Now showing items 1-20 of 7848

    • “Havens of mercy”: health, medical research, and the governance of the movement of dogs in twentieth-century America

      Kirk, Robert G. W.; orcid: 0000-0002-6541-5915; email: robert.g.kirk@manchester.ac.uk; Ramsden, Edmund (Springer International Publishing, 2021-12-02)
      Abstract: This article argues that the movement of dogs from pounds to medical laboratories played a critically important role in debates over the use of animals in science and medicine in the United States in the twentieth century, not least by drawing the scientific community into every greater engagement with bureaucratic political governance. If we are to understand the unique characteristics of the American federal legislation that emerges in the 1960s, we need to understand the long and protracted debate over the use of pound animals at the local municipal and state level between antivivisectionists, humane activists, and scientific and medical researchers. We argue that the Laboratory Animal Care Act of 1966 reflects the slow evolution of a strategy that proved most successful in local conflicts, and which would characterize a “new humanitarianism”: not the regulation of experimental practices but of the care and transportation of the animals being provided to the laboratory. Our analysis is consistent with, and draws upon, scholarship which has established the productive power of public agencies and civil society on the periphery of the American state.
    • Proteomics of colorectal cancer liver metastasis: A quantitative focus on drug elimination and pharmacodynamics effects

      Vasilogianni, Areti‐Maria; orcid: 0000-0001-6665-6115; Al‐Majdoub, Zubida M.; Achour, Brahim; orcid: 0000-0002-2595-5626; Peters, Sheila Annie; Rostami‐Hodjegan, Amin; Barber, Jill; email: jill.barber@manchester.ac.uk (2021-12-03)
      Aims: This study aims to quantify drug‐metabolising enzymes, transporters, receptor tyrosine kinases (RTKs) and protein markers (involved in pathways affected in cancer) in pooled healthy, histologically normal and matched cancerous liver microsomes from colorectal cancer liver metastasis (CRLM) patients. Methods: Microsomal fractionation was performed and pooled microsomes were prepared. Global and accurate mass and retention time liquid chromatography–mass spectrometry proteomics were used to quantify proteins. A QconCAT (KinCAT) for the quantification of RTKs was designed and applied for the first time. Physiologically based pharmacokinetic (PBPK) simulations were performed to assess the contribution of altered abundance of drug‐metabolising enzymes and transporters to changes in pharmacokinetics. Results: Most CYPs and UGTs were downregulated in histologically normal relative to healthy samples, and were further reduced in cancer samples (up to 54‐fold). The transporters, MRP2/3, OAT2/7 and OATP2B1/1B3/1B1 were downregulated in CRLM. Application of abundance data in PBPK models for substrates with different attributes indicated substantially lower (up to 13‐fold) drug clearance when using cancer‐specific instead of default parameters in cancer population. Liver function markers were downregulated, while inflammation proteins were upregulated (by up to 76‐fold) in cancer samples. Various pharmacodynamics markers (e.g. RTKs) were altered in CRLM. Using global proteomics, we examined proteins in pathways relevant to cancer (such as metastasis and desmoplasia), including caveolins and collagen chains, and confirmed general over‐expression of such pathways. Conclusion: This study highlights impaired drug metabolism, perturbed drug transport and altered abundance of cancer markers in CRLM, demonstrating the importance of population‐specific abundance data in PBPK models for cancer.
    • Is skipped nodal metastasis a phenomenon of cutaneous melanoma?

      El-Omar, Omar; Ragavan, Sharanniyan; Yoon, Won Young; Grant, Megan E; email: megan.grant@manchester.ac.uk; Green, Adele C; Oudit, Deemesh; email: deemesh.oudit@nhs.uk (2021-11-10)
      Skipped nodal metastasis (SNM) is a recognized phenomenon of visceral cancers when metastases bypass the regional basin and skip to a distant nodal basin without evidence of distant metastases. Its occurrence is undocumented in cutaneous melanoma patients but of potential prognostic significance. We therefore assessed the frequency of SNM in a large series of patients with limb melanomas. We studied melanoma patients attending a tertiary oncology hospital in northwest England using two approaches. First, we systematically searched medical records of an unselected patient sample treated 2002-2015, and second, we studied lymphoscintigrams of all patients with limb melanoma who underwent sentinel node biopsy 2008-2019. Of 672 melanoma patients whose clinical records were examined, 16 had regional nodal metastases without apparent visceral spread and one appeared to have SNM but further scans were uncovered that showed concurrent pulmonary metastases. Of 667 limb melanoma patients with lymphoscintigrams, 7 showed dual lymphatic drainage patterns to distal as well as regional nodal basins, but none had micro-metastases solely in the distant basin. Occurrence of SNM in cutaneous melanoma is highly unlikely. [Abstract copyright: Copyright © 2021. Published by Elsevier Ltd.]
    • About this title - Celebrating 100 Years of Female Fellowship of the Geological Society: Discovering Forgotten Histories

      Burek, C. V.; Higgs, B. M. (Geological Society of London, 2021-03-15)
      The Geological Society of London was founded in 1807. At the time, membership was restricted to men, many of whom became well-known names in the history of the geological sciences. On the 21 May 1919, the first female Fellows were elected to the Society, 112 years after its formation.This Special Publication celebrates the centenary of that important event. In doing so it presents the often untold stories of pioneering women geoscientists from across the world who navigated male-dominated academia and learned societies, experienced the harsh realities of Siberian field-exploration, or responded to the strategic necessity of the ‘petroleum girls’ in early American oil exploration and production.It uncovers important female role models in the history of science, and investigates why not all of these women received due recognition from their contemporaries and peers. The work has identified a number of common issues that sometimes led to original work and personal achievements being lost or unacknowledged, and as a consequence, to histories being unwritten.
    • Margaret Chorley Crosfield, FGS: the very first female Fellow of the Geological Society

      Burek, C. V.; orcid: 0000-0002-7931-578X (Geological Society of London, 2020-07-10)
      AbstractIn May 1919 the first female Fellows of the Geological Society were elected and from then on attended meetings at the Society. The first person on the female fellows’ list was Margaret Chorley Crosfield. She was born in 1859 and died in 1952. She lived all her life in Reigate in Surrey. After studying and then leaving Cambridge, Margaret had sought to join the Geological Society of London for many years, in order to gain recognition of her research work, but also to attend meetings and use the library. This paper will look at her history and trace her geological achievements in both stratigraphy and palaeontology, as well as her extraordinary field notebooks that she left to the Geological Survey. She worked closely with two female geological colleagues, Mary Johnston and Ethel Skeat. Margaret Crosfield epitomizes the educated, amateur, independent woman who wanted to be recognized for her work, especially fieldwork, at a time when female contributions, especially in the field sciences, were not always acknowledged or even appreciated.
    • Gertrude Elles: the pioneering graptolite geologist in a woolly hat. Her career, achievements and personal reflections from her family and colleagues

      Tubb, J.; Burek, C. V. (Geological Society of London, 2020-10-26)
      AbstractGertrude Elles gained worldwide renown for her seminal work with Ethel Wood on A Monograph of British Graptolites, which is still used today. She gained the MBE, pioneered female geological education, became the first female reader in Cambridge University and one of the first tranche of female Fellows of the Geological Society in 1919. An eccentric with a vast array of hats, PhD students and lodgers, she was a stalwart member of the Sedgwick Club and life member of the British Federation of University Women. She wrote obituaries for colleagues describing their achievements with humour and good nature. Her family describe her as ‘a fabulous woman’ with a huge range of interests including archaeology, botany and music. She related her geological and botanical knowledge in showing a nephew that plants growing along the Moine Thrust reflected change in the underlying rocks. Cambridge colleagues recall her as a ‘marvellous and well-respected figure’ who caused some amusement by her big old cluttered table from which she swept away material making room for new samples (and work for technicians). She died in 1960 in her beloved Scotland. However, her legacy survives in the classification of a group of fossils extinct for nearly 400 myr.
    • Mabel Elizabeth Tomlinson and Isabel Ellie Knaggs: two overlooked early female Fellows of the Geological Society

      Burek, Cynthia V.; orcid: 0000-0002-7931-578X (Geological Society of London, 2020-07-10)
      AbstractThe first female Fellows of the Geological Society of London were elected in May 1919. Brief biographies were documented by Burek in 2009 as part of the celebrations for the bicentenary of the Geological Society. While some of those women were well known (e.g. Gertrude Elles and Ethel Wood), others had seemingly been forgotten. In the decade since that publication, information has come to light about those we knew so little about. There are, however, still some details evading research. From 1919 until 1925, 33 women were elected FGS, including Isobel Ellie Knaggs (1922) and Mabel Tomlinson (1924). Mabel Tomlinson had two careers, and is remembered both as an extraordinary teacher and a Pleistocene geologist. She was awarded the Lyell Fund in 1937 and R.H. Worth Prize in 1961, one of only 13 women to have received two awards from the Geological Society. She inspired the educational Tomlinson–Brown Trust. Isabel Knaggs was born in South Africa and died in Australia but spent all her school, university and working years in England. She made significant contributions to crystallography, working with eminent crystallography scientists while remaining a lifelong FGS. The achievements of Tomlinson and Knaggs are considerable, which makes their relative present-day obscurity rather puzzling.
    • Celebration of the centenary of the first female Fellows: introduction

      Burek, Cynthia Veronica; orcid: 0000-0002-7931-578X; Higgs, Bettie Matheson (Geological Society of London, 2020-11-12)
      AbstractThe Geological Society of London was founded in 1807. In May 1919, the first female Fellows were elected to the Society, 112 years after its foundation. This Special Publication celebrates this centenary. A total of 18 papers have been gathered to highlight recent research, carried out by 24 authors. The publication also builds on stories introduced in a previous Special Publication of the Geological Society, The Role of Women in the History of Geology, edited by Burek and Higgs in 2007, the first book to deal solely with this topic, and in an article by Burek, ‘The first female Fellows and the status of women in the Geological Society of London’, in 2009. It fills in some of the gaps in knowledge with detail that has only recently been uncovered, leading to more in-depth analysis and reporting. The current publication includes more examples from the twentieth century, and a small number into the present century, allowing some trends to be identified. The collective work is finding connections previously undocumented and in danger of being lost forever owing to the age of the interviewees. The same work also identifies several common challenges that female geoscientists faced, which are still evident in the current investigations. By building on what went before, filling gaps in knowledge and enriching the histories, interesting nuanced insights have emerged.
    • Female medal and fund recipients of the Geological Society of London: a historical perspective

      Burek, Cynthia V.; orcid: 0000-0002-7931-578X (Geological Society of London, 2020-06-25)
      AbstractThe Geological Society of London has historically awarded medals and funds to early career geologists and for career achievement recognition. Mid-career and outreach awards were later added as categories. This paper will concentrate on early recipients of funds and medal winners mainly during the nineteenth and twentieth centuries.In the nineteenth century, only two women received recognition by the Geological Society for their work through early career funds (not medals): Catherine Raisin in 1893 and Jane Donald in 1898.From 1900 to 1919, no woman received a medal but funds were collected by men on behalf of Gertrude Elles, Elizabeth Gray, Ethel Wood, Helen Drew, Ida Slater and Ethel Skeat. The first woman to collect her own Fund was Ethel Skeat in 1908.Pre-World War II, only four women received career recognition in the form of a medal. Gertrude Elles in 1919 and Ethel Shakespear in 1920 received the Murchison Medal. No further medals were awarded to women until Maria Ogilvie Gordon in 1932 and Eleanor Mary Reid in 1936. It was not until the end of the 1990s and into the twenty-first century that a significant number of women received medals. It is noted that the William Smith Medal was only received by a woman in 2019 and the Dewey Medal has yet to be received by a woman. An analysis of the different medals and funds awarded to females through the Geological Society is discussed in detail with snapshots of the women who were so recognized. As we move into the twenty-first century we see an increase in these awards to women.
    • A Helminth-Derived Chitinase Structurally Similar to Mammalian Chitinase Displays Immunomodulatory Properties in Inflammatory Lung Disease

      Academic Editor: González, Yolanda; email: ygonzalezh@iner.gob.mx; Ebner, Friederike; orcid: 0000-0002-3485-4077; email: friederike.ebner@fu-berlin.de; Lindner, Katja; email: k.balster@fu-berlin.de; Janek, Katharina; email: katharina.janek@charite.de; Niewienda, Agathe; email: agathe.niewienda@charite.de; Malecki, Piotr H.; email: pimalecki@ibch.poznan.pl; Weiss, Manfred S.; orcid: 0000-0002-2362-7047; email: manfred.weiss@helmholtz-berlin.de; Sutherland, Tara E.; email: tara.sutherland@manchester.ac.uk; Heuser, Arnd; email: heuser@mdc-berlin.de; Kühl, Anja A.; email: anja.kuehl@charite.de; et al. (Hindawi, 2021-11-25)
      Immunomodulation of airway hyperreactivity by excretory-secretory (ES) products of the first larval stage (L1) of the gastrointestinal nematode Trichuris suis is reported by us and others. Here, we aimed to identify the proteins accounting for the modulatory effects of the T. suis L1 ES proteins and studied six selected T. suis L1 proteins for their immunomodulatory efficacy in a murine OVA-induced allergic airway disease model. In particular, an enzymatically active T. suis chitinase mediated amelioration of clinical signs of airway hyperreactivity, primarily associated with suppression of eosinophil recruitment into the lung, the associated chemokines, and increased numbers of RELMα+ interstitial lung macrophages. While there is no indication of T. suis chitinase directly interfering with dendritic cell activation or antigen presentation to CD4 T cells, treatment of allergic mice with the worm chitinase influenced the hosts’ own chitinase activity in the inflamed lung. The three-dimensional structure of the T. suis chitinase as determined by high-resolution X-ray crystallography revealed high similarities to mouse acidic mammalian chitinase (AMCase) but a unique ability of T. suis chitinase to form dimers. Our data indicate that the structural similarities between the parasite and host chitinase contribute to the disease-ameliorating effect of the helminth-derived chitinase on allergic lung inflammation.
    • Identifying older adults with frailty approaching end-of-life: A systematic review

      Hall, Alex; orcid: 0000-0002-8849-744X; email: alex.hall@manchester.ac.uk; Boulton, Elisabeth; Kunonga, Patience; orcid: 0000-0002-6193-1365; Spiers, Gemma; Beyer, Fiona; Bower, Peter; Craig, Dawn; Todd, Chris; Hanratty, Barbara (SAGE Publications, 2021-09-14)
      Background:: People with frailty may have specific needs for end-of-life care, but there is no consensus on how to identify these people in a timely way, or whether they will benefit from intervention. Aim:: To synthesise evidence on identification of older people with frailty approaching end-of-life, and whether associated intervention improves outcomes. Design:: Systematic review (PROSPERO: CRD42020462624). Data sources:: Six databases were searched, with no date restrictions, for articles reporting prognostic or intervention studies. Key inclusion criteria were adults aged 65 and over, identified as frail via an established measure. End-of-life was defined as the final 12 months. Key exclusion criteria were proxy definitions of frailty, or studies involving people with cancer, even if also frail. Results:: Three articles met the inclusion criteria. Strongest evidence came from one study in English primary care, which showed distinct trajectories in electronic Frailty Index scores in the last 12 months of life, associated with increased risk of death. We found no studies evaluating established clinical tools (e.g. Gold Standards Framework) with existing frail populations. We found no intervention studies; the literature on advance care planning with people with frailty has relied on proxy definitions of frailty. Conclusion:: Clear implications for policy and practice are hindered by the lack of studies using an established approach to assessing frailty. Future end-of-life research needs to use explicit approaches to the measurement and reporting of frailty, and address the evidence gap on interventions. A focus on models of care that incorporate a palliative approach is essential.
    • Developing clinical prediction models when adhering to minimum sample size recommendations: The importance of quantifying bootstrap variability in tuning parameters and predictive performance

      Martin, Glen P; orcid: 0000-0002-3410-9472; email: glen.martin@manchester.ac.uk; Riley, Richard D; Collins, Gary S; orcid: 0000-0002-2772-2316; Sperrin, Matthew; orcid: 0000-0002-5351-9960 (SAGE Publications, 2021-10-08)
      Recent minimum sample size formula (Riley et al.) for developing clinical prediction models help ensure that development datasets are of sufficient size to minimise overfitting. While these criteria are known to avoid excessive overfitting on average, the extent of variability in overfitting at recommended sample sizes is unknown. We investigated this through a simulation study and empirical example to develop logistic regression clinical prediction models using unpenalised maximum likelihood estimation, and various post-estimation shrinkage or penalisation methods. While the mean calibration slope was close to the ideal value of one for all methods, penalisation further reduced the level of overfitting, on average, compared to unpenalised methods. This came at the cost of higher variability in predictive performance for penalisation methods in external data. We recommend that penalisation methods are used in data that meet, or surpass, minimum sample size requirements to further mitigate overfitting, and that the variability in predictive performance and any tuning parameters should always be examined as part of the model development process, since this provides additional information over average (optimism-adjusted) performance alone. Lower variability would give reassurance that the developed clinical prediction model will perform well in new individuals from the same population as was used for model development.
    • Mediatization and journalistic agency: Russian television coverage of the Skripal poisonings

      guest-editor: Yablokov, Ilya; guest-editor: Schimpfossl, Elisabeth; guest-editor: Wijermars, Mariëlle; Tolz, Vera; email: vera.tolz@manchester.ac.uk; Hutchings, Stephen; Chatterje-Doody, Precious N; Crilley, Rhys (SAGE Publications, 2020-07-16)
      The 2018 Skripal poisonings prompted the heavy securitisation of UK-Russian relations. Despite the ensuing tight coordination between the Russian government and state-aligned television, this article argues that in today’s mediatised environment – in which social and political activities fuse inextricably with their own mediation – even non-democracies must cope with the shaping of global communications by media logics and related market imperatives. With a range of media actors responding to events, and to each other, on multiple digital platforms, no state could assert full narrative control over the Skripal incident. Counterintuitively, Russian journalists’ journalistic agency was enhanced by mediatisation processes: their state sponsors, seeking to instrumentalise reporting, delegated agency to journalists more attuned to such processes; yet commercial imperatives obliged them to perform independence and professional credibility. These competing forms of agency clashed with one another, and with that of the audiences engaging in real time with the journalists’ outputs, ultimately undermining the Russian state’s efforts to harness news coverage to its political and security goals. The article concludes that in today’s global communications environment, mediatisation substantially constrains the ability of non-democracies to micro-manage journalists’ treatment of major events relating to national security.
    • Public sex, private intimacy and sexual exclusivity in men’s formalized same-sex relationships

      Heaphy, Brian; Hodgson, James; orcid: 0000-0003-2327-6125; email: james.hodgson-2@manchester.ac.uk (SAGE Publications, 2021-07-03)
      This article revisits the personal stories that younger male civil partners told about their sexual practices, in what most termed their ‘marriage’, to generate insights into the extent to which they succumbed to the dangers that critics of same-sex marriage foretold. It provides a baseline analysis against which the findings of future studies of both heterosexual and same-sex marriages and civil partnerships can be compared. The data we discuss are comprised of joint (n = 25) and individual (n = 50) interviews with couples. Participants’ stories about ‘public’, ‘private’ and ‘exclusive’ sex can appear to support the predictions of some key critics. Participants tended to make commitments to sexual monogamy and link their sexual practices to deepening couple intimacy. However, viewed as stories of socioculturally shaped and biographically embedded sexual practices, they offer insights into the more complex relationships between civil partnership, marriage, sexual exclusivity and intimacy. On closer examination, they suggest it is not simply the case that civil partnership or same-sex marriage (and marriage more generally) ‘imposes’ heteronormative sexual conventions but that relational biographies are significant in shaping simultaneously conventional and deconstructive approaches to married sexuality. Partners in formalized same-sex relationships do not simply follow heterosexual norms. Rather, they juggle the often contradictory norms of mainstream and queer sexual cultures. Understanding the implications for marriage as an institution requires approaches to analysis that do not pose heterosexual marriage as the ‘straw man’ of queer analysis.
    • Application of information theoretic feature selection and machine learning methods for the development of genetic risk prediction models

      Jalali-najafabadi, Farideh; email: farideh.jalali@manchester.ac.uk; Stadler, Michael; Dand, Nick; Jadon, Deepak; Soomro, Mehreen; Ho, Pauline; Marzo-Ortega, Helen; Helliwell, Philip; Korendowych, Eleanor; Simpson, Michael A.; et al. (Nature Publishing Group UK, 2021-12-02)
      Abstract: In view of the growth of clinical risk prediction models using genetic data, there is an increasing need for studies that use appropriate methods to select the optimum number of features from a large number of genetic variants with a high degree of redundancy between features due to linkage disequilibrium (LD). Filter feature selection methods based on information theoretic criteria, are well suited to this challenge and will identify a subset of the original variables that should result in more accurate prediction. However, data collected from cohort studies are often high-dimensional genetic data with potential confounders presenting challenges to feature selection and risk prediction machine learning models. Patients with psoriasis are at high risk of developing a chronic arthritis known as psoriatic arthritis (PsA). The prevalence of PsA in this patient group can be up to 30% and the identification of high risk patients represents an important clinical research which would allow early intervention and a reduction of disability. This also provides us with an ideal scenario for the development of clinical risk prediction models and an opportunity to explore the application of information theoretic criteria methods. In this study, we developed the feature selection and psoriatic arthritis (PsA) risk prediction models that were applied to a cross-sectional genetic dataset of 1462 PsA cases and 1132 cutaneous-only psoriasis (PsC) cases using 2-digit HLA alleles imputed using the SNP2HLA algorithm. We also developed stratification method to mitigate the impact of potential confounder features and illustrate that confounding features impact the feature selection. The mitigated dataset was used in training of seven supervised algorithms. 80% of data was randomly used for training of seven supervised machine learning methods using stratified nested cross validation and 20% was selected randomly as a holdout set for internal validation. The risk prediction models were then further validated in UK Biobank dataset containing data on 1187 participants and a set of features overlapping with the training dataset.Performance of these methods has been evaluated using the area under the curve (AUC), accuracy, precision, recall, F1 score and decision curve analysis(net benefit). The best model is selected based on three criteria: the ‘lowest number of feature subset’ with the ‘maximal average AUC over the nested cross validation’ and good generalisability to the UK Biobank dataset. In the original dataset, with over 100 different bootstraps and seven feature selection (FS) methods, HLA_C_*06 was selected as the most informative genetic variant. When the dataset is mitigated the single most important genetic features based on rank was identified as HLA_B_*27 by the seven different feature selection methods, consistent with previous analyses of this data using regression based methods. However, the predictive accuracy of these single features in post mitigation was found to be moderate (AUC= 0.54 (internal cross validation), AUC=0.53 (internal hold out set), AUC=0.55(external data set)). Sequentially adding additional HLA features based on rank improved the performance of the Random Forest classification model where 20 2-digit features selected by Interaction Capping (ICAP) demonstrated (AUC= 0.61 (internal cross validation), AUC=0.57 (internal hold out set), AUC=0.58 (external dataset)). The stratification method for mitigation of confounding features and filter information theoretic feature selection can be applied to a high dimensional dataset with the potential confounders.
    • Ezh2 is essential for the generation of functional yolk sac derived erythro-myeloid progenitors

      Neo, Wen Hao; orcid: 0000-0002-6827-3027; email: wenhao.neo@cruk.manchester.ac.uk; Meng, Yiran; orcid: 0000-0002-9333-2383; Rodriguez-Meira, Alba; Fadlullah, Muhammad Z. H.; Booth, Christopher A. G.; orcid: 0000-0003-3841-6637; Azzoni, Emanuele; orcid: 0000-0002-4572-5692; Thongjuea, Supat; orcid: 0000-0002-9129-4694; de Bruijn, Marella F. T. R.; orcid: 0000-0002-4934-4125; Jacobsen, Sten Eirik W.; Mead, Adam J.; orcid: 0000-0001-8522-1002; email: adam.mead@imm.ox.ac.uk; et al. (Nature Publishing Group UK, 2021-12-02)
      Abstract: Yolk sac (YS) hematopoiesis is critical for the survival of the embryo and a major source of tissue-resident macrophages that persist into adulthood. Yet, the transcriptional and epigenetic regulation of YS hematopoiesis remains poorly characterized. Here we report that the epigenetic regulator Ezh2 is essential for YS hematopoiesis but dispensable for subsequent aorta–gonad–mesonephros (AGM) blood development. Loss of EZH2 activity in hemogenic endothelium (HE) leads to the generation of phenotypically intact but functionally deficient erythro-myeloid progenitors (EMPs), while the generation of primitive erythroid cells is not affected. EZH2 activity is critical for the generation of functional EMPs at the onset of the endothelial-to-hematopoietic transition but subsequently dispensable. We identify a lack of Wnt signaling downregulation as the primary reason for the production of non-functional EMPs. Together, our findings demonstrate a critical and stage-specific role of Ezh2 in modulating Wnt signaling during the generation of EMPs from YS HE.
    • Ketogenic diets for drug-resistant epilepsy

      Martin-McGill, Kirsty J; Bresnahan, Rebecca; Levy, Robert G; Cooper, Paul N (Wiley, 2020-06-24)
    • A fully automatic system to assess foot collapse on lateral weight-bearing foot radiographs: A pilot study.

      Lauder, J; Harris, J; Layton, B; Heire, P; Sorani, A; DeSancha, M; Davison, A K; Sammut-Powell, C; Lindner, C; email: claudia.lindner@manchester.ac.uk (2021-10-30)
      Foot collapse is primarily diagnosed and monitored using lateral weight-bearing foot x-ray images. There are several well-validated measurements which aid assessment. However, these are subject to inter- and intra-user variability. To develop and validate a software system for the fully automatic assessment of radiographic changes associated with foot collapse; automatically generating measurements for calcaneal tilt, cuboid height and Meary's angle. This retrospective study was approved by the Health Research Authority (IRAS 244852). The system was developed using lateral weight-bearing foot x-ray images, and evaluated against manual measurements from five clinical experts. The system has two main components: (i) a Random Forest-based point-finder to outline the bones of interest; and (ii) a geometry-calculator to generate the measurements based on the point positions from the point-finder. The performance of the point-finder was assessed using the point-to-point error (i.e. the mean absolute distance between each found point and the equivalent ground truth point, averaged over all points per image). For assessing the performance of the geometry-calculator, linear mixed models were fitted to estimate clinical inter-observer agreement and to compare the performance of the software system to that of the clinical experts. A total of 200 images were collected from 79 subjects (mean age: 56.4 years ±12.9 SD, 30/49 females/males). There was good agreement among all clinical experts with intraclass correlation estimates between 0.78 and 0.86. The point-finder achieved a median point-to-point error of 2.2 mm. There was no significant difference between the clinical and automatically generated measurements using the point-finder points, suggesting that the fully automatically obtained measurements are in agreement with the manually obtained measurements. The proposed system can be used to support and automate radiographic image assessment for diagnosing and managing foot collapse, saving clinician time, and improving patient outcomes. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Bleeding Data across Baseline FIX Expression Levels in People with Hemophilia B: An Analysis Using the 'Factor Expression Study'

      Burke, Tom; Shaikh, Anum; Ali, Talaha; Li, Nanxin; Konkle, Barbara A; Noone, Declan; O'Mahony, Brian; Pipe, Steven W; O'Hara, Jamie (American Society of Hematology, 2021-11-05)
      Abstract Introduction Complications such as spontaneous and trauma-related bleeding events typically experienced by people with hemophilia B (PWHB) are associated with long-term joint damage and chronic pain, and burdensome treatment with intravenous factor IX administration. Gene therapy, designed to enable the endogenous production of the missing clotting factor, has potential for curative benefit in PWHB (Dolan et al, 2018). Due to its link to risk for bleeding episodes, factor expression level (FEL) is commonly used as an endpoint in hemophilia gene therapy trials. However, little data currently exist linking FEL to bleeding risk in PWHB, most notably within the mild range. As such, the aim of this analysis was to examine the relationship between annual bleed rate (ABR) data across baseline FEL in PWHB. Methods Data from adult non-inhibitor PWHB, across Europe and the United States (US) who received clotting factor on-demand (OD), were drawn from the 'Cost of HaEmophilia in adults: a Socioeconomic Survey' (CHESS) studies. The CHESS studies are retrospective, burden-of-illness studies in people with hemophilia A or B, capturing the economic and humanistic burden associated with living with hemophilia. Additional data were collected to supplement the existing CHESS studies, particularly in people with exogenous FEL in the mild and moderate range. ABR was defined as the physician-reported number of bleed events experienced by the patient in the 12 months to study capture. A generalized linear model (GLM) was used to analyze variation in ABR data across FEL, adjusting for covariates age, body mass index (BMI), and blood-borne viruses. Following this, a multivariable restricted cubic spline (RCS) GLM regression was performed to create, model, and test for the potential non-linear relationship between FEL and ABR. The RCS regression employed 3 knots, located at baseline FEL values of 1, 5, and 10, and controlled once again for age, BMI, and blood-borne viruses. Results A total of 407 adult non-inhibitor PWHB, receiving an OD therapy regimen and with information on ABR, were profiled. The GLM provided adequate fit for the modeling of bleed data; the average marginal effect at the mean was computed from the GLM regression outputs. After controlling for the effects of all other model covariates, the regression analysis showed a significant association between FEL and ABR; for every 1% increase in FEL, the average ABR decreased by 0.08 units (p<0.001). The results of the RCS regression found a significant non-linear relationship between FEL and ABR, ceteris paribus (p<0.001). Conclusions The results of this analysis found baseline FEL to be significantly associated with ABR in PWHB; as baseline FEL increased, ABR reduced. This highlights the clinical importance of new hemophilia gene therapies potentially increasing FEL to that of the mild or non-hemophilic range in terms of reducing patient burden through the better prevention of bleeding events in PWHB. Disclosures Ali: UniQure: Current Employment. Li: UniQure: Current Employment. Konkle: Pfizer, Sangamo, Sanofi, Sigilon, Spark, Takeda and Uniqure: Research Funding; BioMarin, Pfizer and Sigilon: Consultancy. O'Mahony: BioMarin Pharmaceutical Inc.: Consultancy; Freeline: Consultancy; Uniqure: Speakers Bureau. Pipe: Apcintex: Consultancy; ASC Therapeutics: Consultancy; Bayer: Consultancy; Biomarin: Consultancy, Other: Clinical trial investigator; Catalyst Biosciences: Consultancy; CSL Behring: Consultancy; HEMA Biologics: Consultancy; Freeline: Consultancy, Other: Clinical trial investigator; Novo Nordisk: Consultancy; Pfizer: Consultancy; Roche/Genentech: Consultancy, Other; Sangamo Therapeutics: Consultancy; Sanofi: Consultancy, Other; Takeda: Consultancy; Spark Therapeutics: Consultancy; uniQure: Consultancy, Other; Regeneron/ Intellia: Consultancy; Genventiv: Consultancy; Grifols: Consultancy; Octapharma: Consultancy; Shire: Consultancy.