Complete and Prolonged Response to Immune Checkpoint Blockade in POLE-Mutated Colorectal Cancer

Enid Robertson Logan Faculty Fellowship Fund6 month embargo; published online: 21 June 2019This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Educational and health outcomes of children and adolescents receiving antidepressant medication : Scotland-wide retrospective record linkage cohort study of 766 237 schoolchildren

Funding Health Data Research UK (grant reference number MR/S003800/1). Acknowledgements The study was sponsored by Health Data Research UK (www.hdruk.ac.uk), which is a joint investment led by the Medical Research Council, together with the National Institute for Health Research (England), the Chief Scientist Office (Scotland), Health and Care Research Wales, Health and Social Care Research and Development Division (Public Health Agency, Northern Ireland), the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the British Heart Foundation and Wellcome (grant reference number MR/S003800/1). The sponsor and funders 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; or decision to submit the manuscript for publication. This study formed part of a wider PhD thesis undertaken by the lead author within the University of Glasgow and was published in 2017. Certain sections of this paper appear in the thesis, which is accessible and downloadable from the following link: http://theses.gla.ac.uk/8594/1/2017flemingphd.pdf. Author Contributions J.P.P. had the original concept. All authors agreed the study design. D.C. and A.K. provided data and undertook record linkage. M.F. and D.F.M. undertook the statistical analyses. All authors interpreted the results. M.F. and J.P.P. drafted the manuscript and all other authors contributed revisions. All authors reviewed and approved the final version of the manuscript. M.F. is guarantor for the study. Approvals The authors applied for permission to access, link and analyse these data and undertook mandatory training in data protection, IT security and information governance. Therefore, the datasets generated and analysed during the study are not publicly available. The study was approved by the National Health Service Privacy Advisory Committee and covered by a data-processing agreement between Glasgow University and ISD, and a data-sharing agreement between Glasgow University and ScotXed. All data were linked by the Electronic Data Research and Innovation Service (eDRIS), part of NHS National Services Scotland. Ethics The NHS West of Scotland Research Ethics Service confirmed that formal NHS ethics approval was not required, since the study involved anonymized extracts of routinely collected data with an acceptably negligible risk of identification. Conflict of interest: None declaredPeer reviewedPublisher PD

Educational and health outcomes of children and adolescents receiving antiepileptic medication : Scotland-wide record linkage study of 766 244 schoolchildren

Acknowledgements The study was sponsored by Health Data Research UK (www.hdruk.ac.uk) which is a joint investment led by the Medical Research Council, together with the National Institute for Health Research (England), the Chief Scientist Office (Scotland), Health and Care Research Wales, Health and Social Care Research and Development Division (Public Health Agency, Northern Ireland), the Engineering and Physical Sciences Research Council, the Economic and Social Research Council, the British Heart Foundation and Wellcome. This study formed part of a wider PhD thesis undertaken by the lead author within the University of Glasgow, which was published in 2017. Therefore, certain sections of this paper appear in the thesis, which is accessible and downloadable from the following link: http://theses.gla.ac.uk/8594/1/2017flemingphd.pdf. Funding The study was sponsored by Health Data Research UK. The sponsor and funders 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, or decision to submit the manuscript for publication. Availability of data and materials The authors applied for permission to access, link and analyse these data and undertook mandatory training in data protection, IT security and information governance. Therefore, the datasets generated and analysed during the study are not publicly available.Peer reviewedPublisher PD

The Soft-Excess in Mrk 509: Warm Corona or Relativistic Reflection?

We present the analysis of the first NuSTAR observations ($\sim 220$ ks), simultaneous with the last SUZAKU observations ($\sim 50$ ks), of the active galactic nucleus of the bright Seyfert 1 galaxy Mrk 509. The time-averaged spectrum in the $1-79$ keV X-ray band is dominated by a power-law continuum ($\Gamma\sim 1.8-1.9$), a strong soft excess around 1 keV, and signatures of X-ray reflection in the form of Fe K emission ($\sim 6.4$ keV), an Fe K absorption edge ($\sim 7.1$ keV), and a Compton hump due to electron scattering ($\sim 20-30$ keV). We show that these data can be described by two very different prescriptions for the soft excess: a warm ($kT\sim 0.5-1$ keV) and optically thick ($\tau\sim10-20$) Comptonizing corona, or a relativistically blurred ionized reflection spectrum from the inner regions of the accretion disk. While these two scenarios cannot be distinguished based on their fit statistics, we argue that the parameters required by the warm corona model are physically incompatible with the conditions of standard coronae. Detailed photoionization calculations show that even in the most favorable conditions, the warm corona should produce strong absorption in the observed spectrum. On the other hand, while the relativistic reflection model provides a satisfactory description of the data, it also requires extreme parameters, such as maximum black hole spin, a very low and compact hot corona, and a very high density for the inner accretion disk. Deeper observations of this source are thus necessary to confirm the presence of relativistic reflection, and to further understand the nature of its soft excess.Comment: Accepted for publication in ApJ, 18 pages, 7 figure

NICER/NuSTAR Characterization of 4U 1957+11: A Near Maximally Spinning Black Hole Potentially in the Mass Gap

© 2023. The Author(s). Published by the American Astronomical Society. This is an open access article distributed under the Creative Commons Attribution License, to view a copy of the license, see: https://creativecommons.org/licenses/by/4.0/4U 1957+11 is a black hole candidate system that has been in a soft X-ray spectral state since its discovery. We present analyses of recent joint NICER and NuSTAR spectra, which are extremely well described by a highly inclined disk accreting into a near maximally spinning black hole. Owing to the broad X-ray coverage of NuSTAR, the fitted spin and inclination are strongly constrained for our hypothesized disk models. The faintest spectra are observed out to 20 keV, even though their hard tail components are almost absent when described with a simple corona. The hard tail increases with luminosity, but shows clear two-track behavior with one track having appreciably stronger tails. The disk spectrum color-correction factor is anticorrelated with the strength of the hard tail (e.g., as measured by the Compton y parameter). Although the spin and inclination parameters are strongly constrained for our chosen model, the mass and distance are degenerate parameters. We use our spectral fits, along with a theoretical prior on color-correction, an observational prior on likely fractional Eddington luminosity, and an observational prior on distance obtained from Gaia studies, to present mass and distance contours for this system. The most likely parameters, given our presumed disk model, suggest a 4.6 M ⊙ black hole at 7.8 kpc observed at luminosities ranging from ≈1.7% to 9% of Eddington. This would place 4U 1957+11 as one of the few actively accreting sources within the mass gap of ≈2–5 M ⊙ where there are few known massive neutron stars or low-mass black holes. Higher mass and distance, however, remain viable.Peer reviewe

JNK1 is not essential for TNF-mediated joint disease

Tumour necrosis factor (TNF) signalling molecules are considered as promising therapeutic targets of antirheumatic therapy. Among them, mitogen-activated protein kinases are thought to be of central importance. Herein, we investigate the role in vivo of TNF-α signalling through c-Jun N-terminal kinase (JNK)1 in destructive arthritis. Human TNF transgenic (hTNFtg) mice, which develop inflammatory arthritis, were intercrossed with JNK1-deficient (JNK1(-/-)) mice. Animals (n = 35) of all four genotypes (wild-type, JNK1(-/-), hTNFtg, JNK1(-/-)hTNFtg) were assessed for clinical and histological signs of arthritis. Clinical features of arthritis (swelling and decreased grip strength) developed equally in hTNFtg and JNK1(-/-)hTNFtg mice. Histological analyses revealed no differences in the quantity of synovial inflammation and bone erosions or in the cellular composition of the synovial infiltrate. Bone destruction and osteoclast formation were observed to a similar degree in hTNFtg and JNK1(-/-)hTNFtg animals. Moreover, cartilage damage, as indicated by proteoglycan loss in the articular cartilage, was comparable in the two strains. Intact phosphorylation of JNK and c-Jun as well as expression of JNK2 in the synovial tissue of JNK1(-/-)hTNFtg mice suggests that signalling through JNK2 may compensate for the deficiency in JNK1. Thus, JNK1 activation does not seem to be essential for TNF-mediated arthritis

ESTRO-ACROP guideline on surface guided radiation therapy

Surface guidance systems enable patient positioning and motion monitoring without using ionising radiation. Surface Guided Radiation Therapy (SGRT) has therefore been widely adopted in radiation therapy in recent years, but guidelines on workflows and specific quality assurance (QA) are lacking. This ESTRO-ACROP guideline aims to give recommendations concerning SGRT roles and responsibilities and highlights common challenges and potential errors. Comprehensive guidelines for procurement, acceptance, commissioning, and QA of SGRT systems installed on computed tomography (CT) simulators, C-arm linacs, closed-bore linacs, and particle therapy treatment systems are presented that will help move to a consensus among SGRT users and facilitate a safe and efficient implementation and clinical application of SGRT. Keywords: ACROP; ESTRO; Guideline; SGRT; Surface guided radiation therapy

Genomic Resources Notes Accepted 1 August 2014–30 September 2014

This article documents the public availability of (i) transcriptome sequence data, assembly and annotation, and single nucleotide polymorphisms ( SNP s) for the cone snail Conus miliaris ; (ii) a set of SNP markers for two biotypes from the Culex pipiens mosquito complex; (iii) transcriptome sequence data, assembly and annotation for the mountain fly Drosophila nigrosparsa ; (iv) transcriptome sequence data, assembly and annotation and SNP s for the Neotropical toads Rhinella marina and R. schneideri ; and (v) partial genomic sequence assembly and annotation for 35 spiny lizard species (Genus Sceloporus ).Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/1/men12340-sup-0004-AppendixS4.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/2/men12340-sup-0003-AppendixS3.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/3/men12340-sup-0002-AppendixS2.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/4/men12340-sup-0005-AppendixS5.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/5/men12340.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/110107/6/men12340-sup-0001-AppendixS1.pd

Educational and health outcomes of children treated for type 1 diabetes: Scotland-wide record linkage study of 766,047 children

Objective: This study was conducted to determine the association between childhood type 1 diabetes and educational and health outcomes. Research Design and Methods: Record linkage of nine Scotland-wide databases (diabetes register, dispensed prescriptions, maternity records, hospital admissions, death certificates, annual pupil census, school absences/exclusions, school examinations, and unemployment) produced a cohort of 766,047 singleton children born in Scotland who attended Scottish schools between 2009 and 2013. We compared the health and education outcomes of schoolchildren receiving insulin with their peers, adjusting for potential confounders. Results: The 3,330 children (0.47%) treated for type 1 diabetes were more likely to be admitted to the hospital (adjusted hazard ratio [HR] 3.97, 95% CI 3.79–4.16), die (adjusted HR 3.84, 95% CI 1.98–7.43), be absent from school (adjusted incidence rate ratio [IRR] 1.34, 95% CI 1.30–1.39), and have learning difficulties (adjusted odds ratio [OR] 1.19, 95% CI 1.03–1.38). Among children with type 1 diabetes, higher mean HbA1c (particularly HbA1c in the highest quintile) was associated with greater absenteeism (adjusted IRR 1.75, 95% CI 1.56–1.96, P < 0.001), increased school exclusion (adjusted IRR 2.82, 95% CI 1.14–6.98), poorer attainment (adjusted OR 3.52, 95% CI 1.72–7.18), and higher risk of unemployment (adjusted OR 2.01, 95% CI 1.05–3.85). Conclusions: Children with type 1 diabetes fare worse than their peers in respect of education and health outcomes, especially if they have higher mean HbA1c. Interventions are required to minimize school absence and ensure that it does not affect educational attainment

Deep learning-based survival prediction for multiple cancer types using histopathology images

Prognostic information at diagnosis has important implications for cancer treatment and monitoring. Although cancer staging, histopathological assessment, molecular features, and clinical variables can provide useful prognostic insights, improving risk stratification remains an active research area. We developed a deep learning system (DLS) to predict disease specific survival across 10 cancer types from The Cancer Genome Atlas (TCGA). We used a weakly-supervised approach without pixel-level annotations, and tested three different survival loss functions. The DLS was developed using 9,086 slides from 3,664 cases and evaluated using 3,009 slides from 1,216 cases. In multivariable Cox regression analysis of the combined cohort including all 10 cancers, the DLS was significantly associated with disease specific survival (hazard ratio of 1.58, 95% CI 1.28-1.70, p<0.0001) after adjusting for cancer type, stage, age, and sex. In a per-cancer adjusted subanalysis, the DLS remained a significant predictor of survival in 5 of 10 cancer types. Compared to a baseline model including stage, age, and sex, the c-index of the model demonstrated an absolute 3.7% improvement (95% CI 1.0-6.5) in the combined cohort. Additionally, our models stratified patients within individual cancer stages, particularly stage II (p=0.025) and stage III (p<0.001). By developing and evaluating prognostic models across multiple cancer types, this work represents one of the most comprehensive studies exploring the direct prediction of clinical outcomes using deep learning and histopathology images. Our analysis demonstrates the potential for this approach to provide prognostic information in multiple cancer types, and even within specific pathologic stages. However, given the relatively small number of clinical events, we observed wide confidence intervals, suggesting that future work will benefit from larger datasets