The national Targeted Lung Health Checks programme: Focusing on the lungs does not mean missing adrenal lesions.

Recently, the UK's national Targeted Lung Health Checks programme produced recommendations for the management of incidental findings identified during the scans performed as part of the lung cancer screening programme. We identified significant discrepancies between the recommendations for adrenal incidentaloma management and those currently implemented into UK practice (2016 European Society of Endocrinology guidelines).This may create conflict and confusion between referrers (respiratory clinicians) and receivers (endocrinologists), with potential negative impact on patients, delay and inefficient use of resources. We also address the potential cost implications of adopting a more vigilant approach as advised by the European Society of Endocrinology.Urgent multidisciplinary and unified guidelines should be established in the interest of clinical- and cost-effectiveness

Prediction and analysis of near-road concentrations using a reduced-form emission/dispersion model

<p>Abstract</p> <p>Background</p> <p>Near-road exposures of traffic-related air pollutants have been receiving increased attention due to evidence linking emissions from high-traffic roadways to adverse health outcomes. To date, most epidemiological and risk analyses have utilized simple but crude exposure indicators, most typically proximity measures, such as the distance between freeways and residences, to represent air quality impacts from traffic. This paper derives and analyzes a simplified microscale simulation model designed to predict short- (hourly) to long-term (annual average) pollutant concentrations near roads. Sensitivity analyses and case studies are used to highlight issues in predicting near-road exposures.</p> <p>Methods</p> <p>Process-based simulation models using a computationally efficient reduced-form response surface structure and a minimum number of inputs integrate the major determinants of air pollution exposures: traffic volume and vehicle emissions, meteorology, and receptor location. We identify the most influential variables and then derive a set of multiplicative submodels that match predictions from "parent" models MOBILE6.2 and CALINE4. The assembled model is applied to two case studies in the Detroit, Michigan area. The first predicts carbon monoxide (CO) concentrations at a monitoring site near a freeway. The second predicts CO and PM_2.5concentrations in a dense receptor grid over a 1 km²area around the intersection of two major roads. We analyze the spatial and temporal patterns of pollutant concentration predictions.</p> <p>Results</p> <p>Predicted CO concentrations showed reasonable agreement with annual average and 24-hour measurements, e.g., 59% of the 24-hr predictions were within a factor of two of observations in the warmer months when CO emissions are more consistent. The highest concentrations of both CO and PM_2.5were predicted to occur near intersections and downwind of major roads during periods of unfavorable meteorology (e.g., low wind speeds) and high emissions (e.g., weekday rush hour). The spatial and temporal variation among predicted concentrations was significant, and resulted in unusual distributional and correlation characteristics, including strong negative correlation for receptors on opposite sides of a road and the highest short-term concentrations on the "upwind" side of the road.</p> <p>Conclusions</p> <p>The case study findings can likely be generalized to many other locations, and they have important implications for epidemiological and other studies. The reduced-form model is intended for exposure assessment, risk assessment, epidemiological, geographical information systems, and other applications.</p

A Differential Effect of E. coli Toxin-Antitoxin Systems on Cell Death in Liquid Media and Biofilm Formation

Toxin-antitoxin (TA) modules are gene pairs specifying for a toxin and its antitoxin and are found on the chromosomes of many bacteria including pathogens. Here we report how each of five such TA systems in E. coli affect bacterial cell death differently in liquid media and during biofilm formation. Of all these systems, only the TA system mazEF mediated cell death both in liquid media and during biofilm formation. At the other extreme, as our results have revealed here, the TA system dinJ-YafQ is unique in that it is involved only in the death process during biofilm formation. Cell death governed by mazEF and dinJ-YafQ seems to participate in biofilm formation through a novel mechanism

Characterization of Spermatogonial Stem Cells Lacking Intercellular Bridges and Genetic Replacement of a Mutation in Spermatogonial Stem Cells

Stem cells have a potential of gene therapy for regenerative medicine. Among various stem cells, spermatogonial stem cells have a unique characteristic in which neighboring cells can be connected by intercellular bridges. However, the roles of intercellular bridges for stem cell self-renewal, differentiation, and proliferation remain to be elucidated. Here, we show not only the characteristics of testis-expressed gene 14 (TEX14) null spermatogonial stem cells lacking intercellular bridges but also a trial application of genetic correction of a mutation in spermatogonial stem cells as a model for future gene therapy. In TEX14 null testes, some genes important for undifferentiated spermatogonia as well as some differentiation-related genes were activated. TEX14 null spermatogonial stem cells, surprisingly, could form chain-like structures even though they do not form stable intercellular bridges. TEX14 null spermatogonial stem cells in culture possessed both characteristics of undifferentiated and differentiated spermatogonia. Long-term culture of TEX14 null spermatogonial stem cells could not be established likely secondary to up-regulation of CDK4 inhibitors and down-regulation of cyclin E. These results suggest that intercellular bridges are essential for both maintenance of spermatogonial stem cells and their proliferation. Lastly, a mutation in Tex14+/− spermatogonial stem cells was successfully replaced by homologous recombination in vitro. Our study provides a therapeutic potential of spermatogonial stem cells for reproductive medicine if they can be cultured long-term

Systems biology discoveries using non-human primate pluripotent stem and germ cells: novel gene and genomic imprinting interactions as well as unique expression patterns

The study of pluripotent stem cells has generated much interest in both biology and medicine. Understanding the fundamentals of biological decisions, including what permits a cell to maintain pluripotency, that is, its ability to self-renew and thereby remain immortal, or to differentiate into multiple types of cells, is of profound importance. For clinical applications, pluripotent cells, including both embryonic stem cells and adult stem cells, have been proposed for cell replacement therapy for a number of human diseases and disorders, including Alzheimer's, Parkinson's, spinal cord injury and diabetes. One challenge in their usage for such therapies is understanding the mechanisms that allow the maintenance of pluripotency and controlling the specific differentiation into required functional target cells. Because of regulatory restrictions and biological feasibilities, there are many crucial investigations that are just impossible to perform using pluripotent stem cells (PSCs) from humans (for example, direct comparisons among panels of inbred embryonic stem cells from prime embryos obtained from pedigreed and fertile donors; genomic analysis of parent versus progeny PSCs and their identical differentiated tissues; intraspecific chimera analyses for pluripotency testing; and so on). However, PSCs from nonhuman primates are being investigated to bridge these knowledge gaps between discoveries in mice and vital information necessary for appropriate clinical evaluations. In this review, we consider the mRNAs and novel genes with unique expression and imprinting patterns that were discovered using systems biology approaches with primate pluripotent stem and germ cells

Focused HLA analysis in Caucasians with myositis identifies significant associations with autoantibody subgroups

OBJECTIVES: Idiopathic inflammatory myopathies (IIM) are a spectrum of rare autoimmune diseases characterised clinically by muscle weakness and heterogeneous systemic organ involvement. The strongest genetic risk is within the major histocompatibility complex (MHC). Since autoantibody presence defines specific clinical subgroups of IIM, we aimed to correlate serotype and genotype, to identify novel risk variants in the MHC region that co-occur with IIM autoantibodies. METHODS: We collected available autoantibody data in our cohort of 2582 Caucasian patients with IIM. High resolution human leucocyte antigen (HLA) alleles and corresponding amino acid sequences were imputed using SNP2HLA from existing genotyping data and tested for association with 12 autoantibody subgroups. RESULTS: We report associations with eight autoantibodies reaching our study-wide significance level of p<2.9×10^{-5}. Associations with the 8.1 ancestral haplotype were found with anti-Jo-1 (HLA-B*08:01, p=2.28×10^{-53}  and HLA-DRB1*03:01, p=3.25×10^{-9}, anti-PM/Scl (HLA-DQB1*02:01, p=1.47×10^{-26}) and anti-cN1A autoantibodies (HLA-DRB1*03:01, p=1.40×10^{-11}). Associations independent of this haplotype were found with anti-Mi-2 (HLA-DRB1*07:01, p=4.92×10^{-13}) and anti-HMGCR autoantibodies (HLA-DRB1*11, p=5.09×10^{-6}). Amino acid positions may be more strongly associated than classical HLA associations; for example with anti-Jo-1 autoantibodies and position 74 of HLA-DRB1 (p=3.47×10^{-64} and position 9 of HLA-B (p=7.03×10^{-11}). We report novel genetic associations with HLA-DQB1 anti-TIF1 autoantibodies and identify haplotypes that may differ between adult-onset and juvenile-onset patients with these autoantibodies. CONCLUSIONS: These findings provide new insights regarding the functional consequences of genetic polymorphisms within the MHC. As autoantibodies in IIM correlate with specific clinical features of disease, understanding genetic risk underlying development of autoantibody profiles has implications for future research

Association of Diabetes in Pregnancy with Child Weight at Birth, Age 12 Months and 5 Years – A Population-Based Electronic Cohort Study

This study examines the effect of diabetes in pregnancy on offspring weight at birth and ages 1 and 5 years.A population-based electronic cohort study using routinely collected linked healthcare data. Electronic medical records provided maternal diabetes status and offspring weight at birth and ages 1 and 5 years (n = 147,773 mother child pairs). Logistic regression models were used to obtain odds ratios to describe the association between maternal diabetes status and offspring size, adjusted for maternal pre-pregnancy weight, age and smoking status.We identified 1,250 (0.9%) pregnancies with existing diabetes (27.8% with type 1 diabetes), 1,358 with gestational diabetes (0.9%) and 635 (0.4%) who developed diabetes post-pregnancy. Children whose mothers had existing diabetes were less likely to be large at 12 months (OR: 0.7 (95%CI: 0.6, 0.8)) than those without diabetes. Maternal diabetes was associated with high weight at age 5 years in children whose mothers had a high pre-pregnancy weight tertile (gestational diabetes, (OR:2.1 (95%CI:1.25-3.6)), existing diabetes (OR:1.3 (95%CI:1.0 to 1.6)).The prevention of childhood obesity should focus on mothers with diabetes with a high maternal pre-pregnancy weight. We found little evidence that diabetes in pregnancy leads to long term obesity 'programming'

Pan-cancer analysis of whole genomes

Cancer is driven by genetic change, and the advent of massively parallel sequencing has enabled systematic documentation of this variation at the whole-genome scale(1-3). Here we report the integrative analysis of 2,658 whole-cancer genomes and their matching normal tissues across 38 tumour types from the Pan-Cancer Analysis of Whole Genomes (PCAWG) Consortium of the International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA). We describe the generation of the PCAWG resource, facilitated by international data sharing using compute clouds. On average, cancer genomes contained 4-5 driver mutations when combining coding and non-coding genomic elements; however, in around 5% of cases no drivers were identified, suggesting that cancer driver discovery is not yet complete. Chromothripsis, in which many clustered structural variants arise in a single catastrophic event, is frequently an early event in tumour evolution; in acral melanoma, for example, these events precede most somatic point mutations and affect several cancer-associated genes simultaneously. Cancers with abnormal telomere maintenance often originate from tissues with low replicative activity and show several mechanisms of preventing telomere attrition to critical levels. Common and rare germline variants affect patterns of somatic mutation, including point mutations, structural variants and somatic retrotransposition. A collection of papers from the PCAWG Consortium describes non-coding mutations that drive cancer beyond those in the TERT promoter(4); identifies new signatures of mutational processes that cause base substitutions, small insertions and deletions and structural variation(5,6); analyses timings and patterns of tumour evolution(7); describes the diverse transcriptional consequences of somatic mutation on splicing, expression levels, fusion genes and promoter activity(8,9); and evaluates a range of more-specialized features of cancer genomes(8,10-18).Peer reviewe