• Replication catastrophe is responsible for intrinsic PAR glycohydrolase inhibitor-sensitivity in patient-derived ovarian cancer models

      Coulson-Gilmer, Camilla; Morgan, Robert D.; Nelson, Louisa; Barnes, Bethany M.; Tighe, Anthony; Wardenaar, René; Spierings, Diana C. J.; Schlecht, Helene; Burghel, George J.; Foijer, Floris; et al. (BioMed Central, 2021-10-16)
      Abstract: Background: Patients with ovarian cancer often present at advanced stage and, following initial treatment success, develop recurrent drug-resistant disease. PARP inhibitors (PARPi) are yielding unprecedented survival benefits for women with BRCA-deficient disease. However, options remain limited for disease that is platinum-resistant and/or has inherent or acquired PARPi-resistance. PARG, the PAR glycohydrolase that counterbalances PARP activity, is an emerging target with potential to selectively kill tumour cells harbouring oncogene-induced DNA replication and metabolic vulnerabilities. Clinical development of PARG inhibitors (PARGi) will however require predictive biomarkers, in turn requiring an understanding of their mode of action. Furthermore, differential sensitivity to PARPi is key for expanding treatment options available for patients. Methods: A panel of 10 ovarian cancer cell lines and a living biobank of patient-derived ovarian cancer models (OCMs) were screened for PARGi-sensitivity using short- and long-term growth assays. PARGi-sensitivity was characterized using established markers for DNA replication stress, namely replication fibre asymmetry, RPA foci, KAP1 and Chk1 phosphorylation, and pan-nuclear γH2AX, indicating DNA replication catastrophe. Finally, gene expression in sensitive and resistant cells was also examined using NanoString or RNAseq. Results: PARGi sensitivity was identified in both ovarian cancer cell lines and patient-derived OCMs, with sensitivity accompanied by markers of persistent replication stress, and a pre-mitotic cell cycle block. Moreover, DNA replication genes are down-regulated in PARGi-sensitive cell lines consistent with an inherent DNA replication vulnerability. However, DNA replication gene expression did not predict PARGi-sensitivity in OCMs. The subset of patient-derived OCMs that are sensitive to single-agent PARG inhibition, includes models that are PARPi- and/or platinum-resistant, indicating that PARG inhibitors may represent an alternative treatment strategy for women with otherwise limited therapeutic options. Conclusions: We discover that a subset of ovarian cancers are intrinsically sensitive to pharmacological PARG blockade, including drug-resistant disease, underpinned by a common mechanism of replication catastrophe. We explore the use of a transcript-based biomarker, and provide insight into the design of future clinical trials of PARGi in patients with ovarian cancer. However, our results highlight the complexity of developing a predictive biomarker for PARGi sensitivity.
    • The Effect of Authigenic Clays on Fault Zone Permeability

      Farrell, N. J. C.; orcid: 0000-0002-8491-9094; email: natalie.farrell@manchester.ac.uk; Debenham, N.; Wilson, L.; Wilson, M. J.; Healy, D.; orcid: 0000-0003-2685-1498; King, R. C.; Holford, S. P.; orcid: 0000-0002-4524-8822; Taylor, C. W. (2021-10-15)
      Abstract: Clays are understood to form the majority of fluid‐flow barriers in faulted reservoirs and numerous fault gouge and fault seal studies have quantified the volumes of smeared and abraded clays create fluid‐flow barriers along fault surfaces. However, clay‐related permeability adjacent to the fault surface, including in the fault damage zone, has largely been neglected. Previous studies have shown the morphology and distribution of unfaulted authigenic clays, and not just clay volume, exert a significant control on the magnitude of permeability. However, fault‐related studies have neither characterized deformed authigenic clays nor addressed their influence on fluid‐flow. In this study laboratory permeabilities of faulted, authigenic clay bearing sandstones sampled from the Otway basin (Australia) and the Orcadian basin (UK) present trends which; (a) do not correspond to expected patterns of fluid‐flow in faulted clay‐bearing sandstones and, (b) cannot be explained using published models of permeability related to changing clay volume. Microscopic analysis shows that faulting has disaggregated authigenic clays and, similarly to framework grain deformation, comminuted and sheared clay grains. However, instead of impeding fluid‐flow, analysis of pore networks (using mercury injection porosimetry) showed that faulting of authigenic clays has increased pore connectivity, contributing to increased magnitude of permeability and development of permeability anisotropy. Contrary to published results of faulting and fluid‐flow in impure sandstones, our results show that fault related processes involving the formation of clays in the fault zone can increase permeability and reduce the capillary threshold pressures of fault rocks relative to the unfaulted host rock.
    • The impact of COVID-19 on digital data practices in museums and art galleries in the UK and the US

      Noehrer, Lukas; orcid: 0000-0002-9167-0397; email: lukas.noehrer@manchester.ac.uk; Gilmore, Abigail; Jay, Caroline; Yehudi, Yo; orcid: 0000-0003-2705-1724 (Palgrave Macmillan UK, 2021-10-15)
      Abstract: The first quarter of 2020 heralded the beginning of an uncertain future for museums and galleries as the COVID-19 pandemic hit and the only means to stay ‘open’ was to turn towards the digital. In this paper, we investigate how the physical closure of museum buildings due to lockdown restrictions caused shockwaves within their digital strategies and changed their data practices potentially for good. We review the impact of COVID-19 on the museum sector, based on literature and desk research, with a focus on the implications for three museums and art galleries in the United Kingdom and the United States, and their mission, objectives, and digital data practices. We then present an analysis of ten qualitative interviews with expert witnesses working in the sector, representing different roles and types of institutions, undertaken between April and October 2020. Our research finds that digital engagement with museum content and practices around data in institutions have changed and that digital methods for organising and accessing collections for both staff and the general public have become more important. We present evidence that strategic preparedness influenced how well institutions were able to transition during closure and that metrics data became pivotal in understanding this novel situation. Increased engagement online changed traditional audience profiles, challenging museums to find ways of accommodating new forms of engagement in order to survive and thrive in the post-pandemic environment.
    • Stress Corrosion Cracking of Additively Manufactured Alloy 625

      Cabrini, Marina; orcid: 0000-0003-3901-8657; email: marina.cabrini@unibg.it; Lorenzi, Sergio; orcid: 0000-0002-1337-7590; email: sergio.lorenzi@unibg.it; Testa, Cristian; orcid: 0000-0002-6064-9851; email: cristian.testa@guest.unibg.it; Carugo, Francesco; email: francesco.carugo@unibg.it; Pastore, Tommaso; orcid: 0000-0002-1443-7786; email: tommaso.pastore@unibg.it; Manfredi, Diego; orcid: 0000-0002-2876-143X; email: diego.manfredi@polito.it; Biamino, Sara; orcid: 0000-0003-1840-7717; email: sara.biamino@polito.it; Marchese, Giulio; orcid: 0000-0002-4637-5532; email: giulio.marchese@polito.it; Parizia, Simone; orcid: 0000-0002-1616-2800; email: simone.parizia@polito.it; Scenini, Fabio; orcid: 0000-0002-8974-4860; email: fabio.scenini@manchester.ac.uk (MDPI, 2021-10-15)
      Laser bed powder fusion (LPBF) is an additive manufacturing technology for the fabrication of semi-finished components directly from computer-aided design modelling, through melting and consolidation, layer upon layer, of a metallic powder, with a laser source. This manufacturing technique is particularly indicated for poor machinable alloys, such as Alloy 625. However, the unique microstructure generated could modify the resistance of the alloy to environment assisted cracking. The aim of this work was to analyze the stress corrosion cracking (SCC) and hydrogen embrittlement resistance behavior of Alloy 625 obtained by LPBF, both in as-built condition and after a standard heat treatment (grade 1). U-bend testing performed in boiling magnesium chloride at 155 and 170 °C confirmed the immunity of the alloy to SCC. However, slow strain rate tests in simulated ocean water on cathodically polarized specimens highlighted the possibility of the occurrence of hydrogen embrittlement in a specific range of strain rate and cathodic polarization. The very fine grain size and dislocation density of the thermally untreated specimens appeared to increase the hydrogen diffusion and embrittlement effect on pre-charged specimens that were deformed at the high strain rate. Conversely, heat treatment appeared to mitigate hydrogen embrittlement at high strain rates, however at the slow strain rate all the specimens showed a similar behavior.
    • Genetic and process engineering strategies for enhanced recombinant N -glycoprotein production in bacteria

      Pratama, Fenryco; Linton, Dennis; Dixon, Neil; orcid: 0000-0001-9065-6764; email: neil.dixon@manchester.ac.uk (BioMed Central, 2021-10-14)
      Abstract: Background: The production of N-linked glycoproteins in genetically amenable bacterial hosts offers great potential for reduced cost, faster/simpler bioprocesses, greater customisation, and utility for distributed manufacturing of glycoconjugate vaccines and glycoprotein therapeutics. Efforts to optimize production hosts have included heterologous expression of glycosylation enzymes, metabolic engineering, use of alternative secretion pathways, and attenuation of gene expression. However, a major bottleneck to enhance glycosylation efficiency, which limits the utility of the other improvements, is the impact of target protein sequon accessibility during glycosylation. Results: Here, we explore a series of genetic and process engineering strategies to increase recombinant N-linked glycosylation, mediated by the Campylobacter-derived PglB oligosaccharyltransferase in Escherichia coli. Strategies include increasing membrane residency time of the target protein by modifying the cleavage site of its secretion signal, and modulating protein folding in the periplasm by use of oxygen limitation or strains with compromised oxidoreductase or disulphide-bond isomerase activity. These approaches achieve up to twofold improvement in glycosylation efficiency. Furthermore, we also demonstrate that supplementation with the chemical oxidant cystine enhances the titre of glycoprotein in an oxidoreductase knockout strain by improving total protein production and cell fitness, while at the same time maintaining higher levels of glycosylation efficiency. Conclusions: In this study, we demonstrate that improved protein glycosylation in the heterologous host could be achieved by mimicking the coordination between protein translocation, folding and glycosylation observed in native host such as Campylobacter jejuni and mammalian cells. Furthermore, it provides insight into strain engineering and bioprocess strategies, to improve glycoprotein yield and titre, and to avoid physiological burden of unfolded protein stress upon cell growth. The process and genetic strategies identified herein will inform further optimisation and scale-up of heterologous recombinant N-glycoprotein production.
    • Corneal nerve loss is related to the severity of painful diabetic neuropathy

      Kalteniece, Alise; Ferdousi, Maryam; Azmi, Shazli; Khan, Saif Ullah; Worthington, Anne; Marshall, Andrew; Faber, Catharina G.; Lauria, Giuseppe; orcid: 0000-0001-9773-020X; Boulton, Andrew J. M.; Soran, Handrean; et al. (2021-10-13)
      Abstract: Background and purpose: Previously it has been shown that patients with painful diabetic neuropathy (PDN) have greater corneal nerve loss compared to patients with painless diabetic neuropathy. This study investigated if the severity of corneal nerve loss was related to the severity of PDN. Methods: Participants with diabetic neuropathy (n = 118) and healthy controls (n = 38) underwent clinical and neurological evaluation, quantitative sensory testing, nerve conduction testing and corneal confocal microscopy and were categorized into those with no (n = 43), mild (n = 34) and moderate‐to‐severe (n = 41) neuropathic pain. Results: Corneal nerve fibre density (p = 0.003), corneal nerve fibre length (p < 0.0001) and cold perception threshold (p < 0.0001) were lower and warm perception threshold was higher (p = 0.002) in patients with more severe pain, but there was no significant difference in the neuropathy disability score (p = 0.5), vibration perception threshold (p = 0.5), sural nerve conduction velocity (p = 0.3) and amplitude (p = 0.7), corneal nerve branch density (p = 0.06) and deep breathing heart rate variability (p = 0.08) between patients with differing severity of PDN. The visual analogue scale correlated significantly with corneal nerve fibre density (r = −0.3, p = 0.0002), corneal nerve branch density (r = −0.3, p = 0.001) and corneal nerve fibre length (r = −0.4, p < 0.0001). Receiver operating curve analysis showed that corneal nerve fibre density had an area under the curve of 0.78 with a sensitivity of 0.73 and specificity of 0.72 for the diagnosis of PDN. Conclusions: Corneal confocal microscopy reveals increasing corneal nerve fibre loss with increasing severity of neuropathic pain and a good diagnostic outcome for identifying patients with PDN.
    • Nitric oxide mediates activity-dependent change to synaptic excitation during a critical period in Drosophila

      Giachello, Carlo N. G.; Fan, Yuen Ngan; Landgraf, Matthias; Baines, Richard A.; email: Richard.Baines@manchester.ac.uk (Nature Publishing Group UK, 2021-10-13)
      Abstract: The emergence of coordinated network function during nervous system development is often associated with critical periods. These phases are sensitive to activity perturbations during, but not outside, of the critical period, that can lead to permanently altered network function for reasons that are not well understood. In particular, the mechanisms that transduce neuronal activity to regulating changes in neuronal physiology or structure are not known. Here, we take advantage of a recently identified invertebrate model for studying critical periods, the Drosophila larval locomotor system. Manipulation of neuronal activity during this critical period is sufficient to increase synaptic excitation and to permanently leave the locomotor network prone to induced seizures. Using genetics and pharmacological manipulations, we identify nitric oxide (NO)-signaling as a key mediator of activity. Transiently increasing or decreasing NO-signaling during the critical period mimics the effects of activity manipulations, causing the same lasting changes in synaptic transmission and susceptibility to seizure induction. Moreover, the effects of increased activity on the developing network are suppressed by concomitant reduction in NO-signaling and enhanced by additional NO-signaling. These data identify NO signaling as a downstream effector, providing new mechanistic insight into how activity during a critical period tunes a developing network.
    • Environmental Assessment of Latent Heat Thermal Energy Storage Technology System with Phase Change Material for Domestic Heating Applications

      Chocontá Bernal, Daniel; email: Daniel.chocontabernal@postgrad.manchester.ac.uk; Muñoz, Edmundo; orcid: 0000-0002-7258-6069; email: edmundo.munoz@unab.cl; Manente, Giovanni; orcid: 0000-0001-7134-8731; email: G.Manente@bham.ac.uk; Sciacovelli, Adriano; orcid: 0000-0001-9684-3122; email: a.sciacovelli@bham.ac.uk; Ameli, Hossein; orcid: 0000-0003-4056-9819; email: h.ameli14@imperial.ac.uk; Gallego-Schmid, Alejandro; email: alejandro.gallegoschmid@manchester.ac.uk (MDPI, 2021-10-13)
      The emissions generated by the space and water heating of UK homes need to be reduced to meet the goal of becoming carbon neutral by 2050. The combination of solar (S) collectors with latent heat thermal energy storage (LHTES) technologies with phase change materials (PCM) can potentially help to achieve this goal. However, there is limited understanding of the environmental sustainability of LHTES technologies from a full life cycle perspective. This study assesses for the first time 18 environmental impacts of a full S-LHTES-PCM system from a cradle to grave perspective and compares the results with the most common sources of heat in UK homes. The results show that the system’s main environmental hotspots are the solar collector, the PCM, the PCM tank, and the heat exchanger. The main cause of most of the impacts is the extensive consumption of electricity and heat during the production of raw materials for these components. The comparison with other sources of household heat (biomass, heat pump, and natural gas) indicates that the S-LHTES-PCM system generates the highest environmental impact in 11 of 18 categories. However, a sensitivity analysis based on the lifetime of the S-LHTES-PCM systems shows that, when the lifetime increases to 40 years, almost all the impacts are significantly reduced. In fact, a 40-year S-LHTES-PCM system has a lower global warming potential than natural gas.
    • Investigating top tagging with Y m -Splitter and N-subjettiness

      Dasgupta, Mrinal; Helliwell, Jack; orcid: 0000-0002-8725-7794; email: jack.helliwell@manchester.ac.uk (Springer Berlin Heidelberg, 2021-10-12)
      Abstract: We study top-tagging from an analytical QCD perspective focussing on the role of two key steps therein: a step to find three-pronged substructure and a step that places constraints on radiation. For the former we use a recently introduced modification of Y-Splitter, known as Ym-Splitter, and for the latter we use the well-known N-subjettiness variable. We derive resummed results for this combination of variables for both signal jets and background jets, also including pre-grooming of the jet. Our results give new insight into the performance of top tagging tools in particular with regard to the role of the distinct steps involved.
    • Estimating stochastic survey response errors using the multitrait‐multierror model

      Cernat, Alexandru; orcid: 0000-0003-2176-1215; email: alexandru.cernat@manchester.ac.uk; Oberski, Daniel L.; orcid: 0000-0001-7467-2297 (2021-10-12)
      Abstract: Surveys are well known to contain response errors of different types, including acquiescence, social desirability, common method variance and random error simultaneously. Nevertheless, a single error source at a time is all that most methods developed to estimate and correct for such errors consider in practice. Consequently, estimation of response errors is inefficient, their relative importance is unknown and the optimal question format may not be discoverable. To remedy this situation, we demonstrate how multiple types of errors can be estimated concurrently with the recently introduced ‘multitrait‐multierror’ (MTME) approach. MTME combines the theory of design of experiments with latent variable modelling to estimate response error variances of different error types simultaneously. This allows researchers to evaluate which errors are most impactful, and aids in the discovery of optimal question formats. We apply this approach using representative data from the United Kingdom to six survey items measuring attitudes towards immigrants that are commonly used across public opinion studies.
    • The Relationship between the Therapeutic Alliance and Suicidal Experiences in People with Psychosis Receiving Therapy

      Huggett, Charlotte; orcid: 0000-0002-7566-6224; email: charlotte.huggett@postgrad.manchester.ac.uk; Gooding, Patricia; email: Patricia.A.Gooding@manchester.ac.uk; Haddock, Gillian; email: gillian.haddock@manchester.ac.uk; Pratt, Daniel; orcid: 0000-0001-8843-1224; email: daniel.pratt@manchester.ac.uk (MDPI, 2021-10-12)
      Few studies have examined the relationship between the therapeutic alliance in therapy and suicidal experiences. No studies have examined this relationship with people with non-affective psychosis. The present study sought to redress this gap in the literature. Sixty-four participants with non-affective psychosis and suicidal experiences who were receiving a suicide-focused cognitive therapy were recruited. Self-reported suicidal ideation, suicide plans, suicide attempts, depression, and hopelessness were collected from participants prior to starting therapy. Suicidal experience measures were collected again post-therapy at 6 months. Therapeutic alliance ratings were completed by clients and therapists at session 4 of therapy. Dose of therapy was documented in number of minutes of therapy. Data were analyzed using correlation coefficients, independent samples t-tests, a multiple hierarchical regression, and a moderated linear regression. There was no significant relationship found between suicidal ideation prior to therapy and the therapeutic alliance at session 4, rated by both client and therapist. However, there was a significant negative relationship between the client-rated therapeutic alliance at session 4 and suicidal ideation at 6 months, after controlling for pre-therapy suicidal ideation, depression, and hopelessness. Furthermore, the negative relationship between the client-rated alliance and suicidal ideation was the strongest when number of minutes of therapy was 15 h or below. A stronger therapeutic alliance developed in the first few sessions of therapy is important in ameliorating suicidal thoughts in people with psychosis. Nevertheless, it is not necessarily the case that more hours in therapy equates to a cumulative decrease in suicidal ideation of which therapists could be mindful. A limitation of the current study was that the alliance was analyzed only at session 4 of therapy, which future studies could seek to redress.
    • Biallelic TMEM260 variants cause truncus arteriosus, with or without renal defects

      Pagnamenta, Alistair T.; orcid: 0000-0001-7334-0602; Jackson, Adam; Perveen, Rahat; Beaman, Glenda; Petts, Gemma; Gupta, Asheeta; Hyder, Zerin; Chung, Brian Hon‐Yin; orcid: 0000-0002-7044-5916; Kan, Anita Sik‐Yau; Cheung, Ka Wang; et al. (Blackwell Publishing Ltd, 2021-10-11)
      Abstract: Only two families have been reported with biallelic TMEM260 variants segregating with structural heart defects and renal anomalies syndrome (SHDRA). With a combination of genome, exome sequencing and RNA studies, we identified eight individuals from five families with biallelic TMEM260 variants. Variants included one multi‐exon deletion, four nonsense/frameshifts, two splicing changes and one missense change. Together with the published cases, analysis of clinical data revealed ventricular septal defects (12/12), mostly secondary to truncus arteriosus (10/12), elevated creatinine levels (6/12), horse‐shoe kidneys (1/12) and renal cysts (1/12) in patients. Three pregnancies were terminated on detection of severe congenital anomalies. Six patients died between the ages of 6 weeks and 5 years. Using a range of stringencies, carrier frequency for SHDRA was estimated at 0.0007–0.007 across ancestries. In conclusion, this study confirms the genetic basis of SHDRA, expands its known mutational spectrum and clarifies its clinical features. We demonstrate that SHDRA is a severe condition associated with substantial mortality in early childhood and characterised by congenital cardiac malformations with a variable renal phenotype.
    • Cohomology of profinite groups of bounded rank

      Symonds, Peter; email: Peter.Symonds@manchester.ac.uk (2021-10-11)
      Abstract: We generalise to profinite groups some of our previous results on the cohomology of pro‐ p groups of bounded sectional p ‐rank.
    • The Impact of the Performance Appraisal Process on Job Satisfaction of the Academic Staff in Higher Educational Institutions

      Dasanayaka, Chamila H.; email: chamila.dasanayaka@uni.cumbria.ac.uk; Abeykoon, Chamil; orcid: 0000-0002-6797-776X; email: chamil.abeykoon@manchester.ac.uk; Ranaweera, R. A. A. S.; orcid: 0000-0002-7404-196X; email: achala@kln.ac.lk; Koswatte, Isuru; orcid: 0000-0002-1807-1996; email: isuru.k@nsbm.ac.lk (MDPI, 2021-10-11)
      Performance appraisal is one of the key management tools which identifies employees’ strengths and weaknesses. Usually, this is the major mechanism of gathering information for rewarding/training employees based on their performance, and hence a key to achieve organisational goals by creating a satisfied workforce. Therefore, this study was aimed at examining the effects of the Performance Appraisal Process on job satisfaction of the university academic staff. The information collected within one of the largest universities in the UK via questionnaires and semi-structured interviews showed that the existing appraisal process majorly aligned with the requirements of the research-excellence-framework of the UK, which is greatly concerned with research rather than teaching. Furthermore, it was found that there is no clear link between promotions, salary increments, and rewards, etc. with staff performance within the current appraisal process. Eventually, it was realised that the majority of the academic staff of the source university were dissatisfied with the current performance appraisal process, and this could be the situation in the majority of universities in the UK. Therefore, further research in this area is highly recommended to explore extensive information to create a favourable work/study environment for both staff and students within the universities.
    • A Novel Averaging Principle Provides Insights in the Impact of Intratumoral Heterogeneity on Tumor Progression

      Hatzikirou, Haralampos; orcid: 0000-0002-1270-7885; email: haralampos.hatzikirou@ku.ac.ae; Kavallaris, Nikos I.; orcid: 0000-0002-9743-8636; email: n.kavallaris@chester.ac.uk; Leocata, Marta; orcid: 0000-0002-5261-3699; email: mleocata@luiss.it (MDPI, 2021-10-09)
      Typically stochastic differential equations (SDEs) involve an additive or multiplicative noise term. Here, we are interested in stochastic differential equations for which the white noise is nonlinearly integrated into the corresponding evolution term, typically termed as random ordinary differential equations (RODEs). The classical averaging methods fail to treat such RODEs. Therefore, we introduce a novel averaging method appropriate to be applied to a specific class of RODEs. To exemplify the importance of our method, we apply it to an important biomedical problem, in particular, we implement the method to the assessment of intratumoral heterogeneity impact on tumor dynamics. Precisely, we model gliomas according to a well-known Go or Grow (GoG) model, and tumor heterogeneity is modeled as a stochastic process. It has been shown that the corresponding deterministic GoG model exhibits an emerging Allee effect (bistability). In contrast, we analytically and computationally show that the introduction of white noise, as a model of intratumoral heterogeneity, leads to monostable tumor growth. This monostability behavior is also derived even when spatial cell diffusion is taken into account.
    • Advanced cardiovascular risk prediction in the emergency department: updating a clinical prediction model – a large database study protocol

      Reynard, Charles; orcid: 0000-0002-7534-2668; email: Charlie.reynard@manchester.ac.uk; Martin, Glen P.; Kontopantelis, Evangelos; Jenkins, David A.; Heagerty, Anthony; McMillan, Brian; Jafar, Anisa; Garlapati, Rajendar; Body, Richard (BioMed Central, 2021-10-07)
      Abstract: Background: Patients presenting with chest pain represent a large proportion of attendances to emergency departments. In these patients clinicians often consider the diagnosis of acute myocardial infarction (AMI), the timely recognition and treatment of which is clinically important. Clinical prediction models (CPMs) have been used to enhance early diagnosis of AMI. The Troponin-only Manchester Acute Coronary Syndromes (T-MACS) decision aid is currently in clinical use across Greater Manchester. CPMs have been shown to deteriorate over time through calibration drift. We aim to assess potential calibration drift with T-MACS and compare methods for updating the model. Methods: We will use routinely collected electronic data from patients who were treated using TMACS at two large NHS hospitals. This is estimated to include approximately 14,000 patient episodes spanning June 2016 to October 2020. The primary outcome of acute myocardial infarction will be sourced from NHS Digital’s admitted patient care dataset. We will assess the calibration drift of the existing model and the benefit of updating the CPM by model recalibration, model extension and dynamic updating. These models will be validated by bootstrapping and one step ahead prequential testing. We will evaluate predictive performance using calibrations plots and c-statistics. We will also examine the reclassification of predicted probability with the updated TMACS model. Discussion: CPMs are widely used in modern medicine, but are vulnerable to deteriorating calibration over time. Ongoing refinement using routinely collected electronic data will inevitably be more efficient than deriving and validating new models. In this analysis we will seek to exemplify methods for updating CPMs to protect the initial investment of time and effort. If successful, the updating methods could be used to continually refine the algorithm used within TMACS, maintaining or even improving predictive performance over time. Trial registration: ISRCTN number: ISRCTN41008456
    • Dominant‐negative pathogenic variant BRIP1 c. 1045G >C is a high‐risk allele for non‐mucinous epithelial ovarian cancer: A case‐control study

      Flaum, Nicola; orcid: 0000-0001-8900-0645; email: nicola.flaum@manchester.ac.uk; van Veen, Elke M.; orcid: 0000-0001-8618-2332; Smith, Olivia; Amico, Stephanie; Newman, William G.; orcid: 0000-0002-6098-9995; Crosbie, Emma J.; Edmondson, Richard; Smith, Miriam J.; orcid: 0000-0002-3184-0817; Evans, D. Gareth (Blackwell Publishing Ltd, 2021-10-07)
      Abstract: BRIP1 is a moderate susceptibility epithelial ovarian cancer (EOC) gene. Having identified the BRIP1 c.1045G>C missense variant in a number of families with EOC, we aimed to investigate the frequency of this and BRIP1.2392C>T pathogenic variant in patients with breast cancer (BC) and/or EOC. A case‐control study of 3767 cases and 2043 controls was undertaken investigating the presence of these variants using Sanger sequencing and gene panel data. Individuals with BC and/or EOC were grouped by family history. BRIP1 c.1045G>C was associated with increased risk of BC/EOC (OR = 37.7; 95% CI 5.3–444.2; P = 0.0001). The risk was highest for women with EOC (OR = 140.8; 95% CI 23.5–1723.0; P < 0.0001) and lower for BC (OR = 11.1; 95% CI 1.2–106.5; P = 0.1588). BRIP1 c.2392C>T was associated with smaller risks for BC/EOC (OR = 5.4; 95%CI 2.4–12.7; P = 0.0003), EOC (OR = 5.9; 95% CI 1.3–23.0; p = 0.0550) and BC (OR = 5.3; 95%CI 2.3–12.9; P = 0.0009). Our study highlights the importance of BRIP1 as an EOC susceptibility gene, especially in familial EOC. The variant BRIP1 c.1045G>C, rs149364097, is of particular interest as its dominant‐negative effect may confer a higher risk of EOC than that of the previously reported BRIP1 c.2392C>T nonsense variant. Dominant‐negative missense variants may confer higher risks than their loss‐of‐function counterparts.
    • Improving mental health literacy among young people aged 11–15 years in Java, Indonesia: the co-development of a culturally-appropriate, user-centred resource (The IMPeTUs Intervention)

      Brooks, Helen; orcid: 0000-0002-2157-0200; email: helen.brooks@manchester.ac.uk; Syarif, Armaji Kamaludi; Pedley, Rebecca; Irmansyah, Irman; Prawira, Benny; Lovell, Karina; Opitasari, Cicih; Ardisasmita, Adam; Tanjung, Ira Savitri; Renwick, Laoise; et al. (BioMed Central, 2021-10-07)
      Abstract: Background: Many mental health problems emerge in late childhood and contribute significantly to the global burden of disease. Adverse outcomes can extend into adulthood if left untreated. This impact is exacerbated in low- and middle-income countries where significant treatment gaps persist. Improving mental health literacy may offer an effective strategy for early intervention but remains underexplored in these contexts. Methods: An intervention was co-developed with children and young people (CYP) by undertaking a needs analysis combined with stakeholder consensus activities. A systematic review of mental health literacy interventions in South-East Asia was undertaken in addition to semi-structured interviews with 43 children and young people (19 with and 24 without experience of anxiety and depression), 19 parents of children with experience of mental health problems and 25 education and health professionals. A focus group was also held with 8 key stakeholders immersed nationally in policy and practice. Interview schedules explored participants’ experiences of mental health, unmet needs and priorities for intervention. Data were synthesised and presented at a 3-day co-production workshop. Attendees included 13 CYP, 6 parents/guardians, 2 teachers, 8 health professionals, 2 academics and 3 game designers. Consensus exercises were utilised to identify the preferred format, content and delivery of the intervention. A smaller group of patient and public involvement contributors worked with designers to further iterate the intervention. Results: An immersive storyline digital application was co-developed for young people aged 11–15 with the primary aim of improving mental health literacy and self-management. The intervention comprises two chapters; one depression focussed, and the other anxiety focussed. The storyline format is interspersed with interactive games and exercises to promote engagement and encourage self-management. CYP also take part in group sessions delivered by trained facilitators before and after intervention use to discuss outcomes of and issues raised during the game. Conclusion: The IMPeTUs intervention has been co-designed for CYP aged 11–15 to improve mental health literacy and enhance self-management abilities. To the best of our knowledge, this is the first Indonesian digital intervention to improve mental health literacy and self-management for this population. Implementation, acceptability, and impact are currently being explored in a multi-site case study evaluation.
    • Distance, Time, Speed & Energy: A socio-political analysis of technologies of longer distance cycling

      Cox, Peter; orcid: 0000-0003-2374-3125 (University of Westminster Press, 2021-10-07)
      The basic laws of motion governing cycling are wellunderstood. Consideration of the variables of energy use in cycle travel areless frequent. The potentials of both aerodynamically efficient cycle designand the augmentation of human power with e-motors dramatically reconfigure whatwe understand as a cycle and as cycling. The prospect of increasing travel distance in regularjourneying, coupled with the logical application of augmentation (aerodynamicand/ or power), suggest a need to re-evaluate some of the ground expectationsapplied in design and planning for cycle travel if the cycles being designedfor do not fit the existing expectations of what a cycle is and how itperforms. Current e-bike performance is limited principally bynormative legislative intervention, not by the intrinsic potential of thetechnologies. Existing decisions as to what an e-bike can (and should) be, areshaped by the performance expectations of late 19th and early 20thcentury bicycle designs. Shaping modal shift for longer trips returns us tothink about the place of cycling travel time as a function of the relationshipbetween distance and speed. Increased speed allows for greater distance withouttime penalty. However, speed is itself governed by available energy, coupledwith the efficiency of use of that energy. Without entirely substituting humanpower, E-motors allow us to augment the human power available in differentways; Changes in cycle design (as us, for example, in velomobiles) allow us toincrease the efficiency of use of available power in overcoming resistance tomovementIdentifying the assemblage of cycle/cyclist as avariable, rather than a determinate object to be accommodated, raises difficultquestions for cycling provision, especially in relation to longer distancetravel.This paper takes an approach rooted in Actor NetworkTheory and developed through social practice analysis to explore theinteractions of people machines and spaces for longer distance travel. It paysparticular attention to the capacities and affordances of each of theseelements, especially in their interaction. Drawing on the capacities of already existingtechnologies of cycling and e-cycling, the paper focuses on the socialimplications of potentially problematic interactions. It argues that newdecisions will need to be made in regard to speed and distance in cycle traveland that the forging of regulations consequent on those fundamentals&amp;nbsp; will substantially shape the potentials andpossibilities of modal shift for longer distance cycle travel. What emerges isa politics of longer distance cycle, not simply a set of technical barriers andproblems.
    • Effect of Different Root Canal Irrigant Solutions on the Release of Dentin-Growth Factors: A Systematic Review and Meta-Analysis

      Tavares, Sandro; orcid: 0000-0003-4890-4220; email: sandro.tavares04@gmail.com; Pintor, Andrea; email: andrea_pintor@hotmail.com; Mourão, Carlos Fernando de Almeida Barros; orcid: 0000-0001-5775-0222; email: mouraocf@gmail.com; Magno, Marcela; email: marcela.magno@hotmail.com; Montemezzi, Pietro; email: m.montemezzi@libero.it; Sacco, Roberto; email: roberto.sacco@manchester.ac.uk; Alves, Gutemberg; orcid: 0000-0003-0016-4809; email: gutopepe@yahoo.com.br; Scelza, Miriam Zaccaro; orcid: 0000-0002-2132-4755; email: scelza@terra.com.br (MDPI, 2021-10-05)
      Irrigant solutions are used to promote dentin-growth factors (GF) release for regenerative endodontics. This review aimed to evaluate the reports comparing the release of GFs using different root canal irrigant solutions. Eligible studies compared the in vitro GF release in human teeth after the use of at least two distinct solutions. A search was conducted on Pubmed, Scopus, Web of Science, and Lilacs on 11 August 2021. Risk of bias was assessed using SciRAP. Study characteristics and quantitative data were extracted, and meta-analyses were performed for the mean difference (95% confidence interval) of the release of transforming growth factors Beta 1 (TGF-β1) by EDTA compared to other irrigants. Of sixteen eligible studies, eight were included in quantitative analysis. ELISA assays showed higher TGF-β1 release from 10% EDTA compared to 10% citric acid (p 0.00001). Immunogold assays showed higher levels of TGF-β1 for 17% EDTA (p 0.00001) compared to 10% citric acid. GRADE identified a low to very low certainty of evidence. These results point to an increased release of TGF-β1 in dentin treated with EDTA. The high heterogeneity and very low certainty of the evidence demand further studies before EDTA indication as a better irrigant for regenerative endodontics. Registration: CRD42020160871 (PROSPERO).