Can mixed reality technologies teach surgical skills better than traditional methods? A prospective randomised feasibility study

Background Basic surgical skills teaching is often delivered with didactic audio-visual content, and new digital technologies may allow more engaging and effective ways of teaching to be developed. The Microsoft HoloLens 2 (HL2) is a multi-functional mixed reality headset. This prospective feasibility study sought to assess the device as a tool for enhancing technical surgical skills training. Methods A prospective randomised feasibility study was conducted. 36 novice medical students were trained to perform a basic arteriotomy and closure using a synthetic model. Participants were randomised to receive a structured surgical skills tutorial via a bespoke mixed reality HL2 tutorial (n = 18), or via a standard video-based tutorial (n = 18). Proficiency scores were assessed by blinded examiners using a validated objective scoring system and participant feedback collected. Results The HL2 group showed significantly greater improvement in overall technical proficiency compared to the video group (10.1 vs. 6.89, p = 0.0076), and a greater consistency in skill progression with a significantly narrower range of scores (SD 2.48 vs. 4.03, p = 0.026). Participant feedback showed the HL2 technology to be more interactive and engaging with minimal device related problems experienced. Conclusions This study has demonstrated that mixed reality technology may provide a higher quality educational experience, improved skill progression and greater consistency in learning when compared to traditional teaching methodologies for basic surgical skills. Further work is required to refine, translate, and evaluate the scalability and applicability of the technology across a broad range of skills-based disciplines

The use of mixed reality technology for the objective assessment of clinical skills: a validation study

Background Mixed Reality technology may provide many advantages over traditional teaching methods. Despite its potential, the technology has yet to be used for the formal assessment of clinical competency. This study sought to collect validity evidence and assess the feasibility of using the HoloLens 2 mixed reality headset for the conduct and augmentation of Objective Structured Clinical Examinations (OSCEs). Methods A prospective cohort study was conducted to compare the assessment of undergraduate medical students undertaking OSCEs via HoloLens 2 live (HLL) and recorded (HLR), and gold-standard in-person (IP) methods. An augmented mixed reality scenario was also assessed. Results 13 undergraduate participants completed a total of 65 OSCE stations. Overall inter-modality correlation was 0.81 (p=0.01), 0.98 (p=0.01) and 0.82 (p=0.01) for IP vs. HLL, HLL vs. HLR and IP vs. HLR respectively. Skill based correlations for IP vs. HLR were assessed for history taking (0.82, p=0.01), clinical examination (0.81, p=0.01), procedural (0.88, p=0.01) and clinical skills (0.92, p=0.01), and assessment of a virtual mixed reality patient (0.74, p=0.01). The HoloLens device was deemed to be usable and practical (Standard Usability Scale (SUS) score = 51.5), and the technology was thought to deliver greater flexibility and convenience, and have the potential to expand and enhance assessment opportunities. Conclusions HoloLens 2 is comparable to traditional in-person examination of undergraduate medical students for both live and recorded assessments, and therefore is a valid and robust method for objectively assessing performance. The technology is in its infancy, and users need to develop confidence in its usability and reliability as an assessment tool. However, the potential to integrate additional functionality including holographic content, automated tracking and data analysis, and to facilitate remote assessment may allow the technology to enhance, expand and standardise examinations across a range of educational contexts

Loss of human Scribble cooperates with H-Ras to promote cell invasion through deregulation of MAPK signalling

Activating mutations in genes of the Ras-mitogen-activated protein kinase (MAPK) pathway occur in approximately 30% of all human cancers; however, mutation of Ras alone is rarely sufficient to induce tumour development. Scribble is a polarity regulator recently isolated from a Drosophila screen for events that cooperate with Ras mutation to promote tumour progression and cell invasion. In mammals, Scribble regulates directed cell migration and wound healing in vivo; however, no role has been identified for mammalian Scribble in oncogenic transformation. Here we show that in human epithelial cells expressing oncogenic Ras or Raf, loss of Scribble promotes invasion of cells through extracellular matrix in an organotypic culture system. Further, we show that the mechanism by which this occurs is in the regulation of MAPK signalling by Scribble. The suppression of MAPK signalling is a highly conserved function of Scribble as it also prevents Raf-mediated defects in Drosophila wing development. Our data identify Scribble as an important mediator of MAPK signalling and provide a molecular basis for the observation that Scribble expression is decreased in many invasive human cancers. © 2008 Macmillan Publishers Limited All rights reserved

Antimicrobial use in European acute care hospitals: results from the second point prevalence survey (PPS) of healthcare-associated infections and antimicrobial use, 2016 to 2017

Antimicrobial agents used to treat infections are life-saving. Overuse may result in more frequent adverse effects and emergence of multidrug-resistant microorganisms. In 2016-17, we performed the second point-prevalence survey (PPS) of healthcare-associated infections (HAIs) and antimicrobial use in European acute care hospitals. We included 1,209 hospitals and 310,755 patients in 28 of 31 European Union/European Economic Area (EU/EEA) countries. The weighted prevalence of antimicrobial use in the EU/EEA was 30.5% (95% CI: 29.2-31.9%). The most common indication for prescribing antimicrobials was treatment of a community-acquired infection, followed by treatment of HAI and surgical prophylaxis. Over half (54.2%) of antimicrobials for surgical prophylaxis were prescribed for more than 1 day. The most common infections treated by antimicrobials were respiratory tract infections and the most commonly prescribed antimicrobial agents were penicillins with beta-lactamase inhibitors. There was wide variation of patients on antimicrobials, in the selection of antimicrobial agents and in antimicrobial stewardship resources and activities across the participating countries. The results of the PPS provide detailed information on antimicrobial use in European acute care hospitals, enable comparisons between countries and hospitals, and highlight key areas for national and European action that will support efforts towards prudent use of antimicrobials

a pilot study, 2013

Introduction After recognition of European outbreaks of Clostridium difficile infections (CDIs) associated with the emergence of PCR ribotype 027/NAP1 in 2005, CDI surveillance at country level was encouraged by the European Centre for Disease Prevention and Control (ECDC) [1]. In 2008, an ECDC-supported European CDI survey (ECDIS) identified large intercountry variations in incidence rates and distribution of prevalent PCR ribotypes, with the outbreak-related PCR ribotype 027 being detected in 5% (range: 0–26) of the characterised isolates [2]. The surveillance period was limited to one month and the representation of European hospitals was incomplete; however, this has been the only European (comprising European Union (EU)/European Economic Area (EEA) and EU candidate countries) CDI surveillance study. The authors highlighted the need for national and European surveillance to control CDI. Yet, European countries were found to have limited capacity for diagnostic testing, particularly in terms of standard use of optimal methods and absence of surveillance protocols and a fully validated, standardised and exchangeable typing system for surveillance and/or outbreak investigation. As of 2011, 14 European countries had implemented national CDI surveillance, with various methodologies [3]. National surveillance systems have since reported a decrease in CDI incidence rate and/or prevalence of PCR ribotype 027 in some European countries [4-8]. However, CDI generally remains poorly controlled in Europe [9], and PCR ribotype 027 continues to spread in eastern Europe [10-12] and globally [13]. In 2010, ECDC launched a new project, the European C. difficile Infection Surveillance Network (ECDIS-Net), to enhance surveillance of CDI and laboratory capacity to test for CDI in Europe. The goal of ECDIS- Net was to establish a standardised CDI surveillance protocol suitable for application all over Europe in order to: (i) estimate the incidence rate and total infection rate of CDI (including recurrent CDI cases) in European acute care hospitals; (ii) provide participating hospitals with a standardised tool to measure and compare their own incidence rates with those observed in other participating hospitals; (iii) assess adverse outcomes of CDI such as complications and death; and (iv) describe the epidemiology of CDI concerning antibiotic susceptibility, PCR ribotypes, presence of tcdA, tcdB and binary toxins and detect new emerging types at local, national and European level. The primary objectives of the present study were to: (i) test the pilot protocol for the surveillance of CDI in European acute care hospitals developed by ECDIS-Net (methodology, variables and indicators); (ii) assess the feasibility and workload of collecting the required hospital data, case- based epidemiological and microbiological data; and (iii) evaluate the quality of data collected, whether in the presence or absence of existing national CDI surveillance activities. A secondary aim was to assess the relationship between patient and microbiological characteristics and in-hospital outcome of CDI to confirm the added value of collecting detailed epidemiological and microbiological data on CDI at European level

Standardised surveillance of Clostridium Difficile Infection in European acute care hospitals: A pilot study, 2013

Clostridium difficile infection (CDI) remains poorly controlled in many European countries, of which several have not yet implemented national CDI surveillance. In 2013, experts from the European CDI Surveillance Network project and from the European Centre for Disease Prevention and Control developed a protocol with three options of CDI surveillance for acute care hospitals: a ‘minimal’ option (aggregated hospital data), a ‘light’ option (including patient data for CDI cases) and an ‘enhanced’ option (including microbiological data on the first 10 CDI episodes per hospital). A total of 37 hospitals in 14 European countries tested these options for a three-month period (between 13 May and 1 November 2013). All 37 hospitals successfully completed the minimal surveillance option (for 1,152 patients). Clinical data were submitted for 94% (1,078/1,152) of the patients in the light option; information on CDI origin and outcome was complete for 94% (1,016/1,078) and 98% (294/300) of the patients in the light and enhanced options, respectively. The workload of the options was 1.1, 2.0 and 3.0 person-days per 10,000 hospital discharges, respectively. Enhanced surveillance was tested and was successful in 32 of the hospitals, showing that C. difficile PCR ribotype 027 was predominant (30% (79/267)). This study showed that standardised multicountry surveillance, with the option of integrating clinical and molecular data, is a feasible strategy for monitoring CDI in Europe

Genetic and immune landscape evolution in MMR-deficient colorectal cancer.

Mismatch repair-deficient (MMRd) colorectal cancers (CRCs) have high mutation burdens, which make these tumours immunogenic and many respond to immune checkpoint inhibitors. The MMRd hypermutator phenotype may also promote intratumour heterogeneity (ITH) and cancer evolution. We applied multiregion sequencing and CD8 and programmed death ligand 1 (PD-L1) immunostaining to systematically investigate ITH and how genetic and immune landscapes coevolve. All cases had high truncal mutation burdens. Despite pervasive ITH, driver aberrations showed a clear hierarchy. Those in WNT/β-catenin, mitogen-activated protein kinase, and TGF-β receptor family genes were almost always truncal. Immune evasion (IE) drivers, such as inactivation of genes involved in antigen presentation or IFN-γ signalling, were predominantly subclonal and showed parallel evolution. These IE drivers have been implicated in immune checkpoint inhibitor resistance or sensitivity. Clonality assessments are therefore important for the development of predictive immunotherapy biomarkers in MMRd CRCs. Phylogenetic analysis identified three distinct patterns of IE driver evolution: pan-tumour evolution, subclonal evolution, and evolutionary stasis. These, but neither mutation burdens nor heterogeneity metrics, significantly correlated with T-cell densities, which were used as a surrogate marker of tumour immunogenicity. Furthermore, this revealed that genetic and T-cell infiltrates coevolve in MMRd CRCs. Low T-cell densities in the subgroup without any known IE drivers may indicate an, as yet unknown, IE mechanism. PD-L1 was expressed in the tumour microenvironment in most samples and correlated with T-cell densities. However, PD-L1 expression in cancer cells was independent of T-cell densities but strongly associated with loss of the intestinal homeobox transcription factor CDX2. This explains infrequent PD-L1 expression by cancer cells and may contribute to a higher recurrence risk of MMRd CRCs with impaired CDX2 expression. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland

Cell Cycle Genes Are the Evolutionarily Conserved Targets of the E2F4 Transcription Factor

Maintaining quiescent cells in G0 phase is achieved in part through the multiprotein subunit complex known as DREAM, and in human cell lines the transcription factor E2F4 directs this complex to its cell cycle targets. We found that E2F4 binds a highly overlapping set of human genes among three diverse primary tissues and an asynchronous cell line, which suggests that tissue-specific binding partners and chromatin structure have minimal influence on E2F4 targeting. To investigate the conservation of these transcription factor binding events, we identified the mouse genes bound by E2f4 in seven primary mouse tissues and a cell line. E2f4 bound a set of mouse genes that was common among mouse tissues, but largely distinct from the genes bound in human. The evolutionarily conserved set of E2F4 bound genes is highly enriched for functionally relevant regulatory interactions important for maintaining cellular quiescence. In contrast, we found minimal mRNA expression perturbations in this core set of E2f4 bound genes in the liver, kidney, and testes of E2f4 null mice. Thus, the regulatory mechanisms maintaining quiescence are robust even to complete loss of conserved transcription factor binding events

Enteric Microbiome Metabolites Correlate with Response to Simvastatin Treatment

Although statins are widely prescribed medications, there remains considerable variability in therapeutic response. Genetics can explain only part of this variability. Metabolomics is a global biochemical approach that provides powerful tools for mapping pathways implicated in disease and in response to treatment. Metabolomics captures net interactions between genome, microbiome and the environment. In this study, we used a targeted GC-MS metabolomics platform to measure a panel of metabolites within cholesterol synthesis, dietary sterol absorption, and bile acid formation to determine metabolite signatures that may predict variation in statin LDL-C lowering efficacy. Measurements were performed in two subsets of the total study population in the Cholesterol and Pharmacogenetics (CAP) study: Full Range of Response (FR), and Good and Poor Responders (GPR) were 100 individuals randomly selected from across the entire range of LDL-C responses in CAP. GPR were 48 individuals, 24 each from the top and bottom 10% of the LDL-C response distribution matched for body mass index, race, and gender. We identified three secondary, bacterial-derived bile acids that contribute to predicting the magnitude of statin-induced LDL-C lowering in good responders. Bile acids and statins share transporters in the liver and intestine; we observed that increased plasma concentration of simvastatin positively correlates with higher levels of several secondary bile acids. Genetic analysis of these subjects identified associations between levels of seven bile acids and a single nucleotide polymorphism (SNP), rs4149056, in the gene encoding the organic anion transporter SLCO1B1. These findings, along with recently published results that the gut microbiome plays an important role in cardiovascular disease, indicate that interactions between genome, gut microbiome and environmental influences should be considered in the study and management of cardiovascular disease. Metabolic profiles could provide valuable information about treatment outcomes and could contribute to a more personalized approach to therapy

Metabolomic Analysis in Severe Childhood Pneumonia in The Gambia, West Africa: Findings from a Pilot Study

Pneumonia remains the leading cause of death in young children globally and improved diagnostics are needed to better identify cases and reduce case fatality. Metabolomics, a rapidly evolving field aimed at characterizing metabolites in biofluids, has the potential to improve diagnostics in a range of diseases. The objective of this pilot study is to apply metabolomic analysis to childhood pneumonia to explore its potential to improve pneumonia diagnosis in a high-burden setting. and Random Forests (RF). ‘Unsupervised’ (blinded) data were analyzed by Principal Component Analysis (PCA), while ‘supervised’ (unblinded) analysis was by Partial Least Squares-Discriminant Analysis (PLS-DA) and Orthogonal Projection to Latent Structures (OPLS). Potential markers were extracted from S-plots constructed following analysis with OPLS, and markers were chosen based on their contribution to the variation and correlation within the data set. The dataset was additionally analyzed with the machine-learning algorithm RF in order to address issues of model overfitting and markers were selected based on their variable importance ranking. Unsupervised PCA analysis revealed good separation of pneumonia and control groups, with even clearer separation of the groups with PLS-DA and OPLS analysis. Statistically significant differences (p<0.05) between groups were seen with the following metabolites: uric acid, hypoxanthine and glutamic acid were higher in plasma from cases, while L-tryptophan and adenosine-5′-diphosphate (ADP) were lower; uric acid and L-histidine were lower in urine from cases. The key limitation of this study is its small size.Metabolomic analysis clearly distinguished severe pneumonia patients from community controls. The metabolites identified are important for the host response to infection through antioxidant, inflammatory and antimicrobial pathways, and energy metabolism. Larger studies are needed to determine whether these findings are pneumonia-specific and to distinguish organism-specific responses. Metabolomics has considerable potential to improve diagnostics for childhood pneumonia