• Practical Demonstration of a Hybrid Model for Optimising the Reliability, Risk, and Maintenance of Rolling Stock Subsystem

      Appoh, Frederick; orcid: 0000-0003-4228-5799; email: frederick.appoh@manchester.ac.uk; Yunusa-Kaltungo, Akilu; orcid: 0000-0001-5138-3783; Sinha, Jyoti Kumar; orcid: 0000-0001-9202-1789; Kidd, Moray; orcid: 0000-0003-4185-5788 (Springer Berlin Heidelberg, 2021-05-11)
      Abstract: Railway transport system (RTS) failures exert enormous strain on end-users and operators owing to in-service reliability failure. Despite the extensive research on improving the reliability of RTS, such as signalling, tracks, and infrastructure, few attempts have been made to develop an effective optimisation model for improving the reliability, and maintenance of rolling stock subsystems. In this paper, a new hybrid model that integrates reliability, risk, and maintenance techniques is proposed to facilitate engineering failure and asset management decision analysis. The upstream segment of the model consists of risk and reliability techniques for bottom-up and top-down failure analysis using failure mode effects and criticality analysis and fault tree analysis, respectively. The downstream segment consists of a (1) decision-making grid (DMG) for the appropriate allocation of maintenance strategies using a decision map and (2) group decision-making analysis for selecting appropriate improvement options for subsystems allocated to the worst region of the DMG map using the multi-criteria pairwise comparison features of the analytical hierarchy process. The hybrid model was illustrated through a case study for replacing an unreliable pneumatic brake unit (PBU) using operational data from a UK-based train operator where the frequency of failures and delay minutes exceeded the operator’s original target by 300% and 900%, respectively. The results indicate that the novel hybrid model can effectively analyse and identify a new PBU subsystem that meets the operator’s reliability, risk, and maintenance requirements.
    • Predictive approaches to guide the expression of recombinant vaccine targets in Escherichia coli: a case study presentation utilising Absynth Biologics Ltd. proprietary Clostridium difficile vaccine antigens

      Hussain, Hirra; McKenzie, Edward A; Robinson, Andrew M; Gingles, Neill A; Marston, Fiona; Warwicker, Jim; Dickson, Alan J; orcid: 0000-0001-9490-645X; email: alan.dickson@manchester.ac.uk (Springer Berlin Heidelberg, 2021-06-28)
      Abstract: Bacterial expression systems remain a widely used host for recombinant protein production. However, overexpression of recombinant target proteins in bacterial systems such as Escherichia coli can result in poor solubility and the formation of insoluble aggregates. As a consequence, numerous strategies or alternative engineering approaches have been employed to increase recombinant protein production. In this case study, we present the strategies used to increase the recombinant production and solubility of ‘difficult-to-express’ bacterial antigens, termed Ant2 and Ant3, from Absynth Biologics Ltd.’s Clostridium difficile vaccine programme. Single recombinant antigens (Ant2 and Ant3) and fusion proteins (Ant2-3 and Ant3-2) formed insoluble aggregates (inclusion bodies) when overexpressed in bacterial cells. Further, proteolytic cleavage of Ant2-3 was observed. Optimisation of culture conditions and changes to the construct design to include N-terminal solubility tags did not improve antigen solubility. However, screening of different buffer/additives showed that the addition of 1–15 mM dithiothreitol alone decreased the formation of insoluble aggregates and improved the stability of both Ant2 and Ant3. Structural models were generated for Ant2 and Ant3, and solubility-based prediction tools were employed to determine the role of hydrophobicity and charge on protein production. The results showed that a large non-polar region (containing hydrophobic amino acids) was detected on the surface of Ant2 structures, whereas positively charged regions (containing lysine and arginine amino acids) were observed for Ant3, both of which were associated with poor protein solubility. We present a guide of strategies and predictive approaches that aim to guide the construct design, prior to expression studies, to define and engineer sequences/structures that could lead to increased expression and stability of single and potentially multi-domain (or fusion) antigens in bacterial expression systems.
    • Primary glomus tumour of the pituitary gland: diagnostic challenges of a rare and potentially aggressive neoplasm

      Quah, Boon Leong; orcid: 0000-0001-9094-5857; Donofrio, Carmine Antonio; orcid: 0000-0002-9123-8158; La Rosa, Stefano; orcid: 0000-0003-1941-2403; Brouland, Jean-Philippe; orcid: 0000-0003-3475-0101; Cossu, Giulia; orcid: 0000-0003-0913-8965; Djoukhadar, Ibrahim; Mayers, Helen; Shenjere, Patrick; orcid: 0000-0001-9627-6914; Pereira, Marta; Pathmanaban, Omar N.; et al. (Springer Berlin Heidelberg, 2020-09-12)
      Abstract: Primary non-neuroendocrine tumours of the pituitary gland and sella are rare lesions often challenging to diagnose. We describe two cases of clinically aggressive primary glomus tumour of the pituitary gland. The lesions occurred in a 63-year-old male and a 30-year-old female who presented with headache, blurred vision and hypopituitarism. Neuroimaging demonstrated large sellar and suprasellar tumours invading the surrounding structures. Histologically, the lesions were characterised by angiocentric sheets and nests of atypical cells that expressed vimentin, smooth muscle actin and CD34. Perivascular deposition of collagen IV was also a feature. Case 2 expressed synaptophysin. INI-1 (SMARCB1) expression was preserved. Both lesions were mitotically active and demonstrated a Ki-67 labelling index of 30%. Next-generation sequencing performed in case 1 showed no mutations in the reading frame of 37 commonly mutated oncogenes, including BRAF and KRAS. Four pituitary glomus tumours have previously been reported, none of which showed features of malignant glomus tumour. Similar to our two patients, three previous examples displayed aggressive behaviour.
    • Probing the ∆ U = 0 rule in three body charm decays

      Dery, Avital; Grossman, Yuval; Schacht, Stefan; email: stefan.schacht@manchester.ac.uk; Soffer, Abner (Springer Berlin Heidelberg, 2021-05-20)
      Abstract: CP violation in charm decay was observed in the decays D0→ P±P∓ of a D0 meson to two pseudoscalars. When interpreted within the SM, the results imply that the ratio of the relevant rescattering amplitudes has a magnitude and phase that are both of O(1). We discuss ways to probe similar ratios in D0→ V±P∓ decays, where V is a vector that decays to two pseudoscalars, from the Dalitz-plot analysis of time-integrated three-body decays. Compared to two-body decays, three-body decays have the advantage that the complete system can be solved without the need for time-dependent CP violation measurements or use of correlated D0−D¯0 production. We discuss the decays D0→ π+π−π0 and D0→ K+K−π0 as examples by considering a toy model of only two overlapping charged resonances, treating the underlying pseudo two-body decays in full generality.
    • Probing the ∆ U = 0 rule in three body charm decays

      Dery, Avital; Grossman, Yuval; Schacht, Stefan; email: stefan.schacht@manchester.ac.uk; Soffer, Abner (Springer Berlin Heidelberg, 2021-05-20)
      Abstract: CP violation in charm decay was observed in the decays D0→ P±P∓ of a D0 meson to two pseudoscalars. When interpreted within the SM, the results imply that the ratio of the relevant rescattering amplitudes has a magnitude and phase that are both of O(1). We discuss ways to probe similar ratios in D0→ V±P∓ decays, where V is a vector that decays to two pseudoscalars, from the Dalitz-plot analysis of time-integrated three-body decays. Compared to two-body decays, three-body decays have the advantage that the complete system can be solved without the need for time-dependent CP violation measurements or use of correlated D0−D¯0 production. We discuss the decays D0→ π+π−π0 and D0→ K+K−π0 as examples by considering a toy model of only two overlapping charged resonances, treating the underlying pseudo two-body decays in full generality.
    • Redistribution, power sharing and inequality concern

      Debowicz, Dario; orcid: 0000-0003-0944-3097; Saporiti, Alejandro; orcid: 0000-0002-9156-464X; email: alejandro.saporiti@manchester.ac.uk; Wang, Yizhi; orcid: 0000-0002-5723-2609 (Springer Berlin Heidelberg, 2021-03-10)
      Abstract: We analyze a political competition model of redistributive policies. We provide an equilibrium existence result and a full characterization of the net transfers to the different income groups. We also derive several testable predictions about the way in which the net group transfers and the after-tax Gini coefficient vary with the main parameters of the model. In accordance with the theory, the empirical evidence from a sample of developed and developing democracies supports a highly statistically significant association between: (i) the net group transfer and the gap between the population and the group mean initial income, and (ii) the net group transfer (and resp., the Gini coefficient) and power sharing disproportionality. In addition, the data also provide some empirical evidence confirming a significant relationship between the net transfers to the poor (and resp., the Gini) and the concern of the political parties with income inequality.
    • Reliability and prognostic value of radiomic features are highly dependent on choice of feature extraction platform

      Fornacon-Wood, Isabella; orcid: 0000-0002-3736-2967; email: Isabella.fornacon-wood@postgrad.manchester.ac.uk; Mistry, Hitesh; Ackermann, Christoph J.; Blackhall, Fiona; McPartlin, Andrew; Faivre-Finn, Corinne; Price, Gareth J.; O’Connor, James P. B. (Springer Berlin Heidelberg, 2020-06-01)
      Abstract: Objective: To investigate the effects of Image Biomarker Standardisation Initiative (IBSI) compliance, harmonisation of calculation settings and platform version on the statistical reliability of radiomic features and their corresponding ability to predict clinical outcome. Methods: The statistical reliability of radiomic features was assessed retrospectively in three clinical datasets (patient numbers: 108 head and neck cancer, 37 small-cell lung cancer, 47 non-small-cell lung cancer). Features were calculated using four platforms (PyRadiomics, LIFEx, CERR and IBEX). PyRadiomics, LIFEx and CERR are IBSI-compliant, whereas IBEX is not. The effects of IBSI compliance, user-defined calculation settings and platform version were assessed by calculating intraclass correlation coefficients and confidence intervals. The influence of platform choice on the relationship between radiomic biomarkers and survival was evaluated using univariable cox regression in the largest dataset. Results: The reliability of radiomic features calculated by the different software platforms was only excellent (ICC > 0.9) for 4/17 radiomic features when comparing all four platforms. Reliability improved to ICC > 0.9 for 15/17 radiomic features when analysis was restricted to the three IBSI-compliant platforms. Failure to harmonise calculation settings resulted in poor reliability, even across the IBSI-compliant platforms. Software platform version also had a marked effect on feature reliability in CERR and LIFEx. Features identified as having significant relationship to survival varied between platforms, as did the direction of hazard ratios. Conclusion: IBSI compliance, user-defined calculation settings and choice of platform version all influence the statistical reliability and corresponding performance of prognostic models in radiomics. Key Points: • Reliability of radiomic features varies between feature calculation platforms and with choice of software version. • Image Biomarker Standardisation Initiative (IBSI) compliance improves reliability of radiomic features across platforms, but only when calculation settings are harmonised. • IBSI compliance, user-defined calculation settings and choice of platform version collectively affect the prognostic value of features.
    • The incidence of cutaneous squamous cell carcinoma in patients receiving voriconazole therapy for chronic pulmonary aspergillosis

      Kosmidis, Chris; orcid: 0000-0003-0662-1265; email: chris.kosmidis@manchester.ac.uk; Mackenzie, Anna; Harris, Chris; Hashad, Rola; Lynch, Fiona; Denning, David W. (Springer Berlin Heidelberg, 2020-08-21)
      Abstract: Voriconazole has been associated with cutaneous squamous cell carcinoma (cSCC) in transplant patients but less is known about the risk in less severely immunosuppressed patients. Our aim was to estimate the incidence of cSCC after voriconazole exposure in patients with chronic pulmonary aspergillosis on a background of chronic lung disease. The notes of patients seen at a tertiary referral centre from 2009 to 2019 with chronic pulmonary aspergillosis were reviewed for the diagnosis of cSCC and voriconazole use documented. Among 1111 patients, 668 (60.1%) received voriconazole for longer than 28 days. Twelve patients received a diagnosis of cSCC; nine had used voriconazole. Mean duration of voriconazole use was 36.7 months. The crude incidence rate was 4.88 in 1000 person/years in those who had voriconazole and 2.79 in 1000 patient/years in those who did not receive voriconazole for longer than 28 days. On Cox regression, age (HR 1.09, 95% CI 1.02–1.16, p = 0.01) and male gender (HR 3.97, 95% CI 0.84–18.90, p = 0.082) were associated with cSCC. Voriconazole use was associated with a slightly increased risk, which was not significant (HR 1.35, 95% CI 0.35–5.20, p = 0.659). Voriconazole use beyond 28 days did not lead to a significantly increased risk of cSCC in a large cohort of patients with chronic pulmonary aspergillosis.
    • The potential of coffee stems gasification to provide bioenergy for coffee farms: a case study in the Colombian coffee sector

      Garcia-Freites, Samira; orcid: 0000-0002-4136-2724; email: samira.garciafreites@manchester.ac.uk; Welfle, Andrew; Lea-Langton, Amanda; Gilbert, Paul; Thornley, Patricia (Springer Berlin Heidelberg, 2019-08-03)
      Abstract: The coffee industry constitutes an important part of the global economy. Developing countries produce over 90% of world coffee production, generating incomes for around 25 million smallholder farmers. The scale of this industry poses a challenge with the generation of residues along with the coffee cultivation and processing chain. Coffee stems, obtained after pruning of coffee trees, are one of those abundant and untapped resources in the coffee supply chain. Their high lignocellulosic content, the low calorific value ranging between 17.5 and 18 MJ kg−1 and the low ash content make them a suitable solid fuel for thermochemical conversion, such as gasification. This research evaluates the feasibility of using these residues in small-scale downdraft gasifiers coupled to internal combustion engines for power and low-grade heat generation, using process modelling and the Colombian coffee sector as a case study. The producer gas properties (5.6 MJ Nm−3) and the gasifier’s performance characteristics suggest that this gas could be utilized for power generation. A cogeneration system efficiency of 45.6% could be attainable when the system’s low-grade heat is recovered for external applications, like in the coffee drying stage. An analysis of the energy demand and coffee stems availability within the Colombian coffee sector shows that the biomass production level in medium- to large-scale coffee farms is well matched to their energy demands, offering particularly attractive opportunities to deploy this bioenergy system. This work assesses the feasibility of providing coffee stem–sourced low-carbon energy for global coffee production at relevant operating scales in rural areas.
    • Transcription factors that shape the mammalian pancreas

      Jennings, Rachel E.; orcid: 0000-0003-1492-600X; email: rachel.jennings@manchester.ac.uk; Scharfmann, Raphael; orcid: 0000-0001-7619-337X; email: raphael.scharfmann@inserm.fr; Staels, Willem; orcid: 0000-0001-8259-3329; email: willem.staels@vub.be (Springer Berlin Heidelberg, 2020-09-07)
      Abstract: Improving our understanding of mammalian pancreas development is crucial for the development of more effective cellular therapies for diabetes. Most of what we know about mammalian pancreas development stems from mouse genetics. We have learnt that a unique set of transcription factors controls endocrine and exocrine cell differentiation. Transgenic mouse models have been instrumental in studying the function of these transcription factors. Mouse and human pancreas development are very similar in many respects, but the devil is in the detail. To unravel human pancreas development in greater detail, in vitro cellular models (including directed differentiation of stem cells, human beta cell lines and human pancreatic organoids) are used; however, in vivo validation of these results is still needed. The current best ‘model’ for studying human pancreas development are individuals with monogenic forms of diabetes. In this review, we discuss mammalian pancreas development, highlight some discrepancies between mouse and human, and discuss selected transcription factors that, when mutated, cause permanent neonatal diabetes. Graphical abstract
    • Verification and refutation of C programs based on k -induction and invariant inference

      Alhawi, Omar M.; email: omar.alhawi@manchester.ac.uk; Rocha, Herbert; Gadelha, Mikhail R.; Cordeiro, Lucas C.; Batista, Eddie (Springer Berlin Heidelberg, 2020-05-18)
      Abstract: DepthK is a source-to-source transformation tool that employs bounded model checking (BMC) to verify and falsify safety properties in single- and multi-threaded C programs, without manual annotation of loop invariants. Here, we describe and evaluate a proof-by-induction algorithm that combines k-induction with invariant inference to prove and refute safety properties. We apply two invariant generators to produce program invariants and feed these into a k-induction-based verification algorithm implemented in DepthK, which uses the efficient SMT-based context-bounded model checker (ESBMC) as sequential verification back-end. A set of C benchmarks from the International Competition on Software Verification (SV-COMP) and embedded-system applications extracted from the available literature are used to evaluate the effectiveness of the proposed approach. Experimental results show that k-induction with invariants can handle a wide variety of safety properties, in typical programs with loops and embedded software applications from the telecommunications, control systems, and medical domains. The results of our comparative evaluation extend the knowledge about approaches that rely on both BMC and k-induction for software verification, in the following ways. (1) The proposed method outperforms the existing implementations that use k-induction with an interval-invariant generator (e.g., 2LS and ESBMC), in the category ConcurrencySafety, and overcame, in others categories, such as SoftwareSystems, other software verifiers that use plain BMC (e.g., CBMC). Also, (2) it is more precise than other verifiers based on the property-directed reachability (PDR) algorithm (i.e., SeaHorn, Vvt and CPAchecker-CTIGAR). This way, our methodology demonstrated improvement over existing BMC and k-induction-based approaches.