Gladstone and Scott: Family, identity, and nation

In the 175 years since his death, Walter Scott has regularly been hailed as an influence by politicians. Amongst the poet-novelist's nineteenth-century political admirers, William Ewart Gladstone was possibly the most ardent, genuine, and significant. Scott's poems and novels were amongst the earliest texts Gladstone read; he read no works (in English), except the Bible, so consistently or completely over such a length of time. They offered him a plethora of inspirations, ideas, and language, which he imbibed and appropriated into his public and private lives. His concept of self, his understanding of family, and his sense of home, were all forged and conducted within a Scottian frame of reference. Scott's life and works also crucially influenced Gladstone's political understanding of the Scottish nation and its people, and his conception of how he could best serve their political interests. This article casts new light on an important and influential relationship in Gladstone's life, establishing that it was neither the superficial and recreational association some have described, nor simply a ploy of an astute politician. The article falls into three parts. The first elucidates how Gladstone's consumption of Scott's writings was seminal in the formation of his private identity, both individual and familial. The second explains how Gladstone's readings of Scott fitted into the specific and serious character of his other reading and knowledge-gathering, and the third shows how the details of Gladstone's response to Scott related to the broader intellectual and cultural context of his public life. By placing Gladstone within his Scottish context, this article shows how frequently and significantly his private and public worlds intersected

Use of SNP chips to detect rare pathogenic variants: retrospective, population based diagnostic evaluation

This is the final version. Available on open access from the BMJ Publishing Group via the DOI in this recordData sharing: The data reported in this paper are available via application directly to the UK Biobank. Direct to consumer data are available from the Personal Genome Project website.Objective To determine whether the sensitivity and specificity of SNP chips are adequate for detecting rare pathogenic variants in a clinically unselected population. Design Retrospective, population based diagnostic evaluation. Participants 49 908 people recruited to the UK Biobank with SNP chip and next generation sequencing data, and an additional 21 people who purchased consumer genetic tests and shared their data online via the Personal Genome Project. Main outcome measures Genotyping (that is, identification of the correct DNA base at a specific genomic location) using SNP chips versus sequencing, with results split by frequency of that genotype in the population. Rare pathogenic variants in the BRCA1 and BRCA2 genes were selected as an exemplar for detailed analysis of clinically actionable variants in the UK Biobank, and BRCA related cancers (breast, ovarian, prostate, and pancreatic) were assessed in participants through use of cancer registry data. Results Overall, genotyping using SNP chips performed well compared with sequencing; sensitivity, specificity, positive predictive value, and negative predictive value were all above 99% for 108 574 common variants directly genotyped on the SNP chips and sequenced in the UK Biobank. However, the likelihood of a true positive result decreased dramatically with decreasing variant frequency; for variants that are very rare in the population, with a frequency below 0.001% in UK Biobank, the positive predictive value was very low and only 16% of 4757 heterozygous genotypes from the SNP chips were confirmed with sequencing data. Results were similar for SNP chip data from the Personal Genome Project, and 20/21 individuals analysed had at least one false positive rare pathogenic variant that had been incorrectly genotyped. For pathogenic variants in the BRCA1 and BRCA2 genes, which are individually very rare, the overall performance metrics for the SNP chips versus sequencing in the UK Biobank were: sensitivity 34.6%, specificity 98.3%, positive predictive value 4.2%, and negative predictive value 99.9%. Rates of BRCA related cancers in UK Biobank participants with a positive SNP chip result were similar to those for age matched controls (odds ratio 1.31, 95% confidence interval 0.99 to 1.71) because the vast majority of variants were false positives, whereas sequence positive participants had a significantly increased risk (odds ratio 4.05, 2.72 to 6.03). Conclusions SNP chips are extremely unreliable for genotyping very rare pathogenic variants and should not be used to guide health decisions without validation.Wellcome TrustNational Institute for Health Research (NIHR

Inside-Out Evacuation of Transitional Protoplanetary Disks by the Magneto-Rotational Instability

How do T Tauri disks accrete? The magneto-rotational instability (MRI) supplies one means, but protoplanetary disk gas is typically too poorly ionized to be magnetically active. Here we show that the MRI can, in fact, explain observed accretion rates for the sub-class of T Tauri disks known as transitional systems. Transitional disks are swept clean of dust inside rim radii of ~10 AU. Stellar coronal X-rays ionize material in the disk rim, activating the MRI there. Gas flows from the rim to the star, at a rate limited by the depth to which X-rays ionize the rim wall. The wider the rim, the larger the surface area that the rim wall exposes to X-rays, and the greater the accretion rate. Interior to the rim, the MRI continues to transport gas; the MRI is sustained even at the disk midplane by super-keV X-rays that Compton scatter down from the disk surface. Accretion is therefore steady inside the rim. Blown out by radiation pressure, dust largely fails to accrete with gas. Contrary to what is usually assumed, ambipolar diffusion, not Ohmic dissipation, limits how much gas is MRI-active. We infer values for the transport parameter alpha on the order of 0.01 for GM Aur, TW Hyd, and DM Tau. Because the MRI can only afflict a finite radial column of gas at the rim, disk properties inside the rim are insensitive to those outside. Thus our picture provides one robust setting for planet-disk interaction: a protoplanet interior to the rim will interact with gas whose density, temperature, and transport properties are definite and decoupled from uncertain initial conditions. Our study also supplies half the answer to how disks dissipate: the inner disk drains from the inside out by the MRI, while the outer disk photoevaporates by stellar ultraviolet radiation.Comment: Accepted to Nature Physics June 7, 2007. The manuscript for publication is embargoed per Nature policy. This arxiv.org version contains more technical details and discussion, and is distributed with permission from the editors. 10 pages, 4 figure

Large copy number variants in UK Biobank caused by clonal haematopoiesis may confound penetrance estimates

This is the author accepted manuscript. The final version is available from Elsevier via the DOI in this recordThis study did not generate new datasets or code. The code used during this study is available at https://github.com/WGLab/PennCNV. All bona fide researchers can apply to use the UK Biobank resource for health related research that is in the public interest, https://www.ukbiobank.ac.uk/.Large copy number variants (CNVs) are strongly associated with both developmental delay and cancer, but the type of disease depends strongly on when and where the mutation occurred, i.e. germline versus somatic. We used microarray data from UK Biobank to investigate the prevalence and penetrance of large autosomal CNVs and chromosomal aneuploidies using a standard CNV detection algorithm not designed for detecting mosaic variants. We found 160 individuals that carry >10Mb copy number changes, including 56 with whole chromosome aneuploidies. Nineteen (12%) individuals had a diagnosis of Down’s syndrome or other developmental disorder, while 84 (52.5%) individuals had a diagnosis of haematological malignancies or chronic myeloproliferative disorders. Notably, there was no evidence of mosaicism in the blood for many of these large CNVs, so they could easily be mistaken for germline alleles even when caused by somatic mutations. We therefore suggest that somatic mutations associated with blood cancers may result in false estimates of rare variant penetrance from population biobanks

Influence of family history on penetrance of hereditary cancers in a population setting

This is the final version. Available on open access from Elsevier via the DOI in this recordData sharing statement: All data used in this study can be accessed via application to UK Biobank and approval via the data access committee. The authors are not permitted to directly share this data. The code used to perform GRS is available at https://github.com/hdg204/Rdna-nexus. Variants classified as pathogenic and used in this study are defined in the methods and can be replicated, however a list is available on request.BACKGROUND: We sought to investigate how penetrance of familial cancer syndromes varies with family history using a population-based cohort. METHODS: We analysed 454,712 UK Biobank participants with exome sequence and clinical data (data collected between March 2006 and June 2021). We identified participants with a self-reported family history of breast or colorectal cancer and a pathogenic/likely pathogenic variant in the major genes responsible for hereditary breast cancer or Lynch syndrome. We calculated survival to cancer diagnosis (controlled for sex, death, recruitment centre, screening and prophylactic surgery). FINDINGS: Women with a pathogenic BRCA1 or BRCA2 variant had an increased risk of breast cancer that was higher in those with a first-degree family history (relative hazard 10.3 and 7.8, respectively) than those without (7.2 and 4.7). Penetrance to age 60 was also higher in those with a family history (44.7%, CI 32.2-59.3 and 24.1%, CI 17.5-32.6) versus those without (22.8%, CI 15.9-32.0 and 17.9%, CI 13.8-23.0). A similar pattern was seen in Lynch syndrome: individuals with a pathogenic MLH1, MSH2 or MSH6 variant had an increased risk of colorectal cancer that was significantly higher in those with a family history (relative hazard 35.6, 48.0 and 9.9) than those without (13.0, 15.4 and 7.2). Penetrance to age 60 was also higher for carriers of a pathogenic MLH1 or MSH2 variant in those with a family history (30.9%, CI 18.1-49.3 and 38.3%, CI 21.5-61.8) versus those without (20.5% CI 9.6-40.5 and 8.3% CI 2.1-30.4), but not for MSH6 (6.5% CI 2.7-15.1 with family history versus 8.3%, CI 5.1-13.2). Relative risk increases were also observed both within and across conditions. INTERPRETATION: Individuals with pathogenic cancer syndrome variants may be at a less elevated risk of cancer in the absence of a first-degree family history, so in the context of results return, family history should be considered when counselling patients on the risks and benefits of potential follow-up care. FUNDING: The current work is supported by the MRC (grant no MR/T00200X/1). The MRC had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.Medical Research Council (MRC

Single Cut Integration

We present an analytic technique for evaluating single cuts for one-loop integrands, where exactly one propagator is taken to be on shell. Our method extends the double-cut integration formalism of one-loop amplitudes to the single-cut case. We argue that single cuts give meaningful information about amplitudes when taken at the integrand level. We discuss applications to the computation of tadpole coefficients.Comment: v2: corrected typo in abstrac

Therapeutic Benefit of Radial Optic Neurotomy in a Rat Model of Glaucoma

Radial optic neurotomy (RON) has been proposed as a surgical treatment to alleviate the neurovascular compression and to improve the venous outflow in patients with central retinal vein occlusion. Glaucoma is characterized by specific visual field defects due to the loss of retinal ganglion cells and damage to the optic nerve head (ONH). One of the clinical hallmarks of glaucomatous neuropathy is the excavation of the ONH. The aim of this work was to analyze the effect of RON in an experimental model of glaucoma in rats induced by intracameral injections of chondroitin sulfate (CS). For this purpose, Wistar rats were bilaterally injected with vehicle or CS in the eye anterior chamber, once a week, for 10 weeks. At 3 or 6 weeks of a treatment with vehicle or CS, RON was performed by a single incision in the edge of the neuro-retinal ring at the nasal hemisphere of the optic disk in one eye, while the contralateral eye was submitted to a sham procedure. Electroretinograms (ERGs) were registered under scotopic conditions and visual evoked potentials (VEPs) were registered with skull-implanted electrodes. Retinal and optic nerve morphology was examined by optical microscopy. RON did not affect the ocular hypertension induced by CS. In eyes injected with CS, a significant decrease of retinal (ERG a- and b-wave amplitude) and visual pathway (VEP N2-P2 component amplitude) function was observed, whereas RON reduced these functional alterations in hypertensive eyes. Moreover, a significant loss of cells in the ganglion cell layer, and Thy-1-, NeuN- and Brn3a- positive cells was observed in eyes injected with CS, whereas RON significantly preserved these parameters. In addition, RON preserved the optic nerve structure in eyes with chronic ocular hypertension. These results indicate that RON reduces functional and histological alterations induced by experimental chronic ocular hypertension

The Tissue Microlocalisation and Cellular Expression of CD163, VEGF, HLA-DR, iNOS, and MRP 8/14 Is Correlated to Clinical Outcome in NSCLC

BACKGROUND: We have previously investigated the microlocalisation of M1 and M2 macrophages in NSCLC. This study investigated the non-macrophage (NM) expression of proteins associated with M1 and M2 macrophages in NSCLC. METHODS: Using immunohistochemistry, CD68(+) macrophages and proteins associated with either a cytotoxic M1 phenotype (HLA-DR, iNOS, and MRP 8/14), or a non-cytotoxic M2 phenotype (CD163 and VEGF) were identified. NM expression of the markers was analysed in the islets and stroma of surgically resected tumours from 20 patients with extended survival (ES) (median 92.7 months) and 20 patients with poor survival (PS) (median 7.7 months). RESULTS: The NM expression of NM-HLA-DR (p<0.001), NM-iNOS (p = 0.02) and NM-MRP 8/14 (p = 0.02) was increased in ES compared to PS patients in the tumour islets. The tumour islet expression of NM-VEGF, was decreased in ES compared to PS patients (p<0.001). There was more NM-CD163 expression (p = 0.04) but less NM-iNOS (p = 0.002) and MRP 8/14 (p = 0.01) expression in the stroma of ES patients compared with PS patients. The 5-year survival for patients with above and below median NM expression of the markers in the islets was 74.9% versus 4.7% (NM-HLA-DR p<0.001), 65.0% versus 14.6% (NM-iNOS p = 0.003), and 54.3% versus 22.2% (NM-MRP 8/14 p = 0.04), as opposed to 34.1% versus 44.4% (NM-CD163 p = 0.41) and 19.4% versus 59.0% (NM-VEGF p = 0.001). CONCLUSIONS: Cell proteins associated with M1 and M2 macrophages are also expressed by other cell types in the tumour islets and stroma of patients with NSCLC. Their tissue and cellular microlocalisation is associated with important differences in clinical outcome

A protocol for emulating a published randomised controlled trial using registry data: effects of azithromycin in young adults with cystic fibrosis

Target trial emulation can be used to evaluate the effects of treatments using observational data. The trial emulation approach involves specifying key elements of a protocol for a target trial (a randomised controlled trial designed to address the question of interest) and then describing how best to emulate the trial using observational data. Recent years have seen an uptake of target trial emulation in several disease areas, although there are limited examples in cystic fibrosis. This protocol describes a study which aims to assess the applicability of target trial emulation in cystic fibrosis (CF). We aim to emulate an existing trial in CF and assess to what extent the results from the trial can be replicated using registry data. We aim to emulate a published trial (i.e., the target trial) which found evidence for beneficial effects of azithromycin use on lung function in young adults with cystic fibrosis. Two emulated trials are planned: one using data from the UK CF Registry and one using data from the US CF Registry. The inclusion and exclusion criteria, treatment and outcome definitions, follow-up period, and estimand of interest are all designed to match the published trial as closely as possible. Inverse-probability-of-treatment weighting will be used in the emulated trials to account for confounding bias. Results obtained in the emulated trials using registry data will be compared to the results obtained in the published randomised controlled trial

Tumour necrosis factor-alpha expression in tumour islets confers a survival advantage in non-small cell lung cancer

<p>Abstract</p> <p>Background</p> <p>The role of TNFα in cancer is complex with both pro-tumourigenic and anti-tumourigenic roles proposed. We hypothesised that anatomical microlocalisation is critical for its function.</p> <p>Methods</p> <p>This study used immunohistochemistry to investigate the expression of TNFα in the tumour islets and stroma with respect to survival in 133 patients with surgically resected NSCLC.</p> <p>Results</p> <p>TNFα expression was increased in the tumour islets of patients with above median survival (AMS) compared to those with below median survival (BMS)(p = 0.006), but similar in the stroma of both groups. Increasing tumour islet TNFα density was a favorable independent prognostic indicator (p = 0.048) while stromal TNFα density was an independent predictor of reduced survival (p = 0.007). Patients with high TNFα expression (upper tertile) had a significantly higher 5-year survival compared to patients in the lower tertile (43% versus 22%, p = 0.01). In patients with AMS, 100% of TNFα⁺cells were macrophages and mast cells, compared to only 28% in the islets and 50% in the stroma of BMS patients (p < 0.001).</p> <p>Conclusions</p> <p>The expression of TNFα in the tumour islets of patients with NSCLC is associated with improved survival suggesting a role in the host anti-tumour immunological response. The expression of TNFα by macrophages and mast cells is critical for this relationship.</p