Genotypic determinants of fluoroquinolone and macrolide resistance in Neisseria gonorrhoeae.

Background:High rates of antimicrobial resistance (AMR) in Neisseria gonorrhoeae hinder effective treatment, but molecular AMR diagnostics may help address the challenge. This study aimed to appraise the literature for resistance-associated genotypic markers linked to fluoroquinolones and macrolides, to identify and review their use in diagnostics. Methods: Medline and EMBASE databases were searched and data pooled to evaluate associations between genotype and phenotypic resistance. The minimum inhibitory concentration (MIC) cut-offs were ≤ 0.06 mg L-1 for non-resistance to ciprofloxacin and ≤ 0.5 mg L-1 for non-resistance to azithromycin. Results: Diagnostic accuracy estimates were limited by data availability and reporting. It was found that: 1) S91 and D95 mutations in the GyrA protein independently predicted ciprofloxacin resistance and, used together, gave 98.6% (95% confidence interval (CI) 98.0-99.0%) sensitivity and 91.4% (95%CI 88.6-93.7%) specificity; 2) the number of 23S rRNA gene alleles with C2611T or A2059G mutations was highly correlated with azithromycin resistance, with mutation in any allele giving a sensitivity and specificity of 66.1% (95%CI 62.1-70.0%) and 98.9% (95%CI 97.5-99.5%) respectively. Estimated negative (NPV) and positive predictive values (PPV) for a 23S rRNA diagnostic were 98.6% (95%CI 96.8-99.4%) and 71.5% (95%CI 68.0-74.8%) respectively; 3) mutation at amino acid position G45 in the MtrR protein independently predicted azithromycin resistance; however, when combined with 23S rRNA, did not improve the PPV or NPV. Conclusions: Viable candidates for markers of resistance detection for incorporation into diagnostics were demonstrated. Such tests may enhance antibiotic stewardship and treatment options

Contrasting inducible knockdown of the auxiliary PTEX component PTEX88 in P. falciparum and P. berghei unmasks a role in parasite virulence

Pathogenesis of malaria infections is linked to remodeling of erythrocytes, a process dependent on the trafficking of hundreds of parasite-derived proteins into the host erythrocyte. Recent studies have demonstrated that the Plasmodium translocon of exported proteins (PTEX) serves as the central gateway for trafficking of these proteins, as inducible knockdown of the core PTEX constituents blocked the trafficking of all classes of cargo into the erythrocyte. However, the role of the auxiliary component PTEX88 in protein export remains less clear. Here we have used inducible knockdown technologies in P. falciparum and P. berghei to assess the role of PTEX88 in parasite development and protein export, which reveal that the in vivo growth of PTEX88-deficient parasites is hindered. Interestingly, we were unable to link this observation to a general defect in export of a variety of known parasite proteins, suggesting that PTEX88 functions in a different fashion to the core PTEX components. Strikingly, PTEX88-deficient P. berghei were incapable of causing cerebral malaria despite a robust pro-inflammatory response from the host. These parasites also exhibited a reduced ability to sequester in peripheral tissues and were removed more readily from the circulation by the spleen. In keeping with these findings, PTEX88-deficient P. falciparum-infected erythrocytes displayed reduced binding to the endothelial cell receptor, CD36. This suggests that PTEX88 likely plays a specific direct or indirect role in mediating parasite sequestration rather than making a universal contribution to the trafficking of all exported proteins

The current understanding of precision medicine and personalised medicine in selected research disciplines:study protocol of a systematic concept analysis

INTRODUCTION: The terms ‘precision medicine’ and ‘personalised medicine’ have become key terms in health-related research and in science-related public communication. However, the application of these two concepts and their interpretation in various disciplines are heterogeneous, which also affects research translation and public awareness. This leads to confusion regarding the use and distinction of the two concepts. Our aim is to provide a snapshot of the current understanding of these concepts. METHODS AND ANALYSIS: Our study will use Rodgers’ evolutionary concept analysis to systematically examine the current understanding of the concepts ‘precision medicine’ and ‘personalised medicine’ in clinical medicine, biomedicine (incorporating genomics and bioinformatics), health services research, physics, chemistry, engineering, machine learning and artificial intelligence, and to identify their respective attributes (clusters of characteristics) and surrogate and related terms. A systematic search of the literature will be conducted for 2016–2022 using databases relevant to each of these disciplines: ACM Digital Library, CINAHL, Cochrane Library, F1000Research, IEEE Xplore, PubMed/Medline, Science Direct, Scopus and Web of Science. These are among the most representative databases for the included disciplines. We will examine similarities and differences in definitions of ‘precision medicine’ and ‘personalised medicine’ in the respective disciplines and across (sub)disciplines, including attributes of each term. This will enable us to determine how these two concepts are distinguished. ETHICS AND DISSEMINATION: Following ethical and research standards, we will comprehensively report the methodology for a systematic analysis following Rodgers’ concept analysis method. Our systematic concept analysis will contribute to the clarification of the two concepts and distinction in their application in given settings and circumstances. Such a broad concept analysis will contribute to non-systematic syntheses of the concepts, or occasional systematic reviews on one of the concepts that have been published in specific disciplines, in order to facilitate interdisciplinary communication, translational medical research and implementation science

Transforming training into practice with the conflict management framework: a mixed methods study

Objective To implement and evaluate the use of the conflict management framework (CMF) in four tertiary UK paediatric services. Design Mixed methods multisite evaluation including prospective pre and post intervention collection of conflict data alongside semistructured interviews. Setting Eight inpatient or day care wards across four tertiary UK paediatric services. Interventions The two-stage CMF was used in daily huddles to prompt the recognition and management of conflict. Results Conflicts were recorded for a total of 67 weeks before and 141 weeks after implementation of the CMF across the four sites. 1000 episodes of conflict involving 324 patients/families across the four sites were recorded. After implementation of the CMF, time spent managing episodes of conflict around the care of a patient was decreased by 24% (p < 0.001) (from 73 min to 55 min) and the estimated cost of this staff time decreased by 20% (p < 0.02) (from £26 to £21 sterling per episode of conflict). This reduction occurred despite conflict episodes after implementation of the CMF having similar severity to those before implementation. Semistructured interviews highlighted the importance of broad multidisciplinary leadership and training to embed a culture of proactive and collaborative conflict management. Conclusions The CMF offers an effective adjunct to conflict management training, reducing time spent managing conflict and the associated staff costs

An exported protein-interacting complex involved in the trafficking of virulence determinants in Plasmodium-infected erythrocytes

The malaria parasite, Plasmodium falciparum, displays the P. falciparum erythrocyte membrane protein 1 (PfEMP1) on the surface of infected red blood cells (RBCs). We here examine the physical organization of PfEMP1 trafficking intermediates in infected RBCs and determine interacting partners using an epitope-tagged minimal construct (PfEMP1B). We show that parasitophorous vacuole (PV)-located PfEMP1B interacts with components of the PTEX (Plasmodium Translocon of EXported proteins) as well as a novel protein complex, EPIC (Exported Protein-Interacting Complex). Within the RBC cytoplasm PfEMP1B interacts with components of the Maurer\u27s clefts and the RBC chaperonin complex. We define the EPIC interactome and, using an inducible knockdown approach, show that depletion of one of its components, the parasitophorous vacuolar protein-1 (PV1), results in altered knob morphology, reduced cell rigidity and decreased binding to CD36. Accordingly, we show that deletion of the Plasmodium berghei homologue of PV1 is associated with attenuation of parasite virulence in vivo

Search for dark matter produced in association with bottom or top quarks in √s = 13 TeV pp collisions with the ATLAS detector

A search for weakly interacting massive particle dark matter produced in association with bottom or top quarks is presented. Final states containing third-generation quarks and miss- ing transverse momentum are considered. The analysis uses 36.1 fb−1 of proton–proton collision data recorded by the ATLAS experiment at √s = 13 TeV in 2015 and 2016. No significant excess of events above the estimated backgrounds is observed. The results are in- terpreted in the framework of simplified models of spin-0 dark-matter mediators. For colour- neutral spin-0 mediators produced in association with top quarks and decaying into a pair of dark-matter particles, mediator masses below 50 GeV are excluded assuming a dark-matter candidate mass of 1 GeV and unitary couplings. For scalar and pseudoscalar mediators produced in association with bottom quarks, the search sets limits on the production cross- section of 300 times the predicted rate for mediators with masses between 10 and 50 GeV and assuming a dark-matter mass of 1 GeV and unitary coupling. Constraints on colour- charged scalar simplified models are also presented. Assuming a dark-matter particle mass of 35 GeV, mediator particles with mass below 1.1 TeV are excluded for couplings yielding a dark-matter relic density consistent with measurements

Future Experiences: Sustainable Development and the Global South

The Sustainable Development and the Global South project was jointly conceived by the Innovation School at Glasgow School of Art in partnership with the Sustainable Futures in Africa Network (SFA), and the University of Glasgow. Graduating final year BDes Product Design students from the Innovation School were presented with a challenge-based project to produce a vision of the future based on current trends that relate to Sustainable Development work and the Global South. This project involved working closely with researchers, academics and professionals specialising in human geography, education, health, environment, engineering, cultural practice and community engagement who are part of the Sustainable Futures in Africa Network which includes a Scottish hub, led from the University of Glasgow. Included in the network was a representative from an NGO that builds schools in Malawi, an entrepreneur who runs an ethical clothing company that partners with producers in the Global South, a senior governance officer from the UK Government’s Department for International Development (DFID), a research network administrator, and international graduate students from Africa based at Scottish institutions. In addition to the SFA, external experts from design studio AndThen and GOODD design consultancy were engaged. The objective of this project was to investigate, in both analytical and speculative ways, future forms and functions of Sustainable Development work in relation to the Global South in ten years from now, to develop future scenarios and design the artefacts, services and the experiences associated with these future visions. On completion of the project and learning experience it was intended that the students would be able to recognise and articulate the impact and sustainability of their design propositions, consider the life-cycle of their proposals and the values these might create for the intended users, communities and contexts. The project was completed in January 2020, as the Covid-19 pandemic was just beginning its spread around the world. This unprecedented catastrophe reinforced the importance of supporting those most in need – the citizens of developing regions in the Global South. In April 2020, the heads of all the UN’s major agencies issued an open letter warning of the risks the virus posed to the world’s most vulnerable countries. It called on wealthier nations to increase funding and help to tackle issues such as the cessation of aid as a result of cancelled flights and disrupted supply routes. These and many other concerns highlighted during the crisis are among the topics explored in this project, which feels even more relevant and urgent than when it was initiated in the summer of 2019. One of the most significant societal shifts currently taking place within the field of sustainable development work is its transformation from being understood as a process of growth or, at its most benign, poverty alleviation, to one of community empowerment and civic participation. The public’s role is developing beyond once-passive community members and recipients of aid, into stakeholders valued for their local knowledge, lived experiences, participation in development projects, and contribution towards policy-making and decision-making. This new dynamic is changing the traditional North-South relationship and holds the potential to challenge the geopolitical hegemony of International Development. The impetus for this shift is a decolonial, collaborative approach to development, research and practice; increased local empowerment, and sustainable solutions to problems that are co-created in context with those affected by and affecting the issue in question. This project asked students to consider what happens in this global landscape ten years from now where Sustainable Development has evolved to the extent that new forms of work and communities of practice transform how people engage, learn and interact with each other, with stakeholders and with the global community around them. The brief gave students the opportunity to explore the underlying complexities regarding sustainable futures, the post-colonial dynamic between ‘norths’ and ‘souths’, post-capitalism and human agency, to envision a future world context, develop it as an experiential exhibit, and produce the designed products, services and experiences for the people who might live and work within it. The project was divided into two sections: The first was a collaborative stage where groups of students were assigned a specific domain to collectively research one aspect of the project challenge, these domains included; Health, Energy, Mobility, Economies, Education, Societal Structures and Environment. Each of these domains were examined through the lenses of Social, Technological, Economic, Ethical, Educational, Values, Political, Legal and Ecological (STEEEVPLE) and were tailored in use, as appropriate per domain. The groups focused on researching and exploring their specific domain and gathering as much information and understanding while working with the external experts to further their knowledge. This group stage culminated in a series of Future World exhibits which tangibly manifest the cohort’s collective knowledge and collaborative understanding of what the future could look like in 10 years from now, after exploring the possible consequences of current actions. The second stage saw students explore their individual response to the Future World that had been created in the first stage. Each student developed their own response to the research by iteratively creating a design outcome that was appropriate to the subject matter. This culminated in each student producing a designed product, service or system and a visual communication of the future experience which they had created. A visual summary of the journey and stages (Project Journey Map) is included within the repository and outlines the collaborative process of designing and the innovative nature of the project’s pedagogical model. The project aims to reveal and address the emerging possibilities collaboratively created by Sustainable Development professionals and designers interacting and learning from each other, to present preferable futures which reveal socio-ecological innovations in development work with the Global South in the near future. The deposited materials are arranged as follows: Readme files - two readme files relate to stage one and stage two of the project as outlined above. Project Journey Map - gives a visual overview of the pedagogical structure and timeline of the project. Data folders - the data folders for stage one of the project are named by the domains through which each group explored possible futures. The data folders for stage two of the project are named for the individual students who conducted the work