GSUE: urban geochemical mapping in Great Britain

The British Geological Survey is responsible for the national strategic geochemical survey of Great Britain. As part of this programme, the Geochemical Surveys of Urban Environments (GSUE) project was initiated in 1992 and to date, 21 cities have been mapped. Urban sampling is based upon the collection of top (0.05 to 0.20 m) and deeper (0.35 to 0.50 m) soil samples on a 500 m grid across the built environment (1 sample per 0.25 km2). Samples are analysed for c. 46 total element concentrations by X-ray Fluorescence Spectrometry (XRFS), pH and loss on ignition (LOI) as an indicator of organic matter content. The data provide an overview of the urban geochemical signature and because they are collected as part of a national baseline programme, can be readily compared with soils in the rural hinterland to assess the extent of urban contamination. The data are of direct relevance to current UK land use planning, urban regeneration and contaminated land legislative regimes. An overview of the project and applications of the data to human health risk assessment, water quality protection and contaminant source identification are presented

Models of KPTN-related disorder implicate mTOR signalling in cognitive and overgrowth phenotypes

KPTN-related disorder is an autosomal recessive disorder associated with germline variants in KPTN (previously known as kaptin), a component of the mTOR regulatory complex KICSTOR. To gain further insights into the pathogenesis of KPTN-related disorder, we analysed mouse knockout and human stem cell KPTN loss-of-function models.Kptn−/− mice display many of the key KPTN-related disorder phenotypes, including brain overgrowth, behavioural abnormalities, and cognitive deficits. By assessment of affected individuals, we have identified widespread cognitive deficits (n = 6) and postnatal onset of brain overgrowth (n = 19). By analysing head size data from their parents (n = 24), we have identified a previously unrecognized KPTN dosage-sensitivity, resulting in increased head circumference in heterozygous carriers of pathogenic KPTN variants.Molecular and structural analysis of Kptn−/− mice revealed pathological changes, including differences in brain size, shape and cell numbers primarily due to abnormal postnatal brain development. Both the mouse and differentiated induced pluripotent stem cell models of the disorder display transcriptional and biochemical evidence for altered mTOR pathway signalling, supporting the role of KPTN in regulating mTORC1.By treatment in our KPTN mouse model, we found that the increased mTOR signalling downstream of KPTN is rapamycin sensitive, highlighting possible therapeutic avenues with currently available mTOR inhibitors. These findings place KPTN-related disorder in the broader group of mTORC1-related disorders affecting brain structure, cognitive function and network integrity.Genetics of disease, diagnosis and treatmen

Whole-genome sequencing reveals host factors underlying critical COVID-19

Critical COVID-19 is caused by immune-mediated inflammatory lung injury. Host genetic variation influences the development of illness requiring critical care1 or hospitalization2,3,4 after infection with SARS-CoV-2. The GenOMICC (Genetics of Mortality in Critical Care) study enables the comparison of genomes from individuals who are critically ill with those of population controls to find underlying disease mechanisms. Here we use whole-genome sequencing in 7,491 critically ill individuals compared with 48,400 controls to discover and replicate 23 independent variants that significantly predispose to critical COVID-19. We identify 16 new independent associations, including variants within genes that are involved in interferon signalling (IL10RB and PLSCR1), leucocyte differentiation (BCL11A) and blood-type antigen secretor status (FUT2). Using transcriptome-wide association and colocalization to infer the effect of gene expression on disease severity, we find evidence that implicates multiple genes—including reduced expression of a membrane flippase (ATP11A), and increased expression of a mucin (MUC1)—in critical disease. Mendelian randomization provides evidence in support of causal roles for myeloid cell adhesion molecules (SELE, ICAM5 and CD209) and the coagulation factor F8, all of which are potentially druggable targets. Our results are broadly consistent with a multi-component model of COVID-19 pathophysiology, in which at least two distinct mechanisms can predispose to life-threatening disease: failure to control viral replication; or an enhanced tendency towards pulmonary inflammation and intravascular coagulation. We show that comparison between cases of critical illness and population controls is highly efficient for the detection of therapeutically relevant mechanisms of disease

Geogenic signatures detectable in topsoils of urban and rural domains in the London region, UK, using parent material classified data

Systematic mapping of the chemical environment of urban areas from around the world have shown varying degrees of control of element distributions by the underlying parent material (PM). The purpose of the study reported here is to assess whether geogenic signatures that dominate soil chemistry in rural domains of Eastern England and which are not strongly impacted by human activities, can also be detected in the London urban region. A PM soil chemistry mapping method is used to determine the spatial variation of topsoil chemistry data in London and the surrounding rural areas. Analysis of variance (ANOVA) of the soil data for the London region indicates that 26–33% of the variance of Al, Ce, Cs, Ga, K, La, Mg, Mn, Nb, Nd, Rb, Ti, V and Y is explained by soil PM (surface geology), and a slightly lesser proportion (19–25%) of the variance for Ca, Co, Fe, I, Ni, Sc, Sr and Th. In comparison, soil PM explains only 5% of the variance of Cd. The variance of some other elements appears to be influenced by a mixture of geogenic and anthropogenic controls, including As, Ba, Cr, Cu, Mo, P, Pb, Sb, Se, Sn and Zn for which PM controls 12–16% of the variance. Geogenic soil chemistry patterns observed for the elements strongly influenced by PM in the rural areas surrounding London can be quite clearly followed into and through the London urban area. Spatial patterns of a range of elements primarily controlled by PM have not been destroyed even in a major urban centre with a recorded history dating back over 2000 years and which has been subjected to extensive urban development, destruction and redevelopment especially during the last 200–300 years

A statistical perspective on the design of drug-court studies

Recent meta-analyses of drug-court studies recognized the poor methodological quality of the evaluations, with only a few being randomized. This article critiques the design of the randomized studies from a statistical perspective. Learning points are identified for future drug-court studies and are applicable to evaluations both of other specialist courts and of court-based interventions more generally. The specific issues covered are randomization, describing the intervention, and baseline characteristics; study outcomes, and sample size calculations; in-program and postprogram behavior, analysis plan, and presentation of results

The Human Lung Cell Atlas: A high-resolution reference map of the human lung in health and disease.

Lung disease accounts for every sixth death globally. Profiling the molecular state of all lung cell types in health and disease is currently revolutionizing the identification of disease mechanisms and will aid the design of novel diagnostic and personalized therapeutic regimens. Recent progress in high-throughput techniques for single-cell genomic and transcriptomic analyses has opened up new possibilities to study individual cells within a tissue, classify these into cell types, and characterize variations in their molecular profiles as a function of genetics, environment, cell-cell interactions, developmental processes, aging, or disease. Integration of these cell state definitions with spatial information allows the in-depth molecular description of cellular neighborhoods and tissue microenvironments, including the tissue resident structural and immune cells, the tissue matrix, and the microbiome. The Human Cell Atlas consortium aims to characterize all cells in the healthy human body and has prioritized lung tissue as one of the flagship projects. Here, we present the rationale, the approach, and the expected impact of a Human Lung Cell Atlas