• Mining a stroke knowledge graph from literature

      Yang, Xi; Wu, Chengkun; Nenadic, Goran; email: g.nenadic@manchester.ac.uk; Wang, Wei; Lu, Kai (BioMed Central, 2021-07-29)
      Abstract: Background: Stroke has an acute onset and a high mortality rate, making it one of the most fatal diseases worldwide. Its underlying biology and treatments have been widely studied both in the “Western” biomedicine and the Traditional Chinese Medicine (TCM). However, these two approaches are often studied and reported in insolation, both in the literature and associated databases. Results: To aid research in finding effective prevention methods and treatments, we integrated knowledge from the literature and a number of databases (e.g. CID, TCMID, ETCM). We employed a suite of biomedical text mining (i.e. named-entity) approaches to identify mentions of genes, diseases, drugs, chemicals, symptoms, Chinese herbs and patent medicines, etc. in a large set of stroke papers from both biomedical and TCM domains. Then, using a combination of a rule-based approach with a pre-trained BioBERT model, we extracted and classified links and relationships among stroke-related entities as expressed in the literature. We construct StrokeKG, a knowledge graph includes almost 46 k nodes of nine types, and 157 k links of 30 types, connecting diseases, genes, symptoms, drugs, pathways, herbs, chemical, ingredients and patent medicine. Conclusions: Our Stroke-KG can provide practical and reliable stroke-related knowledge to help with stroke-related research like exploring new directions for stroke research and ideas for drug repurposing and discovery. We make StrokeKG freely available at (Please click "Connect" directly) and the source structured data for stroke at https://github.com/yangxi1016/Stroke
    • Distinct patterns of disease activity over time in patients with active SLE revealed using latent class trajectory models

      Reynolds, John A.; Prattley, Jennifer; Geifman, Nophar; Lunt, Mark; Gordon, Caroline; Bruce, Ian N.; orcid: 0000-0003-3047-500X; email: ian.bruce@manchester.ac.uk (BioMed Central, 2021-07-29)
      Abstract: Background: Systemic lupus erythematosus (SLE) is a heterogeneous systemic autoimmune condition for which there are limited licensed therapies. Clinical trial design is challenging in SLE due at least in part to imperfect outcome measures. Improved understanding of how disease activity changes over time could inform future trial design. The aim of this study was to determine whether distinct trajectories of disease activity over time occur in patients with active SLE within a clinical trial setting and to identify factors associated with these trajectories. Methods: Latent class trajectory models were fitted to a clinical trial dataset of a monoclonal antibody targeting CD22 (Epratuzumab) in patients with active SLE using the numerical BILAG-2004 score (nBILAG). The baseline characteristics of patients in each class and changes in prednisolone over time were identified. Exploratory PK-PD modelling was used to examine cumulative drug exposure in relation to latent class membership. Results: Five trajectories of disease activity were identified, with 3 principal classes: non-responders (NR), slow responders (SR) and rapid-responders (RR). In both the SR and RR groups, significant changes in disease activity were evident within the first 90 days of the trial. The SR and RR patients had significantly higher baseline disease activity, exposure to epratuzumab and activity in specific BILAG domains, whilst NR had lower steroid use at baseline and less change in steroid dose early in the trial. Conclusions: Longitudinal nBILAG scores reveal different trajectories of disease activity and may offer advantages over fixed endpoints. Corticosteroid use however remains an important confounder in lupus trials and can influence early response. Changes in disease activity and steroid dose early in the trial were associated with the overall disease activity trajectory, supporting the feasibility of performing adaptive trial designs in SLE.
    • Error Estimates of a Continuous Galerkin Time Stepping Method for Subdiffusion Problem

      Yan, Yuyuan; Egwu, Bernard A.; Liang, Zongqi; Yan, Yubin; orcid: 0000-0002-5686-5017; email: y.yan@chester.ac.uk (Springer US, 2021-07-29)
      Abstract: A continuous Galerkin time stepping method is introduced and analyzed for subdiffusion problem in an abstract setting. The approximate solution will be sought as a continuous piecewise linear function in time t and the test space is based on the discontinuous piecewise constant functions. We prove that the proposed time stepping method has the convergence order O(τ1+α), α∈(0, 1) for general sectorial elliptic operators for nonsmooth data by using the Laplace transform method, where τ is the time step size. This convergence order is higher than the convergence orders of the popular convolution quadrature methods (e.g., Lubich’s convolution methods) and L-type methods (e.g., L1 method), which have only O(τ) convergence for the nonsmooth data. Numerical examples are given to verify the robustness of the time discretization schemes with respect to data regularity.
    • Pathogenic noncoding variants in the neurofibromatosis and schwannomatosis predisposition genes

      Perez‐Becerril, Cristina; orcid: 0000-0003-1630-1943; Evans, D. Gareth; orcid: 0000-0002-8482-5784; Smith, Miriam J.; orcid: 0000-0002-3184-0817; email: miriam.smith@manchester.ac.uk (2021-07-29)
      Abstract: Neurofibromatosis type 1 (NF1), type 2 (NF2), and schwannomatosis are a group of autosomal dominant disorders that predispose to the development of nerve sheath tumors. Pathogenic variants (PVs) that cause NF1 and NF2 are located in the NF1 and NF2 loci, respectively. To date, most variants associated with schwannomatosis have been identified in the SMARCB1 and LZTR1 genes, and a missense variant in the DGCR8 gene was recently reported to predispose to schwannomas. In spite of the high detection rate for PVs in NF1 and NF2 (over 90% of non‐mosaic germline variants can be identified by routine genetic screening) underlying PVs for a proportion of clinical cases remain undetected. A higher proportion of non‐NF2 schwannomatosis cases have no detected PV, with PVs currently only identified in around 70%–86% of familial cases and 30%–40% of non‐NF2 sporadic schwannomatosis cases. A number of variants of uncertain significance have been observed for each disorder, many of them located in noncoding, regulatory, or intergenic regions. Here we summarize noncoding variants in this group of genes and discuss their established or potential role in the pathogenesis of NF1, NF2, and schwannomatosis.
    • A Review on Microcellular Injection Moulding

      Ding, Yifei; email: yifei.ding@manchester.ac.uk; Hassan, Mohammed H.; orcid: 0000-0002-0832-8559; email: Mohamed.hassan@manchester.ac.uk; Bakker, Otto; orcid: 0000-0002-1862-6955; email: ottojan.bakker@manchester.ac.uk; Hinduja, Srichand; email: sri.hinduja@manchester.ac.uk; Bártolo, Paulo; orcid: 0000-0003-3683-726X; email: paulojorge.dasilvabartolo@manchester.ac.uk (MDPI, 2021-07-28)
      Microcellular injection moulding (MuCell®) is a polymer processing technology that uses a supercritical fluid inert gas, CO2 or N2, to produce light-weight products. Due to environmental pressures and the requirement of light-weight parts with good mechanical properties, this technology recently gained significant attention. However, poor surface appearance and limited mechanical properties still prevent the wide applications of this technique. This paper reviews the microcellular injection moulding process, main characteristics of the process, bubble nucleation and growth, and major recent developments in the field. Strategies to improve both the surface quality and mechanical properties are discussed in detail as well as the relationships between processing parameters, morphology, and surface and mechanical properties. Modelling approaches to simulate microcellular injection moulding and the mathematical models behind Moldex 3D and Moldflow, the two most commonly used software tools by industry and academia, are reviewed, and the main limitations are highlighted. Finally, future research perspectives to further develop this technology are also discussed.
    • The Genomic Architecture of Bladder Exstrophy Epispadias Complex

      Beaman, Glenda M.; email: glenda.beaman@manchester.ac.uk; Cervellione, Raimondo M.; email: raimondo.cervellione@mft.nhs.uk; Keene, David; email: David.Keene@mft.nhs.uk; Reutter, Heiko; email: Heiko.Reutter@ukbonn.de; Newman, William G.; email: william.newman@manchester.ac.uk (MDPI, 2021-07-28)
      The bladder exstrophy–epispadias complex (BEEC) is an abdominal midline malformation comprising a spectrum of congenital genitourinary abnormalities of the abdominal wall, pelvis, urinary tract, genitalia, anus, and spine. The vast majority of BEEC cases are classified as non-syndromic and the etiology of this malformation is still unknown. This review presents the current knowledge on this multifactorial disorder, including phenotypic and anatomical characterization, epidemiology, proposed developmental mechanisms, existing animal models, and implicated genetic and environmental components.
    • Comprehensive Library Generation for Identification and Quantification of Endometrial Cancer Protein Biomarkers in Cervico-Vaginal Fluid

      Njoku, Kelechi; orcid: 0000-0001-6528-3476; email: kelechi.njoku@manchester.ac.uk; Chiasserini, Davide; email: davide.chiasserini@unipg.it; Geary, Bethany; orcid: 0000-0002-5592-5532; email: bethany.geary@manchester.ac.uk; Pierce, Andrew; email: andrew.pierce@manchester.ac.uk; Jones, Eleanor R.; email: eleanor.jones-3@manchester.ac.uk; Whetton, Anthony D.; orcid: 0000-0002-1098-3878; email: tony.whetton@manchester.ac.uk; Crosbie, Emma J.; orcid: 0000-0003-0284-8630; email: emma.crosbie@manchester.ac.uk (MDPI, 2021-07-28)
      Endometrial cancer is the most common gynaecological malignancy in high-income countries and its incidence is rising. Early detection, aided by highly sensitive and specific biomarkers, has the potential to improve outcomes as treatment can be provided when it is most likely to effect a cure. Sequential window acquisition of all theoretical mass spectra (SWATH-MS), an accurate and reproducible platform for analysing biological samples, offers a technological advance for biomarker discovery due to its reproducibility, sensitivity and potential for data re-interrogation. SWATH-MS requires a spectral library in order to identify and quantify peptides from multiplexed mass spectrometry data. Here we present a bespoke spectral library of 154,206 transitions identifying 19,394 peptides and 2425 proteins in the cervico-vaginal fluid of postmenopausal women with, or at risk of, endometrial cancer. We have combined these data with a library of over 6000 proteins generated based on mass spectrometric analysis of two endometrial cancer cell lines. This unique resource enables the study of protein biomarkers for endometrial cancer detection in cervico-vaginal fluid. Data are available via ProteomeXchange with unique identifier PXD025925.
    • Towards the Determination of Safe Operating Envelopes for Autonomous UAS in Offshore Inspection Missions

      Page, Vincent; email: v.page@liverpool.ac.uk; Dadswell, Christopher; email: c.m.dadswell@liverpool.ac.uk; Webster, Matt; email: m.p.webster@ljmu.ac.uk; Jump, Mike; email: mjump1@liverpool.ac.uk; Fisher, Michael; orcid: 0000-0002-0875-3862; email: michael.fisher@manchester.ac.uk (MDPI, 2021-07-28)
      A drive to reduce costs, carbon emissions, and the number of required personnel in the offshore energy industry has led to proposals for the increased use of autonomous/robotic systems for many maintenance tasks. There are questions over how such missions can be shown to be safe. A corollary exists in the manned aviation world for helicopter–ship operations where a test pilot attempts to operate from a ship under a range of wind conditions and provides subjective feedback on the level of difficulty encountered. This defines the ship–helicopter operating limit envelope (SHOL). Due to the cost of creating a SHOL there has been considerable research activity to demonstrate that much of this process can be performed virtually. Unmanned vehicles, however, have no test pilot to provide feedback. This paper therefore explores the possibility of adapting manned simulation techniques to the unmanned world to demonstrate that a mission is safe. Through flight modelling and simulation techniques it is shown that operating envelopes can be created for an oil rig inspection task and that, by using variable performance specifications, these can be tailored to suit the level of acceptable risk. The operating envelopes produced provide condensed and intelligible information regarding the environmental conditions under which the UAS can perform the task.
    • In-situ nanospectroscopic imaging of plasmon-induced two-dimensional [4+4]-cycloaddition polymerization on Au(111)

      Shao, Feng; orcid: 0000-0003-3879-5884; email: feng.shao@manchester.ac.uk; Wang, Wei; Yang, Weimin; Yang, Zhilin; Zhang, Yao; orcid: 0000-0002-6524-0289; Lan, Jinggang; email: jinggang.lan@chem.uzh.ch; Dieter Schlüter, A.; Zenobi, Renato; orcid: 0000-0001-5211-4358; email: zenobi@org.chem.ethz.ch (Nature Publishing Group UK, 2021-07-27)
      Abstract: Plasmon-induced chemical reactions (PICRs) have recently become promising approaches for highly efficient light-chemical energy conversion. However, an in-depth understanding of their mechanisms at the nanoscale still remains challenging. Here, we present an in-situ investigation by tip-enhanced Raman spectroscopy (TERS) imaging of the plasmon-induced [4+4]-cycloaddition polymerization within anthracene-based monomer monolayers physisorbed on Au(111), and complement the experimental results with density functional theory (DFT) calculations. This two-dimensional (2D) polymerization can be flexibly triggered and manipulated by the hot carriers, and be monitored simultaneously by TERS in real time and space. TERS imaging provides direct evidence for covalent bond formation with ca. 3.7 nm spatial resolution under ambient conditions. Combined with DFT calculations, the TERS results demonstrate that the lateral polymerization on Au(111) occurs by a hot electron tunneling mechanism, and crosslinks form via a self-stimulating growth mechanism. We show that TERS is promising to be plasmon-induced nanolithography for organic 2D materials.
    • The promise and challenges of cell therapy for psoriasis

      Lwin, S.M.; orcid: 0000-0002-3325-3675; Snowden, J.A.; orcid: 0000-0001-6819-3476; Griffiths, C.E.M.; orcid: 0000-0001-5371-4427; email: christopher.griffiths@manchester.ac.uk (2021-07-27)
      Summary: The management of moderate‐to‐severe psoriasis has been transformed by the introduction of biological therapies. These medicines, particularly those targeting interleukin (IL)‐17 and IL‐23p19, can offer clear or nearly clear skin for the majority of patients with psoriasis, with good long‐term drug survival. However, as currently used, none of these therapies is curative and disconcertingly there is a small but increasing number of patients with severe psoriasis who have failed all currently available therapeutic modalities. A similar scenario has occurred in other immune‐mediated inflammatory diseases (IMIDs) where treatment options are limited in severely affected patients. In these cases, cell therapy, including haematopoietic stem cell transplantation (HSCT) and mesenchymal stromal cells (MSC), has been utilized. This review discusses the various forms of cell therapy currently available, their utility in the management of IMIDs and emerging evidence for efficacy in severe psoriasis that is unresponsive to biological therapy. Balancing the risks and benefits of treatment vs. the underlying disease is key; cell therapy carries significant risks, costs, regulation and other complexities, which must be justified by outcomes. Although HSCT has anecdotally been reported to benefit severe psoriasis, sometimes with apparent cure, this has mainly been in the setting of other coincidental ‘routine’ indications. In psoriasis, cell therapies, such as MSC and regulatory T cells, with a lower risk of complications are likely to be more appropriate. Well‐designed controlled trials coupled with mechanistic studies are warranted if advanced cell therapies are to be developed and delivered as a realistic option for severe psoriasis.
    • Local Analysis of Heterogeneous Intracellular Transport: Slow and Fast Moving Endosomes

      Korabel, Nickolay; email: nickolay.korabel@manchester.ac.uk; Han, Daniel; orcid: 0000-0002-9088-1651; email: daniel.han@manchester.ac.uk; Taloni, Alessandro; orcid: 0000-0002-8863-7166; email: alessandro.taloni@isc.cnr.it; Pagnini, Gianni; email: gpagnini@bcamath.org; Fedotov, Sergei; email: sergei.fedotov@manchester.ac.uk; Allan, Viki; email: viki.allan@manchester.ac.uk; Waigh, Thomas Andrew; email: t.a.waigh@manchester.ac.uk (MDPI, 2021-07-27)
      Trajectories of endosomes inside living eukaryotic cells are highly heterogeneous in space and time and diffuse anomalously due to a combination of viscoelasticity, caging, aggregation and active transport. Some of the trajectories display switching between persistent and anti-persistent motion, while others jiggle around in one position for the whole measurement time. By splitting the ensemble of endosome trajectories into slow moving subdiffusive and fast moving superdiffusive endosomes, we analyzed them separately. The mean squared displacements and velocity auto-correlation functions confirm the effectiveness of the splitting methods. Applying the local analysis, we show that both ensembles are characterized by a spectrum of local anomalous exponents and local generalized diffusion coefficients. Slow and fast endosomes have exponential distributions of local anomalous exponents and power law distributions of generalized diffusion coefficients. This suggests that heterogeneous fractional Brownian motion is an appropriate model for both fast and slow moving endosomes. This article is part of a Special Issue entitled: “Recent Advances In Single-Particle Tracking: Experiment and Analysis” edited by Janusz Szwabiński and Aleksander Weron.
    • Chronic and rare disease patients' access to healthcare services during a health crisis: The example of the COVID‐19 pandemic in Turkey

      Aktas, Puren; orcid: 0000-0003-0783-8044; email: puren.aktas@postgrad.manchester.ac.uk (2021-07-26)
      Abstract: Objective: The restructuring of healthcare provision for the coronavirus disease 2019 (COVID‐19) pandemic caused disruptions in access for patients with chronic or rare diseases. This study explores the experiences of patients with chronic or rare diseases in access to healthcare services in Turkey during the COVID‐19 pandemic. Methods: Semi‐structured interviews were conducted with representatives (n = 10) of patient organisations (n = 9) based in Istanbul. Thematic analysis with an inductive approach was conducted to analyse the responses obtained through the interviews. Results: The lack of clinical information at the beginning of the pandemic caused fear among patients with chronic or rare diseases. Patients experienced obstacles in access to healthcare services because of the overcrowding of hospitals with COVID‐19 patients. Some treatment procedures were cancelled or postponed by physicians. Of these procedures, some were medically vital for those patients, leading to or exacerbating further health problems. The most positive measures that patients identified were where the Social Security Institution introduced regulations to facilitate access to prescribed medicine for chronic patients. Information exchange between the doctors and their patients was important to alleviate the uncertainty and reduce the anxiety among patients. Discussion: Access problems experienced by patients during the COVID‐19 pandemic were a complex mix of factors including shortages and physical barriers, but also perceptions of barriers. The findings of this study show that patient organisations can provide insights on disease‐specific experiences and problems that are very valuable to improve access to healthcare services to achieve the universal health coverage target. Hence, this study emphasises the inclusion of patient organisations in decision‐making processes during times of health crises. Public Contribution: Representatives of patient organisations participated in the interviews.
    • Patient preferences and priorities for haemophilia gene therapy in the US: A discrete choice experiment

      Witkop, Michelle; Morgan, George; orcid: 0000-0003-2014-3415; email: george.morgan@hcdeconomics.com; O'Hara, Jamie; Recht, Michael; Buckner, Tyler W.; Nugent, Diane; Curtis, Randall; orcid: 0000-0002-6859-6432; O'Mahony, Brian; orcid: 0000-0001-9780-6972; Skinner, Mark W.; orcid: 0000-0002-0934-0680; Mulhern, Brendan; et al. (2021-07-26)
      Abstract: Introduction: Gene therapy has shown promise in clinical trials for patients with haemophilia, but patient preference studies have focused on factor replacement treatments. Aim: We conducted a discrete choice experiment (DCE) to investigate the relative importance and differential preferences patients provide for gene therapy attributes. Methods: We surveyed male adults with haemophilia in the United States recruited from patient panels including the National Hemophilia Foundation Community Voices in Research platform using an online survey over 4 months in 2020/21. Participants indicated preferences for gene therapy attributes including dosing frequency/durability, effect on annual bleeding, uncertainty related to side effects, impact on daily activities, impact on mental health, and post‐treatment requirements. The relative importance of each attribute was analysed overall and for subgroups based on haemophilia type and severity. Results: A total of 183 males with haemophilia A (n = 120) or B (n = 63) were included. Half (47%) had severe haemophilia; most (75%) were White. Overall, participants gave effect on bleeding rate the greatest relative importance (31%), followed by dose frequency/durability (26%), uncertainty regarding safety issues (17%), and impact on daily activities (11%). Dose frequency/durability had the greatest importance for those with haemophilia B (35%). Conclusion: People with haemophilia prioritised reduced bleeding and treatment burden; the former was more important in haemophilia A and the latter in haemophilia B, followed by safety and impact on daily life in this DCE of gene therapy attributes. These findings and differences can inform clinical and health policy decisions to improve health equity for people with haemophilia.
    • Chemical Vapor Deposition of Graphene on Cu-Ni Alloys: The Impact of Carbon Solubility

      Al-Hilfi; email: 100119@uotechnology.edu.iq; Kinloch; email: Ian.Kinloch@manchester.ac.uk; Derby; email: Brian.Derby@manchester.ac.uk (MDPI, 2021-07-26)
      Chemical vapour deposition (CVD) is the most promising graphene synthesis route for film and electronic applications but the growth mechanism is still not fully understood. Herein, we investigate the role of the solubility of carbon in the underlying growth substrate on the CVD growth of graphene. A range of Cu-Ni alloys compositions that cover the carbon (C) solubility range between low C solubility (pure Cu) and high C solubility (pure Ni) were used as the catalytic growth substrates. The CVD of graphene on Cu-Ni alloys showed a transition from bilayer graphene (BLG) to few-layer graphene (FLG) at a substrate Ni concentration of 45 wt.%, which was attributed to an increase in the bulk diffusion of C. The Cu-rich alloys had a high graphene coverage (BLG) at a fast-cooling rate (367 °C/min), while the Ni-rich alloys had a low coverage (FLG) under the same cooling condition. In contrast, at slow cooling rates (27 °C/min), the Cu-rich alloys had a low coverage of graphene (BLG) and the Ni-rich alloys had a high coverage of graphene (FLG). Glow discharge optical emission spectroscopy (GDOES) was used to profile the subsurface composition, particularly the C concentration, as a function of depth.
    • Assessing Fracture Toughness and Impact Strength of PMMA Reinforced with Nano-Particles and Fibre as Advanced Denture Base Materials

      Alhotan, Abdulaziz; email: aalhotan@ksu.edu.sa; Yates, Julian; email: julian.yates@manchester.ac.uk; Zidan, Saleh; email: saleh_0072002@yahoo.co.uk; Haider, Julfikar; orcid: 0000-0001-7010-8285; email: j.haider@mmu.ac.uk; Silikas, Nikolaos; orcid: 0000-0003-4576-4584; email: nikolaos.silikas@manchester.ac.uk (MDPI, 2021-07-24)
      Statement of Problem: Polymethyl methacrylate (PMMA) denture resins commonly fracture as a result of the denture being dropped or when in use due to heavy occlusal forces. Purpose: To investigate the effects of E-glass fibre, ZrO2 and TiO2 nanoparticles at different concentrations on the fracture toughness and impact strength of PMMA denture base. Materials and Methods: To evaluate fracture toughness (dimensions: 40 × 8 × 4 mm3; n = 10/group) and impact strength (dimensions: 80 × 10 × 4 mm3; n = 12/group), 286 rectangular tested specimens were prepared and divided into four groups. Group C consisted of the PMMA specimens without any filler (control group), while the specimens in the remaining three groups varied according to the concentration of three filler materials by weight of PMMA resin: 1.5%, 3%, 5%, and 7%. Three-point bending and Charpy impact tests were conducted to measure the fracture toughness and impact strength respectively. Scanning Electron Microscope (SEM) was utilised to examine the fractured surfaces of the specimens after the fracture toughness test. One-way analysis of variance (ANOVA) followed by Tukey post-hoc tests were employed to analyse the results at a p ≤ 0.05 significance level. Results: Fracture toughness of groups with 1.5 and 3 wt.% ZrO2, 1.5 wt.% TiO2, and all E-glass fibre concentrations were significantly higher (p 0.05) than the control group. The samples reinforced with 3 wt.% ZrO2 exhibited the highest fracture toughness. Those reinforced with a 3 wt.%, 5 wt.%, and 7 wt.% of E-glass fibres had a significantly (p 0.05) higher impact strength than the specimens in the control group. The heat-cured PMMA modified with either ZrO2 or TiO2 nanoparticles did not exhibit a statistically significant difference in impact strength (p > 0.05) in comparison to the control group. Conclusions: 1.5 wt.%, 3 wt.% of ZrO2; 1.5 wt.% ratios of TiO2; and 1.5 wt.%, 3 wt.%, 5 wt.%, and 7 wt.% of E-glass fibre can effectively enhance the fracture toughness of PMMA. The inclusion of E-glass fibres does significantly improve impact strength, while ZrO2 or TiO2 nanoparticles did not.
    • Access to systemic anti-cancer therapies for women with secondary breast cancer—protocol for a mixed methods systematic review

      Pearson, Sally Anne; orcid: 0000-0002-7796-2617; email: sally.pearson@postgrad.manchester.ac.uk; Taylor, Sally; Marsden, Antonia; Yorke, Janelle (BioMed Central, 2021-07-23)
      Abstract: Background: It is well recognised that access and receipt of appropriate guideline recommended treatment with systemic anti-cancer therapies for secondary breast cancer is a key determinant in overall survival. Where there is disparity in access this may result in unwarranted variation and disparity in outcomes. Individual, clinical and wider contextual factors have been associated with these disparities, however this remains poorly understood for women with secondary breast cancer. The purpose of the review is to examine individual, clinical and contextual factors which influence access to evidence-based systemic anti-cancer therapies for women with secondary breast cancer. This will include barriers and facilitators for access and receipt of treatment and an exploration of women and clinicians experience and perspectives on access. Methods: A mixed methods approach with a segregated design will be used to examine and explore factors which influence access to systemic anti-cancer therapies for women with secondary breast cancer. Electronic databases to be searched from January 2000 onwards will be EBSCO CINAHL Plus, Ovid MEDLINE, Ovid EMBASE, PsychINFO and the Cochrane Library and JBI database. This will include NHS Evidence which will be searched for unpublished studies and gray literature. Title and abstract citations and full-text articles will be screened by the author and second reviewer. Data will be extracted by the author and validated by the second reviewer. An overarching synthesis will be produced which brings together quantitative and qualitative findings. Methodological quality and risk of bias will be assessed using the Mixed Methods Appraisal Tool. Discussion: Understanding individual, clinical and wider contextual factors associated with access and receipt of systemic anti-cancer therapies for secondary breast cancer is a complex phenomenon. These will be examined to determine any association with access. Review findings will be used to guide future research in this area and the development of an evidence-based service level intervention designed to address unwarranted variation in access based upon the Medical Research Council (MRC) approach to the development, implementation and evaluation of complex interventions. Systematic review registration: The review protocol has been registered in PROSPERO CRD42020196490.
    • Systematic Roadmap for Cancer Drug Screening Using Zebrafish Embryo Xenograft Cancer Models: Melanoma Cell Line as a Case Study

      Letrado, Patricia; email: patricia.letrado@ikanbiotech.com; Mole, Holly; email: holly.mole@manchester.ac.uk; Montoya, María; email: mmontoya68@gmail.com; Palacios, Irene; email: irene.palacios@cnic.es; Barriuso, Jorge; orcid: 0000-0002-5641-9105; email: jorge.barriuso@manchester.ac.uk; Hurlstone, Adam; orcid: 0000-0001-5260-9457; email: adam.hurlstone@manchester.ac.uk; Díez-Martínez, Roberto; email: roberto.diez@ikanbiotech.com; Oyarzabal, Julen; email: julenoyarzabal@external.unav.es (MDPI, 2021-07-23)
      Zebrafish embryo tumor transplant models are widely utilized in cancer research. Compared with traditional murine models, the small size and transparency of zebrafish embryos combined with large clutch sizes that increase statistical power and cheap husbandry make them a cost-effective and versatile tool for in vivo drug discovery. However, the lack of a comprehensive analysis of key factors impacting the successful use of these models impedes the establishment of basic guidelines for systematic screening campaigns. Thus, we explored the following crucial factors: (i) user-independent inclusion criteria, focusing on sample homogeneity; (ii) metric definition for data analysis; (iii) tumor engraftment criteria; (iv) image analysis versus quantification of human cancer cells using qPCR (RNA and gDNA); (v) tumor implantation sites; (vi) compound distribution (intratumoral administration versus alternative inoculation sites); and (vii) efficacy (intratumoral microinjection versus compound solution in media). Based on these analyses and corresponding assessments, we propose the first roadmap for systematic drug discovery screening in zebrafish xenograft cancer models using a melanoma cell line as a case study. This study aims to help the wider cancer research community to consider the adoption of this versatile model for cancer drug screening projects.
    • Scaling of axial muscle architecture in juvenile Alligator mississippiensis reveals an enhanced performance capacity of accessory breathing mechanisms

      Rose, Kayleigh A. R.; Tickle, Peter G.; Elsey, Ruth M.; Sellers, William I.; orcid: 0000-0002-2913-5406; Crossley, Dane A., II; Codd, Jonathan R.; orcid: 0000-0003-0211-1786; email: jonathan.codd@manchester.ac.uk (2021-07-23)
      Abstract: Quantitative functional anatomy of amniote thoracic and abdominal regions is crucial to understanding constraints on and adaptations for facilitating simultaneous breathing and locomotion. Crocodilians have diverse locomotor modes and variable breathing mechanics facilitated by basal and derived (accessory) muscles. However, the inherent flexibility of these systems is not well studied, and the functional specialisation of the crocodilian trunk is yet to be investigated. Increases in body size and trunk stiffness would be expected to cause a disproportionate increase in muscle force demands and therefore constrain the basal costal aspiration mechanism, necessitating changes in respiratory mechanics. Here, we describe the anatomy of the trunk muscles, their properties that determine muscle performance (mass, length and physiological cross‐sectional area [PCSA]) and investigate their scaling in juvenile Alligator mississippiensis spanning an order of magnitude in body mass (359 g–5.5 kg). Comparatively, the expiratory muscles (transversus abdominis, rectus abdominis, iliocostalis), which compress the trunk, have greater relative PCSA being specialised for greater force‐generating capacity, while the inspiratory muscles (diaphragmaticus, truncocaudalis ischiotruncus, ischiopubis), which create negative internal pressure, have greater relative fascicle lengths, being adapted for greater working range and contraction velocity. Fascicle lengths of the accessory diaphragmaticus scaled with positive allometry in the alligators examined, enhancing contractile capacity, in line with this muscle's ability to modulate both tidal volume and breathing frequency in response to energetic demand during terrestrial locomotion. The iliocostalis, an accessory expiratory muscle, also demonstrated positive allometry in fascicle lengths and mass. All accessory muscles of the infrapubic abdominal wall demonstrated positive allometry in PCSA, which would enhance their force‐generating capacity. Conversely, the basal tetrapod expiratory pump (transversus abdominis) scaled isometrically, which may indicate a decreased reliance on this muscle with ontogeny. Collectively, these findings would support existing anecdotal evidence that crocodilians shift their breathing mechanics as they increase in size. Furthermore, the functional specialisation of the diaphragmaticus and compliance of the body wall in the lumbar region against which it works may contribute to low‐cost breathing in crocodilians.
    • Author Correction: The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival

      Valpione, Sara; Mundra, Piyushkumar A.; Galvani, Elena; Campana, Luca G.; orcid: 0000-0002-8466-8459; Lorigan, Paul; orcid: 0000-0002-8875-2164; De Rosa, Francesco; orcid: 0000-0003-0511-1298; Gupta, Avinash; Weightman, John; Mills, Sarah; Dhomen, Nathalie; et al. (Nature Publishing Group UK, 2021-07-22)
    • An Ecosystem View of Peer-to-Peer Electricity Trading: Scenario Building by Business Model Matrix to Identify New Roles

      Montakhabi; email: mehdi.montakhabi@vub.be; Zobiri; email: fairouz.zobiri@kuleuven.be; van der Graaf; orcid: 0000-0002-3338-3453; email: shenja.vandergraaf@utwente.nl; Deconinck; orcid: 0000-0002-2225-3987; email: geert.deconinck@kuleuven.be; Orlando; email: nico.orlando@kuleuven.be; Ballon; email: pieter.ballon@vub.be; Mustafa; email: mustafa.mustafa@manchester.ac.uk (MDPI, 2021-07-22)
      This article introduces new roles in future peer-to-peer electricity trading markets. Following a qualitative approach, firstly, the value network of the current electricity market is presented. To do so, service streams, critical roles, activities, and their setting in the electricity market are identified. Secondly, in order to identify the main sources of uncertainty, the business model matrix framework is utilized to analyze peer-to-peer electricity trading. Thirdly, four future scenarios are built based on user involvement and customer ownership. The outcome of the scenario building is the emergence of new roles, brokers, and representatives in the future peer-to-peer electricity markets. Fourth, based on the four future scenarios, changes in the value network, new roles, and emerging/evolving activities are identified. Finally, the two new roles are discussed from grid structure, security and privacy, legal, and data protection perspectives. The data is gathered by conducting semi-structured interviews with stakeholders in the current electricity market as well as potential disruptors. This article elaborates on the configuration of the value network in the electricity market and highlights the changes that peer-to-peer trading imposes to the status quo. Through the outcomes of the value network analysis, it assists policy makers to consider the requirements and current market players to reconsider their business models.