reported as prognostic biomarkers of these tumours but analysis of surgically resected tumour tissue allows a more extensive set of metabolites to be measured aiding biomarker discovery and providing validation of in vivo findings. In this study, metabolites were quantified across a range of paediatric brain tumours using 1 H-High-Resolution Magic Angle Spinning nuclear magnetic resonance spectroscopy (HR-MAS) and their prognostic potential investigated. HR-MAS was performed on pre-treatment frozen tumour tissue from a single centre. Univariate and multivariate Cox regression was used to examine the ability of metabolites to predict survival. The models were cross validated using C-indices and further validated by splitting the cohort into two. Higher concentrations of glutamine were predictive of a longer overall survival, whilst higher concentrations of lipids were predictive of a shorter overall survival. These metabolites were predictive independent of diagnosis, as demonstrated in multivariate Cox regression models. Whilst accurate quantification of metabolites such as glutamine in vivo is challenging, metabolites show promise as prognostic markers due to development of optimised detection methods and increasing use of 3 T clinical scanners.

[Introductory paragraph] The present generation must confront a challenge. The challenge is to determine what it must do for the sake of future generations. This challenge is quite puzzling because the present generation, like its predecessors, will pass on to future generations a complex mix of goods, inventions, institutions and opportunities containing a range of benefits and burdens. In this thesis, I focus on one key intergenerational problem – anthropogenic climate change – considering some of the questions of intergenerational justice that it raises. While it has not always been the case, climate and climate change have recently taken on new significance as a process to which humans can, and in fact do, contribute. More specifically, while paleoclimatic data show substantial variation in the Earth’s climate (Masson- Delmotte, Schulz, Abe-Ouchi, Beer, Ganopolski, J.F. González Rouco, E. Jansen, et al., 2013: 385), an ever-growing mass of evidence shows that human activity – particularly the sustained emission of greenhouse gases (GHGs) – is beginning to change the global climate, with much greater changes still to come (IPCC, 2013b: 4, 19ff). This produces what is known as anthropogenic climate change, “a change in the state of the climate that can be identified (e.g., by using statistical tests) by changes in the mean and/or the variability of its properties, and that persists for an extended period, typically decades or longer”, and that results from human activities (IPCC, 2013a: 1448, 1450).

Emergency department (ED) screening is an important strategy to address the persistent human immunodefiency virus (HIV) epidemic; however, ED screening rates remain low. This study describes the development of a quality measure to improve screening rates for HIV among ED patients. A panel of 10 emergency physicians with expertise in ED-based preventive health and quality measurement employed a 3-round modified Delphi process. The panel reviewed peer-reviewed literature and national guidelines to identify high-risk patient populations; participated in anonymous surveys to rank ED screening approaches based on the impact and feasibility of measurement and practice; and discussed survey rankings in consensus discussions. The highest impact and most feasible group to target for quality measurement were ED patients already undergoing testing for other sexually transmitted infections (ie, “co-screening”). This study successfully designed a quality measure to improve coscreening for HIV in the ED. Implementing this measure could enhance detection and subsequent linkage to care, ultimately contributing to the control of these epidemics. The focus on combining screening for HIV with diagnostic testing for patients with signs and symptoms of sexually transmitted infection aligns with an emerging approach in health care settings that balances expected health impact with feasibility challenges.

To describe first author gender differences and characteristics in 1) Society for Academic Emergency Medicine (SAEM) Annual Meeting abstracts and 2) resulting manuscript publications. We performed cross-sectional evaluation of SAEM abstracts from 1990, 1995, 2000, 2005, 2010, 2015, and 2020, compiling and reviewing a random sample of 100 abstracts for each year (total n = 700 abstracts). We documented abstract characteristics, including first author gender, and used the 2020 SAEM scoring rubric. We then searched PubMed to identify manuscript publications resulting from abstracts from 1990 to 2015 (n = 600). Finally, among abstracts that resulted in manuscript publication, we identified first and last author gender on both the abstracts and the resulting publication. Overall, 29% (202/695; n = 5 missing gender) of abstracts had female first authors. Female first authors increased over time (e.g., 17% in 1990 to 35% in 2020). Abstract quality scores were similar (both median [interquartile range] of 11 ([9–12]). Overall, 42% (n = 254/600) of abstracts resulted in a manuscript publication, 39% (n = 65/202) with female and 44% (n = 189/493) with male first authors (p = 0.26). The median time (IQR) from abstract to manuscript publication was longer for abstracts with female first authors vs. those with male first authors (2 [1–3] years and 1 [1, 2] years, p < 0.02); 77% and 78% of publications resulting from abstracts with female and male first authors, respectively, had the same first author. Female first author abstracts more often converted to a male first author manuscript publication (18%, n = 12/65) compared to male first author abstracts converting to female first author publications (7%, n = 14/189). A minority of SAEM abstracts, and manuscript publications resulting from them, had female first authors. Abstracts with female first authors took longer to achieve manuscript publication, and almost a fifth of female first author abstracts resulted in male first author manuscript publication.