Now showing items 1-20 of 7312

    • 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.]
    • Slow magnetic relaxation in distorted tetrahedral Dy(III) aryloxide complexes.

      Parmar, Vijay S; orcid: 0000-0002-7133-5532; Gransbury, Gemma K; orcid: 0000-0002-7579-4226; Whitehead, George F S; orcid: 0000-0003-1949-4250; Mills, David P; orcid: 0000-0003-1575-7754; Winpenny, Richard E P; orcid: 0000-0002-7101-3963 (2021-09-14)
      Three distorted tetrahedral Dy(III) aryloxide complexes, [Na(THF) ][Dy(OAr ) Cl ] (1) (OAr = OC H Adamantyl -2,6- Bu-4) and [Na(THF) ][Dy(OMes*) X] (X = Cl, 2; BH , 3), (OMes* = OC H Bu -2,4,6) exhibit easy axis magnetic anisotropy and slow magnetic relaxation at zero field, with relaxation rates 1 < 2 < 3.
    • Radical hydroxymethylation of alkyl iodides using formaldehyde as a C1 synthon.

      Caiger, Lewis; orcid: 0000-0001-5156-9684; Sinton, Conar; orcid: 0000-0002-5588-7548; Constantin, Timothée; orcid: 0000-0001-5376-1557; Douglas, James J; Sheikh, Nadeem S; Juliá, Fabio; orcid: 0000-0001-8903-4482; Leonori, Daniele; orcid: 0000-0002-7692-4504 (2021-07-06)
      Radical hydroxymethylation using formaldehyde as a C1 synthon is challenging due to the reversible and endothermic nature of the addition process. Here we report a strategy that couples alkyl iodide building blocks with formaldehyde through the use of photocatalysis and a phosphine additive. Halogen-atom transfer (XAT) from α-aminoalkyl radicals is leveraged to convert the iodide into the corresponding open-shell species, while its following addition to formaldehyde is rendered irreversible by trapping the transient O-radical with PPh<sub>3</sub>. This event delivers a phosphoranyl radical that re-generates the alkyl radical and provides the hydroxymethylated product.
    • Publication outperformance among global South researchers: An analysis of individual-level and publication-level predictors of positive deviance

      Albanna, Basma; orcid: 0000-0002-6884-1610; email: basma.albanna@manchester.ac.uk; Handl, Julia; Heeks, Richard (Springer International Publishing, 2021-09-13)
      Abstract: Research and development are central to economic growth, and a key challenge for countries of the global South is that their research performance lags behind that of the global North. Yet, among Southern researchers, a few significantly outperform their peers and can be styled research “positive deviants” (PDs). In this paper we ask: who are those PDs, what are their characteristics and how are they able to overcome some of the challenges facing researchers in the global South? We examined a sample of 203 information systems researchers in Egypt who were classified into PDs and non-PDs (NPDs) through an analysis of their publication and citation data. Based on six citation metrics, we were able to identify and group 26 PDs. We then analysed their attributes, attitudes, practices, and publications using a mixed-methods approach involving interviews, a survey and analysis of publication-related datasets. Two predictive models were developed using partial least squares regression; the first predicted if a researcher is a PD or not using individual-level predictors and the second predicted if a paper is a paper of a PD or not using publication-level predictors. PDs represented 13% of the researchers but produced about half of all publications, and had almost double the citations of the overall NPD group. At the individual level, there were significant differences between both groups with regard to research collaborations, capacity development, and research directions. At the publication level, there were differences relating to the topics pursued, publication outlets targeted, and paper features such as length of abstract and number of authors.
    • Methods for quantifying methane emissions using unmanned aerial vehicles: a review

      Shaw, Jacob T.; orcid: 0000-0003-3558-3894; email: jacob.shaw@manchester.ac.uk; Shah, Adil; orcid: 0000-0002-5692-3715; Yong, Han; Allen, Grant; orcid: 0000-0002-7070-3620; email: grant.allen@manchester.ac.uk (The Royal Society, 2021-09-27)
      Methane is an important greenhouse gas, emissions of which have vital consequences for global climate change. Understanding and quantifying the sources (and sinks) of atmospheric methane is integral for climate change mitigation and emission reduction strategies, such as those outlined in the 2015 UN Paris Agreement on Climate Change. There are ongoing international efforts to constrain the global methane budget, using a wide variety of measurement platforms across a range of spatial and temporal scales. The advancements in unmanned aerial vehicle (UAV) technology over the past decade have opened up a new avenue for methane emission quantification. UAVs can be uniquely equipped to monitor natural and anthropogenic emissions at local scales, displaying clear advantages in versatility and manoeuvrability relative to other platforms. Their use is not without challenge, however: further miniaturization of high-performance methane instrumentation is needed to fully use the benefits UAVs afford. Developments in the models used to simulate atmospheric transport and dispersion across small, local scales are also crucial to improved flux accuracy and precision. This paper aims to provide an overview of currently available UAV-based technologies and sampling methodologies which can be used to quantify methane emission fluxes at local scales. This article is part of a discussion meeting issue 'Rising methane: is warming feeding warming? (part 1)'.
    • Developmentally appropriate transitional care during the Covid-19 pandemic for young people with juvenile-onset rheumatic and musculoskeletal diseases: the rationale for a position statement.

      McDonagh, Janet E; orcid: 0000-0002-4555-7270; email: janet.mcdonagh@manchester.ac.uk; Tattersall, Rachel; Clinch, Jacqui; Swan, Joanne; Foster, Helen E; McCann, Liza (2021-08-25)
      <h4>Background</h4>The importance of developmentally appropriate transitional care in young people with juvenile-onset rheumatic and musculoskeletal disease is well recognised. The Paediatric Rheumatology European Society (PReS) / European League Against Rheumatism (EULAR) Taskforce has developed international recommendations and standards for transitional care and a growing evidence base supports the positive benefits of such care. However, there is also evidence that universal implementation has yet to be realised. In 2020, against this background the COVID-19 pandemic arrived with significant impact on all our lives, young and old, patient, public and professional alike. The unfortunate reality of the pandemic with potential for unfavourable outcomes on healthcare provision during transition was acknowledged by the PReS working groups in a position statement to support healthcare professionals, young people and their caregivers.<h4>Aim</h4>The aim of this review is to present the literature which provides the rationale for the recommendations in the PReS Position Statement. The following areas are specifically addressed: the prime importance of care coordination; the impact of the pandemic on the various aspects of the transition process; the importance of ensuring continuity of medication supply; the pros and cons of telemedicine with young people; ensuring meaningful involvement of young people in service development and the importance of core adolescent health practices such as routine developmental assessment psychosocial screening and appropriate parental involvement during transitional care.
    • Accuracy of emergency medical services (EMS) telephone triage in identifying acute coronary syndrome (ACS) for patients with chest pain: a systematic literature review.

      Alotaibi, Ahmed; orcid: 0000-0002-6465-2687; email: ahmed.alotaibi@postgrad.manchester.ac.uk; Alghamdi, Abdulrhman; Reynard, Charles; orcid: 0000-0002-7534-2668; Body, Richard (2021-08-25)
      <h4>Objective</h4>To systematically appraise the available evidence to determine the accuracy of decision aids for emergency medical services (EMS) telephone triage of patients with chest pain suspected to be caused by acute coronary syndrome (ACS) or life-threatening conditions.<h4>Design</h4>Systematic review.<h4>Data sources</h4>Electronic searches were performed in Embase 1974, Medline 1946 and CINAHL 1937 databases from 3 March 2020 to 4 March 2020.<h4>Eligibility criteria</h4>The review included all types of original studies that included adult patients (>18 years) who called EMS with a primary complaint of chest pain and evaluated dispatch triage priority by telephone. Outcomes of interest were a final diagnosis of ACS, acute myocardial infarction or other life-threatening conditions.<h4>Data extraction and synthesis</h4>Two authors independently extracted data on study design, population, study period, outcome and all data for assessment of accuracy, including cross-tabulation of triage priority against the outcomes of interest. Risk of bias was assessed using the Quality Assessment of Diagnostic Accuracy Studies 2 assessment tool.<h4>Results</h4>Searches identified 553 papers, of which 3 were eligible for inclusion. Those reports described the evaluation of three different prediction models with variation in the variables used to detect ACS. The overall results showed that dispatch triage tools have good sensitivity to detect ACS and life-threatening conditions, even though they are used to triage signs and symptoms rather than diagnosing the patients. On the other hand, prediction models were built to detect ACS and life-threatening conditions, and therefore, prediction models showed better sensitivity and negative predictive value than dispatch triage tools.<h4>Conclusion</h4>We have identified three prediction models for telephone triage of patients with chest pain. While they have been found to have greater accuracy than standard EMS dispatch systems, prospective external validation is essential before clinical use is considered.<h4>Prospero registration number</h4>This systematic review was pre-registered on the International prospective register of systematic reviews (PROSPERO) database (reference CRD42020171184).
    • Role of emotional intelligence in effective nurse leadership.

      Lambert, Steve (2021-09-13)
      Emotionally intelligent leaders demonstrate a sensitivity to their own and other people's psychological health and well-being, directing others towards common goals while developing effective personal relationships with their colleagues and team members. Emotional intelligence is particularly relevant in the context of the coronavirus disease 2019 pandemic, where nurse leaders need to demonstrate this skill when supporting their teams to manage high levels of stress, exhaustion and the risk of moral injury. This article explores emotional intelligence, discusses its importance as a characteristic of effective nurse leaders and managers, and suggests practical activities that leaders can undertake to develop their emotional intelligence skills. [Abstract copyright: © 2021 RCN Publishing Company Ltd. All rights reserved. Not to be copied, transmitted or recorded in any way, in whole or part, without prior permission of the publishers.]
    • A Novel Ship Collision Avoidance Awareness Approach for Cooperating Ships Using Multi-Agent Deep Reinforcement Learning

      Chen, Chen; orcid: 0000-0003-1064-4961; email: chenchen0120@wit.edu.cn; Ma, Feng; orcid: 0000-0002-1357-3006; email: martin7wind@whut.edu.cn; Xu, Xiaobin; email: xuxiaobin1980@hdu.edu.cn; Chen, Yuwang; orcid: 0000-0002-2007-1821; email: Yu-wang.Chen@manchester.ac.uk; Wang, Jin; email: J.Wang@ljmu.ac.uk (MDPI, 2021-09-25)
      Ships are special machineries with large inertias and relatively weak driving forces. Simulating the manual operations of manipulating ships with artificial intelligence (AI) and machine learning techniques becomes more and more common, in which avoiding collisions in crowded waters may be the most challenging task. This research proposes a cooperative collision avoidance approach for multiple ships using a multi-agent deep reinforcement learning (MADRL) algorithm. Specifically, each ship is modeled as an individual agent, controlled by a Deep Q-Network (DQN) method and described by a dedicated ship motion model. Each agent observes the state of itself and other ships as well as the surrounding environment. Then, agents analyze the navigation situation and make motion decisions accordingly. In particular, specific reward function schemas are designed to simulate the degree of cooperation among agents. According to the International Regulations for Preventing Collisions at Sea (COLREGs), three typical scenarios of simulation, which are head-on, overtaking and crossing, are established to validate the proposed approach. With sufficient training of MADRL, the ship agents were capable of avoiding collisions through cooperation in narrow crowded waters. This method provides new insights for bionic modeling of ship operations, which is of important theoretical and practical significance.
    • Uncertainty, Anxiety and Isolation: Experiencing the COVID-19 Pandemic and Lockdown as a Woman with Polycystic Ovary Syndrome (PCOS)

      Atkinson, Lou; email: l.atkinson1@aston.ac.uk; Kite, Chris; orcid: 0000-0003-1342-274X; email: c.kite@chester.ac.uk; McGregor, Gordon; orcid: 0000-0001-8963-9107; email: ac4378@coventry.ac.uk; James, Tamsin; email: jamestno@aston.ac.uk; Clark, Cain C. T.; orcid: 0000-0002-6610-4617; email: ad0183@coventry.ac.uk; Randeva, Harpal S.; email: harpal.randeva@uhcw.nhs.uk; Kyrou, Ioannis; email: ad6702@coventry.ac.uk (MDPI, 2021-09-25)
      Background: The COVID-19 pandemic and the related lockdown measures presented a significant risk to physical and mental wellbeing in affected populations. Women with polycystic ovary syndrome (PCOS) are predisposed to several cardio-metabolic risk factors which increase the susceptibility to severe COVID-19 and also exhibit increased likelihood of impaired mental health wellbeing. Therefore, these women who usually receive care from multiple primary and specialist healthcare services may be disproportionately impacted by this pandemic and the related restrictions. This study aimed to explore the lived experience of the first UK national lockdown as a woman with PCOS. Methods: As part of a larger cross-sectional study, 12 women with PCOS living in the UK during the first national COVID-19 lockdown were recruited to a qualitative study. Telephone interviews were conducted in June/July of 2020, and data collected were subjected to thematic analysis. Results: Five themes were identified. “My PCOS Journey” describes participants’ experiences of diagnosis, treatment and ongoing management of their PCOS. “Living Through Lockdown” describes the overall experience and impact of the lockdown on all aspects of participants’ lives. “Self-care and Managing Symptoms” describe multiple challenges to living well with PCOS during the lockdown, including lack of access to supplies and services, and disruption to weight management. “Healthcare on Hold” describes the uncertainty and anxiety associated with delays in accessing specialised healthcare for a range of PCOS aspects, including fertility treatment. “Exacerbating Existing Issues” captures the worsening of pre-existing mental health issues, and an increase in health anxiety and feelings of isolation. Conclusion: For the women with PCOS in this study, the COVID-19 pandemic and the first national lockdown was mostly experienced as adding to the pre-existing challenges of living with their condition. The mental health impact experienced by the study participants was increased due to lack of access to their normal support strategies, limitations on healthcare services and uncertainty about their risk of COVID-19.
    • Facilitators of probation-based domestic violence perpetrator programmes: ‘Who’s in the room?’

      Renehan, Nicole; orcid: 0000-0002-5674-7539; email: nicole.renehan@manchester.ac.uk (SAGE Publications, 2021-06-22)
      The role that probation practitioners play in the desistance process has begun to receive much needed attention. Yet, the experiences of facilitators of probation-based, domestic violence perpetrator programmes have long been neglected. This article explores the experiences and wellbeing of eight facilitators from one cohort of the Building Better Relationships (BBR) programme in England. Drawing upon five-months’ observations and in-depth interviews, I demonstrate how working with domestically violent men with insufficient knowledge, experience, or support, exacerbated within the context of Transforming Rehabilitation reforms, impacted significantly on facilitator well-being, professional identities, and practice. Practice implications are discussed.
    • Sporting celebrity and conspicuous consumption: A case study of professional footballers in England

      Law, Graeme; orcid: 0000-0001-5047-6208; email: g.law@yorksj.ac.uk; Bloyce, Daniel; orcid: 0000-0003-4114-3588; Waddington, Ivan (SAGE Publications, 2020-11-01)
      Association football is a lucrative sport with high financial rewards for top players. However, there has been little empirical work on the lifestyles of professional footballers. Based on interviews with 29 current and former male professional footballers, this paper examines the relationship between money, status and image management within and outside the changing room. The concept of conspicuous consumption is used to help explain players’ attitudes to money, their relationships with others within the football environment and how they advertise their earnings in an environment where open discussion of wages is seen as taboo. Our findings suggest that professional footballers are expected to display a particular image of the professional footballer and this constrains players, even those on lower incomes, to buy expensive clothes and accessories in order to be accepted by others. Players who do not conform to the expected image may be subject to sanctions by their teammates.
    • EVI1 oncoprotein expression and CtBP1-association oscillate through the cell cycle

      Paredes, Roberto; Schneider, Marion; Pearson, Stella; Teng, Hsiang Yin; Kelly, James R.; Pierce, Andrew; Somervaille, Tim C. P.; Whetton, Anthony D.; Meyer, Stefan; orcid: 0000-0002-2283-3690; email: stefan.meyer@manchester.ac.uk (Springer Netherlands, 2020-09-26)
      Abstract: Aberrantly high expression of EVI1 in acute myeloid leukaemia (AML) is associated with poor prognosis. For targeted treatment of EVI1 overexpressing AML a more detailed understanding of aspects of spatiotemporal interaction dynamics of the EVI1 protein is important. EVI1 overexpressing SB1690CB AML cells were used for quantification and protein interaction studies of EVI1 and ΔEVI1. Cells were cell cycle-synchronised by mimosine and nocodazole treatment and expression of EVI1 and related proteins assessed by western blot, immunoprecipitation and immunofluorescence. EVI1 protein levels oscillate through the cell cycle, and EVI1 is degraded partly by the proteasome complex. Both EVI1 and ΔEVI1 interact with the co-repressor CtBP1 but dissociate from CtBP1 complexes during mitosis. Furthermore, a large fraction of EVI1, but not ΔEVI1 or CtBP1, resides in the nuclear matrix. In conclusion, EVI1- protein levels and EVI1-CtBP1 interaction dynamics vary though the cell cycle and differ between EVI1 and ΔEVI1. These data ad to the functional characterisation of the EVI1 protein in AML and will be important for the development of targeted therapeutic approaches for EVI1-driven AML.
    • The Effects of Midline Cerebellar rTMS on Human Pharyngeal Cortical Activity in the Intact Swallowing Motor System

      Sasegbon, Ayodele; orcid: 0000-0003-2050-0726; email: ayodele.sasegbon@manchester.ac.uk; Niziolek, Nikola; Zhang, Mengqing; Smith, Craig J; Bath, Philip M; Rothwell, John; Hamdy, Shaheen (Springer US, 2020-09-26)
      Abstract: We sought to compare the effects of 10 Hz cerebellar vermis (vs. unilateral hemispheric and sham) repetitive transcranial magnetic stimulation (rTMS) on cortical neuroelectrical activity and thereafter 10 Hz cerebellar vermis (vs. sham) rTMS on swallowing behaviour. Healthy participants (n = 25) were randomly allocated to receive vermis, unilateral hemisphere or sham 10 Hz cerebellar rTMS. Recordings were made using pharyngeal electromyography and manometry catheters, obtaining motor-evoked potentials (MEPs) and pressure recordings. The amplitudes of MEPs elicited using single-pulse TMS delivered to the pharyngeal areas of the motor cortex bilaterally were measured pre- and post-cerebellar stimulation. As in previous studies, abductor policis brevis (APB) MEPs were measured to assess post-rTMS modulation specificity. Swallowing was assessed using a swallowing accuracy task. Measurements were made at baseline and 15-min intervals for an hour post-intervention. Measurements involved TMS being used to elicit 10 MEPs bilaterally over the pharyngeal areas of the motor cortex, over the APB cortical representation adjacent to the pharyngeal area with the lowest resting motor threshold and 5 MEPs bilaterally over pharyngeal areas of the cerebellar hemispheres. Swallowing accuracy was assessed by giving participants 10 attempts to swallow and hit a digital target. Cerebellar vermis rTMS caused significant suppression of cortical pharyngeal MEP amplitudes compared with unilateral rTMS and sham (P = 0.0005, 0.002). APB and cerebellar MEP amplitudes were unaffected as were pharyngeal and APB MEP latencies. Following cerebellar vermis rTMS there was a significant reduction in swallowing accuracy compared with sham (P = 0.001). Our findings demonstrate cerebellar vermis rTMS exerts a suppressive effect on pharyngeal motor cortical activity and swallowing behaviour.
    • HE4 as a Biomarker for Endometrial Cancer

      Behrouzi, Roya; email: rbehrouzi@doctors.org.uk; Barr, Chloe E.; email: Chloe.Barr@mft.nhs.uk; Crosbie, Emma J.; orcid: 0000-0003-0284-8630; email: Emma.Crosbie@manchester.ac.uk (MDPI, 2021-09-23)
      There are currently no blood biomarkers in routine clinical use in endometrial carcinoma (EC). Human epididymis protein 4 (HE4) is a glycoprotein that is overexpressed in the serum of patients with EC, making it a good candidate for use as a diagnostic and/or prognostic biomarker. HE4 is correlated with poor prognostic factors, including stage, myometrial invasion and lymph node metastases, which means it could be used to guide decisions regarding the extent of surgery and need for adjuvant therapy. Serum HE4 has also shown promise for predicting responses to progestin therapy in early-stage EC. The use of algorithms and indices incorporating serum HE4 and other biomarkers, including clinical and imaging variables, is an area of increasing interest. Serum HE4 levels rise with age and renal dysfunction, which may affect the interpretation of results. This review covers the evidence supporting the use of HE4 as an EC biomarker for diagnosis, prognosis, recurrence monitoring, and prediction of therapy response. The evidence for combining serum HE4 with other biomarkers, including clinical and imaging variables, its value as a biomarker in other biofluids and potential challenges of its clinical use are also discussed.
    • Benefits and harms of Risperidone and Paliperidone for treatment of patients with schizophrenia or bipolar disorder: a meta-analysis involving individual participant data and clinical study reports.

      Hodkinson, Alexander; orcid: 0000-0003-2063-0977; email: alexander.hodkinson@manchester.ac.uk; Heneghan, Carl; Mahtani, Kamal R; Kontopantelis, Evangelos; Panagioti, Maria (2021-08-25)
      <h4>Background</h4>Schizophrenia and bipolar disorder are severe mental illnesses which are highly prevalent worldwide. Risperidone and Paliperidone are treatments for either illnesses, but their efficacy compared to other antipsychotics and growing reports of hormonal imbalances continue to raise concerns. As existing evidence on both antipsychotics are solely based on aggregate data, we aimed to assess the benefits and harms of Risperidone and Paliperidone in the treatment of patients with schizophrenia or bipolar disorder, using individual participant data (IPD), clinical study reports (CSRs) and publicly available sources (journal publications and trial registries).<h4>Methods</h4>We searched MEDLINE, Central, EMBASE and PsycINFO until December 2020 for randomised placebo-controlled trials of Risperidone, Paliperidone or Paliperidone palmitate in patients with schizophrenia or bipolar disorder. We obtained IPD and CSRs from the Yale University Open Data Access project. The primary outcome Positive and Negative Syndrome Scale (PANSS) score was analysed using one-stage IPD meta-analysis. Random-effect meta-analysis of harm outcomes involved methods for coping with rare events. Effect-sizes were compared across all available data sources using the ratio of means or relative risk. We registered our review on PROSPERO, CRD42019140556.<h4>Results</h4>Of the 35 studies, IPD meta-analysis involving 22 (63%) studies showed a significant clinical reduction in the PANSS in patients receiving Risperidone (mean difference - 5.83, 95% CI - 10.79 to - 0.87, I<sup>2</sup> = 8.5%, n = 4 studies, 1131 participants), Paliperidone (- 6.01, 95% CI - 8.7 to - 3.32, I<sup>2</sup> = 4.3%, n = 13, 3821) and Paliperidone palmitate (- 7.89, 95% CI - 12.1 to - 3.69, I<sup>2</sup> = 2.9%, n = 5, 2209). CSRs reported nearly two times more adverse events (4434 vs. 2296 publication, relative difference (RD) = 1.93, 95% CI 1.86 to 2.00) and almost 8 times more serious adverse events (650 vs. 82; RD = 7.93, 95% CI 6.32 to 9.95) than the journal publications. Meta-analyses of individual harms from CSRs revealed a significant increased risk among several outcomes including extrapyramidal disorder, tardive dyskinesia and increased weight. But the ratio of relative risk between the different data sources was not significant. Three treatment-related gynecomastia events occurred, and these were considered mild to moderate in severity.<h4>Conclusion</h4>IPD meta-analysis conclude that Risperidone and Paliperidone antipsychotics had a small beneficial effect on reducing PANSS score over 9 weeks, which is more conservative than estimates from reviews based on journal publications. CSRs also contained significantly more data on harms that were unavailable in journal publications or trial registries. Sharing of IPD and CSRs are necessary when performing meta-analysis on the efficacy and safety of antipsychotics.