Just In Time: defining historical chronographics

The paper is historical in two respects, both concerned with visual representations of past time. Its first purpose is to enquire how visual representations of historical time can be used to bring out patterns in a museum collection. A case study is presented of the visualisation of data with sufficient subtlety to be useful to historians and curators. Such a visual analytics approach raises questions about the proper representation of time and of objects and events within it. It is argued that such chronographics can support both an externalised, objectivising point of view from ‘outside’ time and one which is immersive and gives a sense of the historic moment. These modes are set in their own historical context through original historical research, highlighting the shift to an Enlightenment view of time as a uniform container for events. This in turn prompts new ways of thinking about chronological visualisation, in particular the separation of the ‘ideal’ image of time from contingent, temporary rendered views

Statistical aspects of haplotype-based association studies

A decade ago, genomewide association studies were proposed as a tool to unravel the genetic basis of complex diseases. It is only now that they are becoming practical realities due to improved technology and reduced genotyping costs. For such studies, the issues of power and efficiency are crucial due to the quantity of markers genotyped and the moderate effect sizes involved. Haplotype-based analysis incorporates information from multiple markers, and so is potentially more powerful than single-SNP analysis. Unfortunately, not only is it computationally more intensive, but since haplotypes are not directly observed, there exists a major analytical challenge with haplotype association analysis. Several methods are available to infer individual haplotypes from unphased genotype data, but using the inferred haplotypes in the ensuing association analysis can result in biased estimates and reduced power. We investigate the situations for which the disadvantages of the imputation process may outweigh its convenience. In addition, we describe alternatives to imputation which result in efficient haplotype association analysis. For case-control studies, we develop methods for use in genomewide studies which account for the correlation between SNPs in multiple test correction. Simulation studies based on the HapMap data showed that the proposed method performs well in realistic situations. We applied it to a case-control dataset of 2,300 SNPs to test for association with rheumatoid arthritis. For quantitative trait loci, we focus on gains in power which may be made via selective genotyping designs, where only those individuals with extreme phenotypes are genotyped. Because selection depends on the phenotype, the resulting data cannot be properly analyzed by standard statistical methods. We provide appropriate likelihoods for assessing the effects of genotypes and haplotypes on quantitative traits under such designs. We demonstrate that the likelihood-based methods are highly effective in identifying causal variants, and are substantially more powerful than existing methods. We initially consider two practical designs, then extend the methods to a two-phase sampling design. Additionally, we provide methods to test for haplotype-disease association in the presence of covariates. Simulations demonstrate the effectiveness of these likelihood-based methods

Emergency first responders and professional wellbeing: a qualitative systematic review

Emergency first responders (EFRs) such as police officers, firefighters, paramedics and logistics personnel often suffer high turnover due to work-related stress, high workloads, fatigue, and declining professional wellbeing. As attempts to counter this through resilience programmes tend to have limited success, there is a need for further research into how organisational policies could change to improve EFRs’ professional wellbeing. Aim: To identify the factors that may contribute to or affect EFRs’ professional wellbeing. Methods: A systematic literature review has been carried out. Three databases (Science Direct, ProQuest, and PubMed) were searched using keywords developed based on the PICo (population, interest, and context) framework. A total of 984 articles were extracted. These were then critically appraised for the quality of the evidence presented, leading to a total of five being ultimately included for review. Results: Thematic analysis revealed that although EFRs may be exposed daily to traumatic events, factors that contribute to a decline in professional wellbeing emerge from within the organisational environment, rather than from the event itself. Conclusion: The study concludes that organisational and team relations factors significantly impact EFRs ability to cope with stress. As such, organisational policy should evolve to emphasise team relations over resilience programmes

MOG analogues to explore the MCT2 pharmacophore, α-ketoglutarate biology and cellular effects of N-oxalylglycine

α-ketoglutarate (αKG) is a central metabolic node with a broad influence on cellular physiology. The αKG analogue N-oxalylglycine (NOG) and its membrane-permeable pro-drug derivative dimethyl-oxalylglycine (DMOG) have been extensively used as tools to study prolyl hydroxylases (PHDs) and other αKG-dependent processes. In cell culture media, DMOG is rapidly converted to MOG, which enters cells through monocarboxylate transporter MCT2, leading to intracellular NOG concentrations that are sufficiently high to inhibit glutaminolysis enzymes and cause cytotoxicity. Therefore, the degree of (D)MOG instability together with MCT2 expression levels determine the intracellular targets NOG engages with and, ultimately, its effects on cell viability. Here we designed and characterised a series of MOG analogues with the aims of improving compound stability and exploring the functional requirements for interaction with MCT2, a relatively understudied member of the SLC16 family. We report MOG analogues that maintain ability to enter cells via MCT2, and identify compounds that do not inhibit glutaminolysis or cause cytotoxicity but can still inhibit PHDs. We use these analogues to show that, under our experimental conditions, glutaminolysis-induced activation of mTORC1 can be uncoupled from PHD activity. Therefore, these new compounds can help deconvolute cellular effects that result from the polypharmacological action of NOG

An updated seabed bathymetry beneath Larsen C Ice Shelf, west Antarctic

Abstract. In recent decades, rapid ice-shelf disintegration along the Antarctic Peninsula has had a global impact through enhancing outlet glacier flow, and hence sea level rise, and the freshening of Antarctic Bottom Water. Ice shelf thinning due to basal melting results from the circulation of relatively warm water in the underlying ocean cavity. However, the effect of sub-shelf circulation on future ice-shelf stability cannot be predicted accurately with computer simulations if the geometry of the ice-shelf cavity is unknown. To address this deficit for Larsen C Ice Shelf, west Antarctica, we integrate new water-column thickness measurements with existing observations. We present these new data here along with an updated bathymetry grid of the ocean cavity. Key findings include relatively deep seabed to the south-east of the Kenyon Peninsula, along the grounding line and around the key ice shelf pinning point of Bawden Ice Rise. In addition, we can confirm that the cavity’s southern trough stretches from Mobiloil Inlet to the open ocean. These areas of deep seabed will influence ocean circulation and tidal mixing, and will therefore affect the basal-melt distribution. These results will help constrain models of ice-shelf cavity circulation with the aim of improving our understanding of sub-shelf processes and their potential influence on ice shelf stability. The data set comprises all point measurements of seabed depth and a gridded data product, derived using additional measurements of both offshore seabed depth and the thickness of grounded ice. We present all new depth measurements here as well as a compilation of previously published measurements used in the gridding process. The gridded data product is included in the supplementary material. The underlying seismic data sets which were used to determine bed depth and ice thickness are available at https://doi.org/10.5285/315740B1-A7B9-4CF0-9521-86F046E33E9A (Brisbourne et al., 2019), https://doi.org/10.5285/5D63777D-B375-4791-918F-9A5527093298 (Booth, 2019), https://doi.org/10.5285/FFF8AFEE-4978-495E-9210-120872983A8D (Kulessa and Bevan, 2019) and https://doi.org/10.5285/147BAF64-B9AF-4A97-8091-26AEC0D3C0BB (Booth et al., 2019). </jats:p

An updated seabed bathymetry beneath Larsen C Ice Shelf, Antarctic Peninsula

Abstract. In recent decades, rapid ice shelf disintegration along the Antarctic Peninsula has had a global impact through enhancing outlet glacier flow and hence sea level rise and the freshening of Antarctic Bottom Water. Ice shelf thinning due to basal melting results from the circulation of relatively warm water in the underlying ocean cavity. However, the effect of sub-shelf circulation on future ice shelf stability cannot be predicted accurately with computer simulations if the geometry of the ice shelf cavity is unknown. To address this deficit for Larsen C Ice Shelf, West Antarctica, we integrate new water column thickness measurements from recent seismic campaigns with existing observations. We present these new data here along with an updated bathymetry grid of the ocean cavity. Key findings include a relatively deep seabed to the southeast of the Kenyon Peninsula, along the grounding line and around the key ice shelf pinning-point of Bawden Ice Rise. In addition, we can confirm that the cavity's southern trough stretches from Mobiloil Inlet to the open ocean. These areas of deep seabed will influence ocean circulation and tidal mixing and will therefore affect the basal-melt distribution. These results will help constrain models of ice shelf cavity circulation with the aim of improving our understanding of sub-shelf processes and their potential influence on ice shelf stability. The datasets are comprised of all the new point measurements of seabed depth. We present the new depth measurements here, as well as a compilation of previously published measurements. To demonstrate the improvements to the sub-shelf bathymetry map that these new data provide we include a gridded data product in the Supplement of this paper, derived using the additional measurements of both offshore seabed depth and the thickness of grounded ice. The underlying seismic datasets that were used to determine bed depth and ice thickness are available at https://doi.org/10.5285/315740B1-A7B9-4CF0-9521-86F046E33E9A (Brisbourne et al., 2019), https://doi.org/10.5285/5D63777D-B375-4791-918F-9A5527093298 (Booth, 2019), https://doi.org/10.5285/FFF8AFEE-4978-495E-9210-120872983A8D (Kulessa and Bevan, 2019) and https://doi.org/10.5285/147BAF64-B9AF-4A97-8091-26AEC0D3C0BB (Booth et al., 2019). </jats:p

A phase I pharmacokinetic and pharmacodynamic study of the oral mitogen-activated protein kinase kinase (MEK) inhibitor, WX-554, in patients with advanced solid tumours

Purpose: We performed a multi-centre phase I study to assess the safety, pharmacokinetics (PK) and pharmacodynamics (PD) of the orally available small molecule mitogen-activated protein kinase kinase (MEK) 1/2 inhibitor, WX-554, and to determine the optimal biological dose for subsequent trials. Experimental design: Patients with treatment-refractory, advanced solid tumours, with adequate performance status and organ function were recruited to a dose-escalation study in a standard 3 + 3 design. The starting dose was 25 mg orally once weekly with toxicity, PK and PD guided dose-escalation with potential to explore alternative schedules. Results: Forty-one patients with advanced solid tumours refractory to standard therapies and with adequate organ function were recruited in eight cohorts up to doses of 150 mg once weekly and 75 mg twice weekly. No dose-limiting toxicities were observed during the study, and a maximum tolerated dose (MTD) was not established. The highest dose cohorts demonstrated sustained inhibition of extracellular signal-regulated kinase (ERK) phosphorylation in peripheral blood mononuclear cells following ex-vivo phorbol 12-myristate 13-acetate stimulation. There was a decrease of 70 ± 26% in mean phosphorylated (p)ERK in C1 day 8 tumour biopsies when compared with pre-treatment tumour levels in the 75 mg twice a week cohort. Prolonged stable disease (&gt;6 months) was seen in two patients, one with cervical cancer and one with ampullary carcinoma. Conclusions: WX-554 was well tolerated, and an optimal biological dose was established for further investigation in either a once or twice weekly regimens. The recommended phase 2 dose is 75 mg twice weekly

Genome-wide association study identifies a variant in HDAC9 associated with large vessel ischemic stroke

Genetic factors have been implicated in stroke risk but few replicated associations have been reported. We conducted a genome-wide association study (GWAS) in ischemic stroke and its subtypes in 3,548 cases and 5,972 controls, all of European ancestry. Replication of potential signals was performed in 5,859 cases and 6,281 controls. We replicated reported associations between variants close to PITX2 and ZFHX3 with cardioembolic stroke, and a 9p21 locus with large vessel stroke. We identified a novel association for a SNP within the histone deacetylase 9(HDAC9) gene on chromosome 7p21.1 which was associated with large vessel stroke including additional replication in a further 735 cases and 28583 controls (rs11984041, combined P = 1.87×10−11, OR=1.42 (95% CI) 1.28-1.57). All four loci exhibit evidence for heterogeneity of effect across the stroke subtypes, with some, and possibly all, affecting risk for only one subtype. This suggests differing genetic architectures for different stroke subtypes