• Fanconi Anaemia, Childhood Cancer and the BRCA Genes

      Woodward, Emma R.; orcid: 0000-0002-6297-2855; email: stefan.meyer@manchester.ac.uk; Meyer, Stefan; orcid: 0000-0002-2283-3690; email: emma.woodward@mft.nhs.uk (MDPI, 2021-09-27)
      Fanconi anaemia (FA) is an inherited chromosomal instability disorder characterised by congenital and developmental abnormalities and a strong cancer predisposition. In less than 5% of cases FA can be caused by bi-allelic pathogenic variants (PGVs) in BRCA2/FANCD1 and in very rare cases by bi-allelic PGVs in BRCA1/FANCS. The rarity of FA-like presentation due to PGVs in BRCA2 and even more due to PGVs in BRCA1 supports a fundamental role of the encoded proteins for normal development and prevention of malignant transformation. While FA caused by BRCA1/2 PGVs is strongly associated with distinct spectra of embryonal childhood cancers and AML with BRCA2-PGVs, and also early epithelial cancers with BRCA1 PGVs, germline variants in the BRCA1/2 genes have also been identified in non-FA childhood malignancies, and thereby implying the possibility of a role of BRCA PGVs also for non-syndromic cancer predisposition in children. We provide a concise review of aspects of the clinical and genetic features of BRCA1/2-associated FA with a focus on associated malignancies, and review novel aspects of the role of germline BRCA2 and BRCA1 PGVs occurring in non-FA childhood cancer and discuss aspects of clinical and biological implications.
    • Novel Reviews

      Toivanen, Anna-Leena; email: anna-leena.toivanen@uef.fi; Taylor, Joanna E.; email: joanna.taylor@manchester.ac.uk (Berghahn Books, 2021-03-01)
      Michèle Rakotoson, Elle, au printemps (Saint-Maur: Sépia, 1996), 122 pp.Kathleen Jamie, Surfacing (UK: Sort of Books, 2019), 240 pp., £7.99. Kathleen Jamie (ed.), Antlers of Water: Writing on the Nature and Environment of Scotland (Edinburgh: Canongate Books, 2020), 232pp., £20.
    • Bimekizumab versus Adalimumab in Plaque Psoriasis. Reply.

      Warren, Richard B; email: richard.warren@manchester.ac.uk; Cioffi, Christopher; Peterson, Luke (2021-09-16)
    • Pandemic Drones

      Hildebrand, Julia M.; email: hildebjm@eckerd.edu; Sodero, Stephanie; email: stephanie.sodero@manchester.ac.uk (Berghahn Books, 2021-03-01)
      When the novel coronavirus moved around the planet in early 2020, reconfiguring, slowing down, or halting everyday mobilities, another transport mode was mobilized: the pandemic drone. We highlight the increasing prominence of this aerial device by surveying international media coverage of pandemic drone use in the spring of 2020. To address a range of pandemic drone affordances and applications, we organize manifold cases under two broad categories: sensing and moving with the pandemic drone. Here we ask: what roles do, and could, drones play during the pandemic? Following the empirical examples and related mobilities research, we theorize the drone versus virus and the drone as virus. As such, the work identifies avenues for mobilities research into pandemic drones as a growing mobility domain. Moreover, in thinking through the pandemic drone, we demonstrate creative extensions of mobilities thinking that bridge biological and technological, as well as media and mobility frameworks when multiple public health and safety crises unfolded and intersected.
    • Terahertz probing of low temperature degradation in zirconia bio‐ceramics

      Ahmed, Shafique; Zhang, Man; orcid: 0000-0002-1094-7279; Koval, Vladimir; Zou, Lifong; Shen, Zhijian; Chen, Riqing; Yang, Bin; orcid: 0000-0001-5620-9506; Yan, Haixue (Wiley, 2021-09-19)
    • Socio-economic and demographic impacts on the full awareness of the methods for controlling/preventing the spread of COVID-19 among social media users in some African countries at the onset of the pandemic.

      Okorie, Idika E; Afuecheta, Emmanuel; Alaebo, Chinonso G; Nadarajah, Saralees; orcid: 0000-0002-0481-0372; email: saralees.nadarajah@manchester.ac.uk (2021-08-27)
      <h4>Objective</h4>In Africa, most countries continue to battle COVID-19 with cases of newly infected still being recorded. In this note, we investigate how socioeconomic and demographic factors affected individuals awareness on the methods for controlling/preventing the spread of COVID-19 in some parts of Africa at the onset of the pandemic.<h4>Results</h4>Based on regression modelling, we find that having full awareness does not depend on religious affiliation. Men, urban dwelling, holding bachelors or higher degrees, operating multiple social media accounts or being employed are associated with having full awareness of the recommended practices for the prevention and control of COVID-19 at the early stage of the pandemic. No occupation, business or older people are associated with not having full awareness.
    • Phase stability of the tin monochalcogenides SnS and SnSe: a quasi-harmonic lattice-dynamics study.

      Pallikara, Ioanna; orcid: 0000-0003-4123-6135; Skelton, Jonathan M; orcid: 0000-0002-0395-1202 (2021-09-15)
      The tin monochalcogenides SnS and SnSe adopt four different crystal structures, orthorhombic and and cubic rocksalt and π-cubic ( 2 3) phases, each of which has optimal properties for a range of potential applications. This rich phase space makes it challenging to identify the conditions under which the different phases are obtained. We have performed first-principles quasi-harmonic lattice-dynamics calculations to assess the relative stabilities of the four phases of SnS and SnSe. We investigate dynamical stability through the presence or absence of imaginary modes in the phonon dispersion curves, and we compute Helmholtz and Gibbs free energies to evaluate the thermodynamic stability. We also consider applied pressures up to 15 GPa to obtain simulated temperature-pressure phase diagrams. Finally, the relationships between the orthorhombic crystal phases are investigated by explicitly mapping the potential-energy surfaces along the imaginary harmonic phonon modes in the phase, and the relationships between the cubic phases are found by transition-state modelling using the climbing-image nudged elastic-band method.
    • Reconciling Egg- and Antigen-Based Estimates of Schistosoma mansoni Clearance and Reinfection: A Modeling Study

      Clark, Jessica; orcid: 0000-0003-1692-899X; Moses, Arinaitwe; Nankasi, Andrina; Faust, Christina L; Moses, Adriko; Ajambo, Diana; Besigye, Fred; Atuhaire, Aaron; Wamboko, Aidah; Carruthers, Lauren V; et al. (Oxford University Press (OUP), 2021-08-06)
      Abstract Background Despite decades of interventions, 240 million people have schistosomiasis. Infections cannot be directly observed, and egg-based Kato-Katz thick smears lack sensitivity, affected treatment efficacy and reinfection rate estimates. The point-of-care circulating cathodic antigen (referred to from here as POC-CCA+) test is advocated as an improvement on the Kato-Katz method, but improved estimates are limited by ambiguities in the interpretation of trace results. Method We collected repeated Kato-Katz egg counts from 210 school-aged children and scored POC-CCA tests according to the manufacturer’s guidelines (referred to from here as POC-CCA+) and the externally developed G score. We used hidden Markov models parameterized with Kato-Katz; Kato-Katz and POC-CCA+; and Kato-Katz and G-Scores, inferring latent clearance and reinfection probabilities at four timepoints over six-months through a more formal statistical reconciliation of these diagnostics than previously conducted. Our approach required minimal but robust assumptions regarding trace interpretations. Results Antigen-based models estimated higher infection prevalence across all timepoints compared with the Kato-Katz model, corresponding to lower clearance and higher reinfection estimates. Specifically, pre-treatment prevalence estimates were 85% (Kato-Katz; 95% CI: 79%–92%), 99% (POC-CCA+; 97%–100%) and 98% (G-Score; 95%–100%). Post-treatment, 93% (Kato-Katz; 88%–96%), 72% (POC-CCA+; 64%–79%) and 65% (G-Score; 57%–73%) of those infected were estimated to clear infection. Of those who cleared infection, 35% (Kato-Katz; 27%–42%), 51% (POC-CCA+; 41%–62%) and 44% (G-Score; 33%–55%) were estimated to have been reinfected by 9-weeks. Conclusions Treatment impact was shorter-lived than Kato-Katz–based estimates alone suggested, with lower clearance and rapid reinfection. At 3 weeks after treatment, longer-term clearance dynamics are captured. At 9 weeks after treatment, reinfection was captured, but failed clearance could not be distinguished from rapid reinfection. Therefore, frequent sampling is required to understand these important epidemiological dynamics.
    • Cortical Visual Impairment in Childhood: ‘Blindsight’ and the Sprague Effect Revisited

      Leisman, Gerry; orcid: 0000-0002-9975-7331; email: g.leisman@alumni.manchester.ac.uk; Machado, Calixto; orcid: 0000-0002-0539-5844; email: braind@infomed.sld.cu; Melillo, Robert; email: drrm1019@aol.com (MDPI, 2021-09-27)
      The paper discusses and provides support for diverse processes of brain plasticity in visual function after damage in infancy and childhood in comparison with injury that occurs in the adult brain. We provide support and description of neuroplastic mechanisms in childhood that do not seemingly exist in the same way in the adult brain. Examples include the ability to foster the development of thalamocortical connectivities that can circumvent the lesion and reach their cortical destination in the occipital cortex as the developing brain is more efficient in building new connections. Supporting this claim is the fact that in those with central visual field defects we can note that the extrastriatal visual connectivities are greater when a lesion occurs earlier in life as opposed to in the neurologically mature adult. The result is a significantly more optimized system of visual and spatial exploration within the ‘blind’ field of view. The discussion is provided within the context of “blindsight” and the “Sprague Effect”.
    • Weak Vestibular Response in Persistent Developmental Stuttering

      Gattie, Max; email: max.gattie@manchester.ac.uk; Lieven, Elena V. M.; Kluk, Karolina (Frontiers Media S.A., 2021-09-01)
      Vibrational energy created at the larynx during speech will deflect vestibular mechanoreceptors in humans (Todd et al., 2008; Curthoys, 2017; Curthoys et al., 2019). Vestibular-evoked myogenic potential (VEMP), an indirect measure of vestibular function, was assessed in 15 participants who stutter, with a non-stutter control group of 15 participants paired on age and sex. VEMP amplitude was 8.5 dB smaller in the stutter group than the non-stutter group (p = 0.035, 95% CI [−0.9, −16.1], t = −2.1, d = −0.8, conditional R2 = 0.88). The finding is subclinical as regards gravitoinertial function, and is interpreted with regard to speech-motor function in stuttering. There is overlap between brain areas receiving vestibular innervation, and brain areas identified as important in studies of persistent developmental stuttering. These include the auditory brainstem, cerebellar vermis, and the temporo-parietal junction. The finding supports the disruptive rhythm hypothesis (Howell et al., 1983; Howell, 2004) in which sensory inputs additional to own speech audition are fluency-enhancing when they coordinate with ongoing speech.
    • Correction: How do women experience a false-positive test result from breast screening? A systematic review and thematic synthesis of qualitative studies

      Long, Hannah; orcid: 0000-0001-7306-8987; email: hannah.long@manchester.ac.uk; Brooks, Joanna M.; Harvie, Michelle; orcid: 0000-0001-9761-3089; Maxwell, Anthony; orcid: 0000-0001-8344-4958; French, David P.; orcid: 0000-0002-7663-7804 (Nature Publishing Group UK, 2021-07-30)
    • Frame covariant formalism for fermionic theories

      Finn, Kieran; orcid: 0000-0002-9840-2264; email: kieran.finn@manchester.ac.uk; Karamitsos, Sotirios; Pilaftsis, Apostolos (Springer Berlin Heidelberg, 2021-07-02)
      Abstract: We present a frame- and reparametrisation-invariant formalism for quantum field theories that include fermionic degrees of freedom. We achieve this using methods of field-space covariance and the Vilkovisky–DeWitt (VDW) effective action. We explicitly construct a field-space supermanifold on which the quantum fields act as coordinates. We show how to define field-space tensors on this supermanifold from the classical action that are covariant under field reparametrisations. We then employ these tensors to equip the field-space supermanifold with a metric, thus solving a long-standing problem concerning the proper definition of a metric for fermionic theories. With the metric thus defined, we use well-established field-space techniques to extend the VDW effective action and express any fermionic theory in a frame- and field-reparametrisation-invariant manner.
    • Seasonal patterns of malaria, genital infection, nutritional and iron status in non-pregnant and pregnant adolescents in Burkina Faso: a secondary analysis of trial data

      Roberts, Stephen A.; orcid: 0000-0002-7477-7731; Brabin, Loretta; orcid: 0000-0003-4478-6503; email: loretta.brabin@manchester.ac.uk; Tinto, Halidou; orcid: 0000-0002-0472-3586; Gies, Sabine; Diallo, Salou; orcid: 0000-0002-1253-4726; Brabin, Bernard; orcid: 0000-0001-6860-2508 (BioMed Central, 2021-09-27)
      Abstract: Background: Adolescents are considered at high risk of developing iron deficiency. Studies in children indicate that the prevalence of iron deficiency increased with malaria transmission, suggesting malaria seasonally may drive iron deficiency. This paper examines monthly seasonal infection patterns of malaria, abnormal vaginal flora, chorioamnionitis, antibiotic and antimalarial prescriptions, in relation to changes in iron biomarkers and nutritional indices in adolescents living in a rural area of Burkina Faso, in order to assess the requirement for seasonal infection control and nutrition interventions. Methods: Data collected between April 2011 and January 2014 were available for an observational seasonal analysis, comprising scheduled visits for 1949 non-pregnant adolescents (≤19 years), (315 of whom subsequently became pregnant), enrolled in a randomised trial of periconceptional iron supplementation. Data from trial arms were combined. Body Iron Stores (BIS) were calculated using an internal regression for ferritin to allow for inflammation. At recruitment 11% had low BIS (< 0 mg/kg). Continuous outcomes were fitted to a mixed-effects linear model with month, age and pregnancy status as fixed effect covariates and woman as a random effect. Dichotomous infection outcomes were fitted with analogous logistic regression models. Results: Seasonal variation in malaria parasitaemia prevalence ranged between 18 and 70% in non-pregnant adolescents (P < 0.001), peaking at 81% in those who became pregnant. Seasonal variation occurred in antibiotic prescription rates (0.7–1.8 prescriptions/100 weekly visits, P < 0.001) and chorioamnionitis prevalence (range 15–68%, P = 0.026). Mucosal vaginal lactoferrin concentration was lower at the end of the wet season (range 2–22 μg/ml, P < 0.016), when chorioamnionitis was least frequent. BIS fluctuated annually by up to 53.2% per year around the mean BIS (5.1 mg/kg2, range 4.1–6.8 mg/kg), with low BIS (< 0 mg/kg) of 8.7% in the dry and 9.8% in the wet seasons (P = 0.36). Median serum transferrin receptor increased during the wet season (P < 0.001). Higher hepcidin concentration in the wet season corresponded with rising malaria prevalence and use of prescriptions, but with no change in BIS. Mean Body Mass Index and Mid-Upper-Arm-Circumference values peaked mid-dry season (both P < 0.001). Conclusions: Our analysis supports preventive treatment of malaria among adolescents 15–19 years to decrease their disease burden, especially asymptomatic malaria. As BIS were adequate in most adolescents despite seasonal malaria, a requirement for programmatic iron supplementation was not substantiated.
    • Secret Hunger: The Case of Anorexia Nervosa

      Giordano, Simona; orcid: 0000-0002-3608-0263; email: Simona.giordano@manchester.ac.uk (Springer Netherlands, 2020-09-28)
      Abstract: Anorexia nervosa is currently classed as a mental disorder. It is considered as a puzzling condition, scarcely understood and recalcitrant to treatment. This paper reviews the main hypotheses relating to the aetiology of anorexia nervosa. In particular, it focuses on family and sociological studies of anorexia. By reflecting on the hypotheses provided within these domains, and on the questions that these studies leave unanswered, this paper suggests that anorexic behaviour is understandable and rational, if seen in light of ordinary moral values.
    • Landslides in the Upper Submarine Slopes of Volcanic Islands: The Central Azores

      Chang, Yu‐Chun; orcid: 0000-0003-4941-5437; email: yu-chun.chang@manchester.ac.uk; Mitchell, Neil C.; orcid: 0000-0002-6483-2450; Quartau, Rui; orcid: 0000-0003-3148-7520 (2021-09-28)
      Abstract: Small landslides in the upper submarine slopes of volcanic islands present potential hazards locally because of their high frequency. We examine evidence for landsliding in high‐resolution bathymetric data from Faial, Pico, São Jorge, and Terceira islands of the Azores. Because the rugged morphology of the upper slopes makes landslides difficult to interpret, we develop two classification schemes for the 1,227 identified slope valleys. One scheme addresses how recognizable the valleys were as originating from landslides (whether scarps are prominent or indefinite), whereas the other scheme addresses valley types (whether apparently produced by single or multiple failures). Size distributions are used to assess the relative occurrence of large versus small landslides. Thirteen landslides are predicted to have generated tsunami heights at source of >1 m and one with height of >7 m. Some slopes have gradients far above 30°, the angle of repose of incohesive clastic sediment, so the seabed in those areas is strengthened perhaps by carbonate cementation, by seismic shaking or by the presence of coherent lava or lava talus. Using all types of slope valleys, Faial and Pico have smaller affected volumes per unit slope area than those of São Jorge and Terceira. These differences could be associated with varied seismic activity, with more frequent earthquakes beneath Faial and Pico preventing the build‐up of sediments on their slopes. Submarine landslide statistics are therefore potentially useful for assessing long‐term earthquake hazards of volcanic islands in seismically active environments such as the Azores.
    • We See Data Everywhere Except in the Productivity Statistics

      Goodridge, Peter; email: peter.goodridge@manchester.ac.uk; Haskel, Jonathan; Edquist, Harald (2021-09-28)
      This paper uses Labor Force Survey data for European countries to estimate national investment in data assets, where the asset boundary is extended beyond that for software and databases as currently defined in the System of National Accounts. We find that: (a) in 2011–2018, 1.4 percent of EU‐28 employment was engaged in the formation of (software and) data assets, with a mean growth rate of 5 percent per annum; (b) on average in 2011–2016, expanding the asset boundary raises the level of own‐account GFCF in software and databases in the EU‐16 by 61 percent, and mean growth in real investment in own‐account software and data assets to 6.9 percent pa, compared to 2.7 percent pa in national accounts; (c) in 2011–2016, expansion of the asset boundary raises labor productivity growth in the EU‐13 from 0.79 percent to 0.83 percent pa, and the contribution of software and data capital deepening over three‐fold, from 0.03 percent to 0.10 percent pa.
    • A microenvironment-inspired synthetic three-dimensional model for pancreatic ductal adenocarcinoma organoids.

      Below, Christopher R; orcid: 0000-0003-1545-6281; Kelly, Joanna; Brown, Alexander; Humphries, Jonathan D; orcid: 0000-0002-8953-7079; Hutton, Colin; Xu, Jingshu; Lee, Brian Y; Cintas, Celia; orcid: 0000-0001-8730-9171; Zhang, Xiaohong; Hernandez-Gordillo, Victor; et al. (2021-09-13)
      Experimental in vitro models that capture pathophysiological characteristics of human tumours are essential for basic and translational cancer biology. Here, we describe a fully synthetic hydrogel extracellular matrix designed to elicit key phenotypic traits of the pancreatic environment in culture. To enable the growth of normal and cancerous pancreatic organoids from genetically engineered murine models and human patients, essential adhesive cues were empirically defined and replicated in the hydrogel scaffold, revealing a functional role of laminin-integrin α /α signalling in establishment and survival of pancreatic organoids. Altered tissue stiffness-a hallmark of pancreatic cancer-was recapitulated in culture by adjusting the hydrogel properties to engage mechano-sensing pathways and alter organoid growth. Pancreatic stromal cells were readily incorporated into the hydrogels and replicated phenotypic traits characteristic of the tumour environment in vivo. This model therefore recapitulates a pathologically remodelled tumour microenvironment for studies of normal and pancreatic cancer cells in vitro. [Abstract copyright: © 2021. The Author(s), under exclusive licence to Springer Nature Limited.]
    • Missing data was handled inconsistently in UK prediction models: a review of method used.

      Tsvetanova, Antonia; email: antonia.tsvetanova@manchester.ac.uk; Sperrin, Matthew; Peek, Niels; Buchan, Iain; Hyland, Stephanie; Martin, Glen P (2021-09-11)
      No clear guidance exists on handling missing data at each stage of developing, validating and implementing a clinical prediction model (CPM). We aimed to review the approaches to handling missing data that underly the CPMs currently recommended for use in UK healthcare. A descriptive cross-sectional meta-epidemiological study aiming to identify CPMs recommended by the National Institute for Health and Care Excellence (NICE), which summarized how missing data is handled across their pipelines. 23 CPMs were included through 'sampling strategy'. Six missing data strategies were identified: complete case analysis (CCA), multiple imputation, imputation of mean values, k-nearest neighbours imputation, using an additional category for missingness, considering missing values as risk-factor-absent. 52% of the development articles and 48% of the validation articles did not report how missing data were handled. CCA was the most common approach used for development (40%) and validation (44%). At implementation, 57% of the CPMs required complete data entry, whilst 43% allowed missing values. 3 CPMs had consistent paths in their pipelines. A broad variety of methods for handling missing data underly the CPMs currently recommended for use in UK healthcare. Missing data handling strategies were generally inconsistent. Better quality assurance of CPMs needs greater clarity and consistency in handling of missing data. [Abstract copyright: Copyright © 2021. Published by Elsevier Inc.]
    • Restoring fertility in yeast hybrids: Breeding and quantitative genetics of beneficial traits.

      Naseeb, Samina; orcid: 0000-0003-3599-5813; Visinoni, Federico; orcid: 0000-0001-9840-7017; Hu, Yue; Hinks Roberts, Alex J; Maslowska, Agnieszka; Walsh, Thomas; Smart, Katherine A; Louis, Edward J; orcid: 0000-0003-1157-3608; Delneri, Daniela; orcid: 0000-0001-8070-411X (2021-09-21)
      Hybrids between species can harbor a combination of beneficial traits from each parent and may exhibit hybrid vigor, more readily adapting to new harsher environments. Interspecies hybrids are also sterile and therefore an evolutionary dead end unless fertility is restored, usually via auto-polyploidisation events. In the genus, hybrids are readily found in nature and in industrial settings, where they have adapted to severe fermentative conditions. Due to their hybrid sterility, the development of new commercial yeast strains has so far been primarily conducted via selection methods rather than via further breeding. In this study, we overcame infertility by creating tetraploid intermediates of interspecies hybrids to allow continuous multigenerational breeding. We incorporated nuclear and mitochondrial genetic diversity within each parental species, allowing for quantitative genetic analysis of traits exhibited by the hybrids and for nuclear-mitochondrial interactions to be assessed. Using pooled F12 generation segregants of different hybrids with extreme phenotype distributions, we identified quantitative trait loci (QTLs) for tolerance to high and low temperatures, high sugar concentration, high ethanol concentration, and acetic acid levels. We identified QTLs that are species specific, that are shared between species, as well as hybrid specific, in which the variants do not exhibit phenotypic differences in the original parental species. Moreover, we could distinguish between mitochondria-type-dependent and -independent traits. This study tackles the complexity of the genetic interactions and traits in hybrid species, bringing hybrids into the realm of full genetic analysis of diploid species, and paves the road for the biotechnological exploitation of yeast biodiversity. [Abstract copyright: Copyright © 2021 the Author(s). Published by PNAS.]