• 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; MASTERPLANS Consortium (2021-07-29)
      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. 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. 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. 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. [Abstract copyright: © 2021. The Author(s).]
    • 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 (2021-07-29)
      <h4>Background</h4>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.<h4>Methods</h4>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.<h4>Results</h4>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.<h4>Conclusions</h4>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.
    • Distinct performance profiles on the Brixton test in frontotemporal dementia

      Rao, Sulakshana P.; Nandi, Ranita; Dutt, Aparna; Kapur, Narinder; Harris, Jennifer M.; Thompson, Jennifer C.; Snowden, Julie S.; orcid: 0000-0002-3976-4310; email: julie.snowden@manchester.ac.uk (2020-10-15)
      The Brixton Spatial Anticipation Test is a well‐established test of executive function that evaluates the capacity to abstract, follow, and switch rules. There has been remarkably little systematic analysis of Brixton test performance in the prototypical neurodegenerative disorder of the frontal lobes: behavioural variant frontotemporal dementia (bvFTD) or evaluation of the test’s ability to distinguish frontal from temporal lobe degenerative disease. We carried out a quantitative and qualitative analysis of Brixton performance in 76 patients with bvFTD and 34 with semantic dementia (SD) associated with temporal lobe degeneration. The groups were matched for demographic variables and illness duration. The bvFTD group performed significantly more poorly (U = 348, p < .0001, r = .58), 53% of patients scoring in the poor–impaired range compared with 6% of SD patients. Whereas bvFTD patients showed problems in rule acquisition and switching, SD patients did not, despite their impaired conceptual knowledge. Error analysis revealed more frequent perseverative errors in bvFTD, particularly responses unconnected to the stimulus, as well as random responses. Stimulus‐bound errors were rare. Within the bvFTD group, there was variation in performance profile, which could not be explained by demographic, neurological, or genetic factors. The findings demonstrate sensitivity and specificity of the Brixton test in identifying frontal lobe degenerative disease and highlight the clinical value of qualitative analysis of test performance. From a theoretical perspective, the findings provide evidence that semantic knowledge and the capacity to acquire rules are dissociable. Moreover, they exemplify the separable functional contributions to executive performance.
    • Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes

      Barnes, Bethany M.; Nelson, Louisa; Tighe, Anthony; Burghel, George J.; Lin, I-Hsuan; Desai, Sudha; McGrail, Joanne C.; Morgan, Robert D.; Taylor, Stephen S.; orcid: 0000-0003-4621-9326; email: stephen.taylor@manchester.ac.uk (BioMed Central, 2021-09-01)
      Abstract: Background: Epithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70–80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics. Methods: Non-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2–10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models. Results: Application of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features. Conclusions: This robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes.
    • Distinct transcriptional programs stratify ovarian cancer cell lines into the five major histological subtypes.

      Barnes, Bethany M; Nelson, Louisa; Tighe, Anthony; Burghel, George J; Lin, I-Hsuan; orcid: 0000-0002-6207-1299; Desai, Sudha; McGrail, Joanne C; Morgan, Robert D; Taylor, Stephen S; orcid: 0000-0003-4621-9326; email: stephen.taylor@manchester.ac.uk (2021-09-01)
      <h4>Background</h4>Epithelial ovarian cancer (OC) is a heterogenous disease consisting of five major histologically distinct subtypes: high-grade serous (HGSOC), low-grade serous (LGSOC), endometrioid (ENOC), clear cell (CCOC) and mucinous (MOC). Although HGSOC is the most prevalent subtype, representing 70-80% of cases, a 2013 landmark study by Domcke et al. found that the most frequently used OC cell lines are not molecularly representative of this subtype. This raises the question, if not HGSOC, from which subtype do these cell lines derive? Indeed, non-HGSOC subtypes often respond poorly to chemotherapy; therefore, representative models are imperative for developing new targeted therapeutics.<h4>Methods</h4>Non-negative matrix factorisation (NMF) was applied to transcriptomic data from 44 OC cell lines in the Cancer Cell Line Encyclopedia, assessing the quality of clustering into 2-10 groups. Epithelial OC subtypes were assigned to cell lines optimally clustered into five transcriptionally distinct classes, confirmed by integration with subtype-specific mutations. A transcriptional subtype classifier was then developed by trialling three machine learning algorithms using subtype-specific metagenes defined by NMF. The ability of classifiers to predict subtype was tested using RNA sequencing of a living biobank of patient-derived OC models.<h4>Results</h4>Application of NMF optimally clustered the 44 cell lines into five transcriptionally distinct groups. Close inspection of orthogonal datasets revealed this five-cluster delineation corresponds to the five major OC subtypes. This NMF-based classification validates the Domcke et al. analysis, in identifying lines most representative of HGSOC, and additionally identifies models representing the four other subtypes. However, NMF of the cell lines into two clusters did not align with the dualistic model of OC and suggests this classification is an oversimplification. Subtype designation of patient-derived models by a random forest transcriptional classifier aligned with prior diagnosis in 76% of unambiguous cases. In cases where there was disagreement, this often indicated potential alternative diagnosis, supported by a review of histological, molecular and clinical features.<h4>Conclusions</h4>This robust classification informs the selection of the most appropriate models for all five histotypes. Following further refinement on larger training cohorts, the transcriptional classification may represent a useful tool to support the classification of new model systems of OC subtypes.
    • DNA Interaction with a Polyelectrolyte Monolayer at Solution—Air Interface

      Chirkov, Nikolay S.; email: n.chirkov@spbu.ru; Campbell, Richard A.; orcid: 0000-0002-6296-314X; email: richard.campbell@manchester.ac.uk; Michailov, Alexander V.; orcid: 0000-0003-3273-6170; email: mav030655@gmail.com; Vlasov, Petr S.; email: petr_vlasov@mail.ru; Noskov, Boris A.; email: b.noskov@spbu.ru (MDPI, 2021-08-22)
      The formation of ordered 2D nanostructures of double stranded DNA molecules at various interfaces attracts more and more focus in medical and engineering research, but the underlying intermolecular interactions still require elucidation. Recently, it has been revealed that mixtures of DNA with a series of hydrophobic cationic polyelectrolytes including poly(N, N-diallyl-N-hexyl-N-methylammonium) chloride (PDAHMAC) form a network of ribbonlike or threadlike aggregates at the solution—air interface. In the present work, we adopt a novel approach to confine the same polyelectrolyte at the solution—air interface by spreading it on a subphase with elevated ionic strength. A suite of techniques–rheology, microscopy, ellipsometry, and spectroscopy–are applied to gain insight into main steps of the adsorption layer formation, which results in non-monotonic kinetic dependencies of various surface properties. A long induction period of the kinetic dependencies after DNA is exposed to the surface film results only if the initial surface pressure corresponds to a quasiplateau region of the compression isotherm of a PDAHMAC monolayer. Despite the different aggregation mechanisms, the micromorphology of the mixed PDAHMAC/DNA does not depend noticeably on the initial surface pressure. The results provide new perspective on nanostructure formation involving nucleic acids building blocks.
    • DNA methylation in genes associated with the evolution of ageing and disease: A critical review.

      Mc Auley, Mark Tomás; email: m.mcauley@chester.ac.uk (2021-10-15)
      Ageing is characterised by a physical decline in biological functioning which results in a progressive risk of mortality with time. As a biological phenomenon, it is underpinned by the dysregulation of a myriad of complex processes. Recently, however, ever-increasing evidence has associated epigenetic mechanisms, such as DNA methylation (DNAm) with age-onset pathologies, including cancer, cardiovascular disease, and Alzheimer's disease. These diseases compromise healthspan. Consequently, there is a medical imperative to understand the link between epigenetic ageing, and healthspan. Evolutionary theory provides a unique way to gain new insights into epigenetic ageing and health. This review will: (1) provide a brief overview of the main evolutionary theories of ageing; (2) discuss recent genetic evidence which has revealed alleles that have pleiotropic effects on fitness at different ages in humans; (3) consider the effects of DNAm on pleiotropic alleles, which are associated with age related disease; (4) discuss how age related DNAm changes resonate with the mutation accumulation, disposable soma and programmed theories of ageing; (5) discuss how DNAm changes associated with caloric restriction intersect with the evolution of ageing; and (6) conclude by discussing how evolutionary theory can be used to inform investigations which quantify age-related DNAm changes which are linked to age onset pathology. [Abstract copyright: Crown Copyright © 2021. Published by Elsevier B.V. All rights reserved.]
    • Do Gender and Gender Role Orientation Make a Difference in the Link between Role Demands and Family Interference with Work for Taiwanese Workers?

      Lu, Luo; orcid: 0000-0001-6533-0447; email: luolu@ntu.edu.tw; Chang, Ting-Ting; email: tinapc@ms24.hinet.net; Kao, Shu-Fang; email: d89227002@gmail.com; Cooper, Cary L.; email: cary.cooper@manchester.ac.uk (MDPI, 2021-09-17)
      Based on the gender role orientation perspective, this study extends the resource depletion mechanism that links role demands to family interference with work by testing the moderating effects of gender and gender role orientation (egalitarian vs. traditional) on the relationships. Analysis of the data from 251 employees in Taiwan revealed two significant three-way interactive effects. Specifically, for men, the positive relationship between work demands and family-to-work conflict (FWC) was stronger for egalitarian than traditional individuals. For women, the positive relationship between family demands and FWC was stronger for egalitarian than traditional individuals. We also found a significant two-way interactive effect; that is, within the egalitarian group, the positive relationship between work demands and FWC was stronger for women than men. Our findings, thus, suggest both within-gender and between-gender variations in the links between work-to-family demands and conflict, jointly affected by the individual’s gender and gender role orientation. Contextualized within the cultural traditions of a Chinese society, we highlight the precarious position that egalitarian men and women (especially women) find for themselves in fulfilling work duties and family roles. The theoretical and managerial implications are also discussed.
    • Do oxytocin neurones affect feeding?

      Worth, Amy A.; Luckman, Simon M.; orcid: 0000-0001-5318-5473; email: simon.luckman@manchester.ac.uk (2021-09-08)
      Abstract: There has been a long history of research on the effects of oxytocin on feeding behaviour. The classic‐held view is that the neurohormone is anorexigenic at least in rodents, although the data for humans are not so clear cut. Likewise, a physiological role for oxytocin is disputed. Thus, although pharmacological, anatomical and physiological data suggest oxytocin may have a function in satiety signalling, this view is not supported by the latest research using the genetic recording and manipulation of oxytocin neurones. Here, we avoid a discussion of the pharmacological effects of oxytocin and examine evidence, from both sides of the argument, concerning whether the endogenous oxytocin system has a role in the regulation of normal feeding.
    • Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study

      Slade, Pauline; orcid: 0000-0001-5877-2706; Sheen, Kayleigh; Weeks, Andrew; Wray, Susan; De Pascalis, Leonardo; Lunt, Karen; Bedwell, Carol; Thompson, Belinda; Hill, Johnathan; Sharp, Helen (Wiley, 2021-02-05)
    • Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study

      Slade, Pauline; orcid: 0000-0001-5877-2706; Sheen, Kayleigh; Weeks, Andrew; Wray, Susan; De Pascalis, Leonardo; Lunt, Karen; Bedwell, Carol; Thompson, Belinda; Hill, Johnathan; Sharp, Helen (Wiley, 2021-02-05)
    • Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study

      Slade, Pauline; orcid: 0000-0001-5877-2706; email: pauline.slade@liverpool.ac.uk; Sheen, Kayleigh; Weeks, Andrew; Wray, Susan; De Pascalis, Leonardo; Lunt, Karen; Bedwell, Carol; Thompson, Belinda; Hill, Johnathan; Sharp, Helen (2021-02-05)
      Abstract: Introduction: Despite widespread belief that anxiety causes longer labor, evidence of association is inconsistent. Data gathered as part of a prospective epidemiological longitudinal study were used to investigate associations between antenatal anxiety and pregnancy‐specific stress, and labor progression was assessed by duration and use of augmentation. Material and methods: Pregnant primiparous women completed measures for anxiety and pregnancy‐specific stress at 20 weeks’ gestation (n = 1145). Birth outcome data were extracted from medical records. Regression analyses and a path analysis assessed associations between antenatal anxiety and pregnancy‐specific stress, and indices of labor progression (labor duration and augmentation). Results: Anxiety/pregnancy‐specific stress were not directly associated with duration of stage 1 labor (HIGH/LOW anxiety: mean difference = 13.94 minutes, SD = 20.66, 95% CI −26.60 to 54.49, P < .50)/(HIGH/LOW pregnancy‐specific stress: mean difference = 12.05 minutes, SD = 16.09, 95% CI −19.52 to 43.63, P < .45). However, anxiety/pregnancy‐specific stress were associated with epidural use (HIGH/LOW anxiety: 39% vs 31%, P < .042; HIGH/LOW pregnancy‐specific stress: 38% vs 29%, P < .001), which was itself associated with longer labor (mean difference: 158.79 minutes, SD = 16.76, 95% CI 125.89‐191.68, P < .001). Anxiety and pregnancy‐specific stress were associated with increased likelihood of augmentation but these associations were nonsignificant after accounting for epidural, which was itself highly associated with augmentation. However, path analysis indicated an indirect effect linking pregnancy‐specific stress, but not general anxiety, to labor duration and augmentation: elevated pregnancy‐specific stress led to greater use of epidural, which was linked to both increased rates of augmentation, and increased labor duration. Conclusions: Contrary to general belief, general anxiety and specific pregnancy stress were not directly linked to longer duration of stage one labor. However specific pregnancy stress was associated with epidural use, which in turn was significantly associated with risk of augmentation, and longer stage one labor. Identification of pregnancy‐specific stress could help to identify women for whom psychological interventions could improve birth experience.
    • Do stress and anxiety in early pregnancy affect the progress of labor: Evidence from the Wirral Child Health and Development Study.

      Slade, Pauline; orcid: 0000-0001-5877-2706; Sheen, Kayleigh; Weeks, Andrew; Wray, Susan; De Pascalis, Leonardo; Lunt, Karen; Bedwell, Carol; Thompson, Belinda; Hill, Johnathan; Sharp, Helen (2021-02-05)
      Despite widespread belief that anxiety causes longer labor, evidence of association is inconsistent. Data gathered as part of a prospective epidemiological longitudinal study were used to investigate associations between antenatal anxiety and pregnancy-specific stress, and labor progression was assessed by duration and use of augmentation. Pregnant primiparous women completed measures for anxiety and pregnancy-specific stress at 20 weeks' gestation (n = 1145). Birth outcome data were extracted from medical records. Regression analyses and a path analysis assessed associations between antenatal anxiety and pregnancy-specific stress, and indices of labor progression (labor duration and augmentation). Anxiety/pregnancy-specific stress were not directly associated with duration of stage 1 labor (HIGH/LOW anxiety: mean difference = 13.94 minutes, SD = 20.66, 95% CI -26.60 to 54.49, P < .50)/(HIGH/LOW pregnancy-specific stress: mean difference = 12.05 minutes, SD = 16.09, 95% CI -19.52 to 43.63, P < .45). However, anxiety/pregnancy-specific stress were associated with epidural use (HIGH/LOW anxiety: 39% vs 31%, P < .042; HIGH/LOW pregnancy-specific stress: 38% vs 29%, P < .001), which was itself associated with longer labor (mean difference: 158.79 minutes, SD = 16.76, 95% CI 125.89-191.68, P < .001). Anxiety and pregnancy-specific stress were associated with increased likelihood of augmentation but these associations were nonsignificant after accounting for epidural, which was itself highly associated with augmentation. However, path analysis indicated an indirect effect linking pregnancy-specific stress, but not general anxiety, to labor duration and augmentation: elevated pregnancy-specific stress led to greater use of epidural, which was linked to both increased rates of augmentation, and increased labor duration. Contrary to general belief, general anxiety and specific pregnancy stress were not directly linked to longer duration of stage one labor. However specific pregnancy stress was associated with epidural use, which in turn was significantly associated with risk of augmentation, and longer stage one labor. Identification of pregnancy-specific stress could help to identify women for whom psychological interventions could improve birth experience. [Abstract copyright: © 2020 The Authors. Acta Obstetricia et Gynecologica Scandinavica published by John Wiley & Sons Ltd on behalf of Nordic Federation of Societies of Obstetrics and Gynecology (NFOG).]
    • Does neighbourhood identification buffer against the effects of socioeconomic disadvantage on self-harm?

      McIntyre, Jason; Elahi, Anam; Latham, Cameron; Mullholland, Helen; Haines-Delmont, Alina; Saini, Pooja; Taylor, Peter J; email: peter.taylor-2@manchester.ac.uk (2021-08-01)
      Socioeconomic disadvantage and lack of group belonging (i.e., social identity) have been linked to poor mental health. However, no research has investigated the relationship between neighbourhood identity and self-harm, nor whether identifying with one's neighbourhood can mitigate the effects of economic stress on self-harm. Pre-registered secondary data analysis of a large (N = 3412) community health survey conducted in disadvantaged areas of North West England. Despite the sample having a relatively high and therefore restricted level of disadvantage, individual and geographic indicators of disadvantage, as well as neighbourhood identification, were unique and strong predictors of self-harm thoughts and behaviours across several analyses. Specifically, experiencing disadvantage and disidentification predicted significantly higher odds of self-harm and self-harm thoughts. No consistent interactive effects emerged. The cross-sectional design limits firm conclusions regarding causal effects of neighbourhood identity and disadvantage on self-harm. However, causal direction is supported by past research and theory. The data is self-report, which is subject to response bias. The sample was also recruited from a region of the UK with low numbers of residents from ethnic minority backgrounds. The results are consistent with past research indicating an association between social identity and better mental health, but for the first time extend these effects to self-harm. The findings demonstrate the importance of considering social and economic factors when attempting to prevent suicide and understand and treat self-harm thoughts. [Abstract copyright: Copyright © 2021. Published by Elsevier B.V.]
    • Does posture explain the kinematic differences in a grounded running gait between male and female Svalbard rock ptarmigan ( Lagopus muta hyperborea ) moving on snow?

      Marmol-Guijarro, Andres; orcid: 0000-0001-9316-540X; Nudds, Robert; orcid: 0000-0002-7627-6324; Folkow, Lars; orcid: 0000-0002-6580-9156; Lees, John; orcid: 0000-0002-9627-1790; Codd, Jonathan; orcid: 0000-0003-0211-1786; email: jonathan.codd@manchester.ac.uk (Springer Berlin Heidelberg, 2021-05-05)
      Abstract: The majority of locomotor research is conducted on treadmills and few studies attempt to understand the differences between this and animals moving in the wild. For example, animals may adjust their gait kinematics or limb posture, to a more compliant limb, to increase stability of locomotion to prevent limb failure or falling on different substrates. Here, using video recordings, we compared locomotor parameters (speed range, stride length, stride frequency, stance duration, swing duration and duty factor) of female Svalbard rock ptarmigan (Lagopus muta hyperborea) moving in the wild over snow to previous treadmill-based research. We also compared the absolute and body size (body mass and limb length)-corrected values of kinematic parameters to published data from males to look for any sex differences across walking and grounded running gaits. Our findings indicate that the kinematics of locomotion are largely conserved between the field and laboratory in that none of the female gaits were drastically affected by moving over snow, except for a prolonged swing phase at very slow walking speeds, likely due to toe dragging. Comparisons between the sexes indicate that the differences observed during a walking gait are likely due to body size. However, sexual dimorphism in body size could not explain the disparate grounded running kinematics of the female and male ptarmigan, which might be linked to a more crouched posture in females. Our findings provide insight into how males and females moving in situ may use different strategies to alleviate the effects of a variable substrate.
    • Doing Dirty Theology: How Ensoiled Humans Participate in the Flourishing of All Earthlings

      Biddington, Terry; email: Terry.Biddington@winchester.ac.uk (SAGE Publications, 2021-05-10)
      Traditional theological ideas, language and imagery tend to take their cue and inspiration from the Beyond: from heaven; the transcendent realm and all that is ‘above us’ that we might inspire to attain. But, given that all life arises from and is dependent upon the soil/earth, what possibilities might exist for new ‘ensoiled’ forms of thinking and practice? We are all earthlings and groundlings and our human qualities and spiritual sensitivities and aspirations must, in an evolutionary sense, arise from our connectivity to the soil and earth. What then can the soil and the life it contains teach us about living harmoniously as part of a community of planetary flourishing? This article will explore how a theology influenced by the soil – an ‘edapho-theology’ – might offer fresh perspectives for re-engaging with the need to create a sustainable future for all life on the planet.
    • Donor insulin use during stay in the intensive care unit should not preclude pancreas transplantation. Reply to Ventura-Aguiar P, Montagud-Marrahi E, Amor AJ et al [letter].

      Shapey, Iestyn M; orcid: 0000-0003-3300-1053; email: iestyn.shapey@manchester.ac.uk; Summers, Angela; Khambalia, Hussein; Yiannoullou, Petros; Fullwood, Catherine; Hanley, Neil A; Augustine, Titus; Rutter, Martin K; van Dellen, David (2021-06-25)
    • DP structure and internally headed relatives in Washo

      Hanink, Emily A.; email: emily.hanink@manchester.ac.uk (Springer Netherlands, 2020-07-17)
      Abstract: This paper contributes to recent lines of inquiry addressing the nature of indices in definite expressions. The primary language of investigation is Washo, a North American isolate spoken in the western United States. Building on previous claims about the structure of anaphoric definites, I propose a unified analysis of the Washo DP that lends novel evidence to the claim that indices are best thought of as syntactic objects in their own right, independent from D. The structurally encoded index—introduced by a head idx—is shown to be overtly realized by the morpheme gi/ge in both pronouns and demonstratives, as well as at the periphery of internally headed relative clauses, which are themselves complex DPs. An important aspect of this proposal is the argument that idx can play two related semantic roles: The semantic index it hosts can be interpreted either as a variable, as previously proposed for familiar definites, or itself as a variable binder. The availability of the latter explains the appearance of gi/ge in internally headed relatives. I show moreover that the exponence of idx in Washo is sensitive to the type of complement it takes, a proposal that makes sense of the observed distribution of gi/ge in a range of definite expressions.
    • DRL-Assisted Resource Allocation for NOMA-MEC Offloading with Hybrid SIC

      Li, Haodong; orcid: 0000-0001-8184-400X; email: haodong.li@manchester.ac.uk; Fang, Fang; orcid: 0000-0002-6582-6570; email: fang.fang@durham.ac.uk; Ding, Zhiguo; orcid: 0000-0001-5280-384X; email: zhiguo.ding@manchester.ac.uk (MDPI, 2021-05-14)
      Multi-access edge computing (MEC) and non-orthogonal multiple access (NOMA) are regarded as promising technologies to improve the computation capability and offloading efficiency of mobile devices in the sixth-generation (6G) mobile system. This paper mainly focused on the hybrid NOMA-MEC system, where multiple users were first grouped into pairs, and users in each pair offloaded their tasks simultaneously by NOMA, then a dedicated time duration was scheduled to the more delay-tolerant user for uploading the remaining data by orthogonal multiple access (OMA). For the conventional NOMA uplink transmission, successive interference cancellation (SIC) was applied to decode the superposed signals successively according to the channel state information (CSI) or the quality of service (QoS) requirement. In this work, we integrated the hybrid SIC scheme, which dynamically adapts the SIC decoding order among all NOMA groups. To solve the user grouping problem, a deep reinforcement learning (DRL)-based algorithm was proposed to obtain a close-to-optimal user grouping policy. Moreover, we optimally minimized the offloading energy consumption by obtaining the closed-form solution to the resource allocation problem. Simulation results showed that the proposed algorithm converged fast, and the NOMA-MEC scheme outperformed the existing orthogonal multiple access (OMA) scheme.
    • Drone-Assisted Confined Space Inspection and Stockpile Volume Estimation

      Alsayed, Ahmad; orcid: 0000-0003-1060-066X; email: ahmad.alsayed@manchester.ac.uk; Yunusa-Kaltungo, Akilu; orcid: 0000-0001-5138-3783; email: akilu.kaltungo@manchester.ac.uk; Quinn, Mark K.; orcid: 0000-0001-5788-4837; email: mark.quinn@manchester.ac.uk; Arvin, Farshad; orcid: 0000-0001-7950-3193; email: farshad.arvin@manchester.ac.uk; Nabawy, Mostafa R. A.; orcid: 0000-0002-4252-1635; email: mostafa.ahmednabawy@manchester.ac.uk (MDPI, 2021-08-24)
      The accuracy of stockpile estimations is of immense criticality to process optimisation and overall financial decision making within manufacturing operations. Despite well-established correlations between inventory management and profitability, safe deployment of stockpile measurement and inspection activities remain challenging and labour-intensive. This is perhaps owing to a combination of size, shape irregularity as well as the health hazards of cement manufacturing raw materials and products. Through a combination of simulations and real-life assessment within a fully integrated cement plant, this study explores the potential of drones to safely enhance the accuracy of stockpile volume estimations. Different types of LiDAR sensors in combination with different flight trajectory options were fully assessed through simulation whilst mapping representative stockpiles placed in both open and fully confined areas. During the real-life assessment, a drone was equipped with GPS for localisation, in addition to a 1D LiDAR and a barometer for stockpile height estimation. The usefulness of the proposed approach was established based on mapping of a pile with unknown volume in an open area, as well as a pile with known volume within a semi-confined area. Visual inspection of the generated stockpile surface showed strong correlations with the actual pile within the open area, and the volume of the pile in the semi-confined area was accurately measured. Finally, a comparative analysis of cost and complexity of the proposed solution to several existing initiatives revealed its proficiency as a low-cost robotic system within confined spaces whereby visibility, air quality, humidity, and high temperature are unfavourable.