The Biomarker Toolkit - an evidence-based guideline to predict cancer biomarker success and guide development

BACKGROUND: An increased number of resources are allocated on cancer biomarker discovery, but very few of these biomarkers are clinically adopted. To bridge the gap between Biomarker discovery and clinical use, we aim to generate the Biomarker Toolkit, a tool designed to identify clinically promising biomarkers and promote successful biomarker translation. METHODS: All features associated with a clinically useful biomarker were identified using mixed-methodology, including systematic literature search, semi-structured interviews, and an online two-stage Delphi-Survey. Validation of the checklist was achieved by independent systematic literature searches using keywords/subheadings related to clinically and non-clinically utilised breast and colorectal cancer biomarkers. Composite aggregated scores were generated for each selected publication based on the presence/absence of an attribute listed in the Biomarker Toolkit checklist. RESULTS: Systematic literature search identified 129 attributes associated with a clinically useful biomarker. These were grouped in four main categories including: rationale, clinical utility, analytical validity, and clinical validity. This checklist was subsequently developed using semi-structured interviews with biomarker experts (n=34); and 88.23% agreement was achieved regarding the identified attributes, via the Delphi survey (consensus level:75%, n=51). Quantitative validation was completed using clinically and non-clinically implemented breast and colorectal cancer biomarkers. Cox-regression analysis suggested that total score is a significant driver of biomarker success in both cancer types (BC: p>0.0001, 95.0% CI: 0.869-0.935, CRC: p>0.0001, 95.0% CI: 0.918-0.954). CONCLUSIONS: This novel study generated a validated checklist with literature-reported attributes linked with successful biomarker implementation. Ultimately, the application of this toolkit can be used to detect biomarkers with the highest clinical potential and shape how biomarker studies are designed/performed

Structural insights into Clostridium perfringens delta toxin pore formation

Clostridium perfringens Delta toxin is one of the three hemolysin-like proteins produced by C. perfringens type C and possibly type B strains. One of the others, NetB, has been shown to be the major cause of Avian Nectrotic Enteritis, which following the reduction in use of antibiotics as growth promoters, has become an emerging disease of industrial poultry. Delta toxin itself is cytotoxic to the wide range of human and animal macrophages and platelets that present GM2 ganglioside on their membranes. It has sequence similarity with Staphylococcus aureus β-pore forming toxins and is expected to heptamerize and form pores in the lipid bilayer of host cell membranes. Nevertheless, its exact mode of action remains undetermined. Here we report the 2.4 Å crystal structure of monomeric Delta toxin. The superposition of this structure with the structure of the phospholipid-bound F component of S. aureus leucocidin (LukF) revealed that the glycerol molecules bound to Delta toxin and the phospholipids in LukF are accommodated in the same hydrophobic clefts, corresponding to where the toxin is expected to latch onto the membrane, though the binding sites show significant differences. From structure-based sequence alignment with the known structure of staphylococcal α-hemolysin, a model of the Delta toxin pore form has been built. Using electron microscopy, we have validated our model and characterized the Delta toxin pore on liposomes. These results highlight both similarities and differences in the mechanism of Delta toxin (and by extension NetB) cytotoxicity from that of the staphylococcal pore-forming toxins

Challenges of rapid migration to fully virtual education in the age of the Corona virus pandemic: experiences from across the world

The social disruption caused by the sudden eruption of the Corona Virus pandemic has shaken the whole world, influencing all levels of education immensely. Notwithstanding there was a lack of preparedness for this global public health emergency which continues to affect all aspects of work and life. The problem is, naturally, multifaceted, fast evolving and complex, affecting everyone, threatening our well-being, the global economy, the environment and all societal and cultural norms and our everyday activities. In a recent UNESCO report it is noted that nearly a billion and a quarter (which is 67,7 % of the total number) of learners have been affected by the Corona Virus pandemic worldwide. The education sector at all levels has been one of the hardest hit sectors particularly as the academic/school year was in full swing. The impact of the pandemic is widespread, representing a health hazard worldwide. Being such, it profoundly affects society as a whole, and its members that are, in particular, i) individuals (the learners, their parents, educators, support staff), ii) schools, training organisations, pedagogical institutions and education systems, iii) quickly transformed policies, methods and pedagogies to serve the newly appeared needs of the latter. Lengthy developments of such scale usually take years of consultation, strategic planning and implementation. In addition to raising awareness across the population of the dangers of the virus transmission and instigating total lockdown, it has been necessary to develop mechanisms for continuing the delivery of education as well as demanding mechanisms for assuring the quality of the educational experience and educational results. There is often scepticism about securing quality standards in such a fast moving situation. Often in the recent past, the perception was that courses and degrees leading to an award are inferior if the course modules (and sometimes its assessment components) were wholly online. Over the last three decades most Higher Education institutions developed both considerable infrastructure and knowhow enabling distance mode delivery schools (Primary and Secondary) had hardly any necessary infrastructure nor adequate knowhow for enabling virtual education. In addition, community education and various training providers were mainly delivered face-to-face and that had to either stop altogether or rapidly convert materials, exercises and tests for online delivery and testing. A high degree of flexibility and commitment was demanded of all involved and particularly from the educators, who undertook to produce new educational materials in order to provide online support to pupils and students. Apart from the delivery mode of education, which is serving for certificated programmes, it is essential to ensure that learners’ needs are thoroughly and continuously addressed and are efficiently supported throughout the Coronavirus or any other future lockdown. The latter can be originated by various causes and reasons that vary in nature, such as natural or socioeconomical. Readiness, thus, in addition to preparedness, is the primary key question and solution when it comes to quality education for any lockdown. In most countries, the compulsory primary and secondary education sectors have been facing a more difficult challenge than that faced by Higher Education. The poor or in many cases non-existent technological infrastructure and low technological expertise of the teachers, instructors and parents, make the delivery of virtual education difficult or even impossible. The latter, coupled with phenomena such as social exclusion and digital divide where thousands of households do not have adequate access to broadband Internet, Wi-Fi infrastructure and personal computers hamper the promising and strenuous virtual solutions. The shockwaves of the sudden demands on all sectors of society and on individuals required rapid decisions and actions. We will not attempt to answer the question “Why was the world unprepared for the onslaught of the Coronavirus pandemic” but need to ascertain the level of preparedness and readiness particularly of the education sector, to effect the required rapid transition. We aimed to identify the challenges, and problems faced by the educators and their institutions. Through first-hand experiences we also identify best practices and solutions reached. Thus we constructed a questionnaire to gather our own responses but also experiences from colleagues and members of our environment, family, friends, and colleagues. This paper reports the first-hand experiences and knowledge of 33 co-authors from 27 institutions and from 13 different countries from Europe, Asia, and Africa. The communication technologies and development platforms used are identified; the challenges faced as well as solutions and best practices are reported. The findings are consolidated into the four areas explored i.e. Development Platforms, Communications Technologies, Challenges/Problems and Solutions/Best Practices. The conclusion summarises the findings into emerging themes and similarities. Reflections on the lasting impact of the effect of Coronavirus on education, limitations of study, and indications of future work complete the paper

Rapid migration from traditional or hybrid to fully virtual education in the age of the coronavirus pandemic: challenges, experiences and views of college and university students

The abrupt outbreak of the coronavirus pandemic throughout the world in March 2020 resulted in the sudden closure of all schools, colleges and universities, institutions, and an unprecedented pivot to remote learning. Students and teachers were confronted with the overwhelming challenge of migrating from the traditional face-to-face or hybrid mode of education to fully virtual learning and assessment environments within an extremely short amount of time. This migration was exceptionally difficult, as it took place halfway through the academic or school year in most countries. While pandemic restrictions currently vary across different regions, the 2020-2021 academic session continues to pose challenges despite the experience gained. In addition to a review of the current state-of-the-art in relation to the effects of COVID-19 on teaching and learning, this paper reports on an empirical study carried out in 26 countries (from Asia, Europe, Africa and America), by 36 academics from 29 academic institutions. Through an extensive global survey of college and university students, information was collected about the challenges (technological, economic, psychological) faced by them, as a result of the pandemic. We also asked the students’ to offer their ideas and suggestions for further improvements in teaching and learning, as we look toward a post-COVID world. In this paper, we address issues relating to the availability of, and accessibility to, necessary digital technologies (e.g., learning and communication platforms), isolation, disconnection, and loneliness among students, the overall impact of the pandemic on learning and academic performance, and the reliability of assessment methods., cybercrime dangers and fake information. A total of 1005 responses to the survey were received and analysed. The results are presented in this paper together with reflections of the authors. The paper concludes with a summary of suggestions for process improvements in distance education, and the need for preventive preparedness in the post-COVID period

Hunt for new phenomena using large jet multiplicities and missing transverse momentum with ATLAS in 4.7 fb−1 of s√=7TeV proton-proton collisions

Results are presented of a search for new particles decaying to large numbers of jets in association with missing transverse momentum, using 4.7 fb−1 of pp collision data at s√=7TeV collected by the ATLAS experiment at the Large Hadron Collider in 2011. The event selection requires missing transverse momentum, no isolated electrons or muons, and from ≥6 to ≥9 jets. No evidence is found for physics beyond the Standard Model. The results are interpreted in the context of a MSUGRA/CMSSM supersymmetric model, where, for large universal scalar mass m 0, gluino masses smaller than 840 GeV are excluded at the 95% confidence level, extending previously published limits. Within a simplified model containing only a gluino octet and a neutralino, gluino masses smaller than 870 GeV are similarly excluded for neutralino masses below 100 GeV

Measurements of Higgs boson production and couplings in diboson final states with the ATLAS detector at the LHC

Measurements are presented of production properties and couplings of the recently discovered Higgs boson using the decays into boson pairs, H →γ γ, H → Z Z∗ →4l and H →W W∗ →lνlν. The results are based on the complete pp collision data sample recorded by the ATLAS experiment at the CERN Large Hadron Collider at centre-of-mass energies of √s = 7 TeV and √s = 8 TeV, corresponding to an integrated luminosity of about 25 fb−1. Evidence for Higgs boson production through vector-boson fusion is reported. Results of combined fits probing Higgs boson couplings to fermions and bosons, as well as anomalous contributions to loop-induced production and decay modes, are presented. All measurements are consistent with expectations for the Standard Model Higgs boson

Standalone vertex finding in the ATLAS muon spectrometer

A dedicated reconstruction algorithm to find decay vertices in the ATLAS muon spectrometer is presented. The algorithm searches the region just upstream of or inside the muon spectrometer volume for multi-particle vertices that originate from the decay of particles with long decay paths. The performance of the algorithm is evaluated using both a sample of simulated Higgs boson events, in which the Higgs boson decays to long-lived neutral particles that in turn decay to bbar b final states, and pp collision data at √s = 7 TeV collected with the ATLAS detector at the LHC during 2011

Measurement of the top quark-pair production cross section with ATLAS in pp collisions at \sqrt{s}=7\TeV

A measurement of the production cross-section for top quark pairs(\ttbar) in $pp$ collisions at \sqrt{s}=7 \TeV is presented using data recorded with the ATLAS detector at the Large Hadron Collider. Events are selected in two different topologies: single lepton (electron $e$ or muon $\mu$) with large missing transverse energy and at least four jets, and dilepton ($ee$, $\mu\mu$ or $e\mu$) with large missing transverse energy and at least two jets. In a data sample of 2.9 pb-1, 37 candidate events are observed in the single-lepton topology and 9 events in the dilepton topology. The corresponding expected backgrounds from non-\ttbar Standard Model processes are estimated using data-driven methods and determined to be $12.2 \pm 3.9$ events and $2.5 \pm 0.6$ events, respectively. The kinematic properties of the selected events are consistent with SM \ttbar production. The inclusive top quark pair production cross-section is measured to be \sigmattbar=145 \pm 31 ^{+42}_{-27} pb where the first uncertainty is statistical and the second systematic. The measurement agrees with perturbative QCD calculations.Comment: 30 pages plus author list (50 pages total), 9 figures, 11 tables, CERN-PH number and final journal adde

Measurement of the top quark pair cross section with ATLAS in pp collisions at √s=7 TeV using final states with an electron or a muon and a hadronically decaying τ lepton

A measurement of the cross section of top quark pair production in proton-proton collisions recorded with the ATLAS detector at the Large Hadron Collider at a centre-of-mass energy of 7 TeV is reported. The data sample used corresponds to an integrated luminosity of 2.05 fb -1. Events with an isolated electron or muon and a τ lepton decaying hadronically are used. In addition, a large missing transverse momentum and two or more energetic jets are required. At least one of the jets must be identified as originating from a b quark. The measured cross section, σtt-=186±13(stat.)±20(syst.)±7(lumi.) pb, is in good agreement with the Standard Model prediction