Molecular characterisation of human atopic asthma and house dust mite induced pulmonary inflammation in a murine experimental model

Asthma is one of the most common chronic diseases of the 21st century, affecting over 300 million people worldwide 1. It is an inflammatory disorder of the airways that is a major public concern globally due to increasing prevalence and rates of mortality 2–5, and each year the disease is estimated to cause 250,000 premature deaths 1. There is an unmet need for the identification of phenotype-specific markers and accompanying molecular tools that facilitate the classification of asthma phenotypes/ endotypes. This study utilised a range of molecular techniques to characterise a well-defined group of female adults with poorly controlled atopic asthma associated with a house dust mite (HDM) sensitivity and non-asthmatic subjects. Quantification and differential expression analysis of circulating messenger RNA (mRNA) and microRNA (miRNA) revealed significant alterations to circulating RNA expression in the asthmatic subjects compared to the control subjects that may influence systemic immune activity. Quantification of circulatory inflammatory proteins (IL-4, 5, 10, 13, 17A, eotaxin, GM-CSF, IFNy, MCP-1, RANTES, TARC, TNFα, total IgE) found an overall trend of increased inflammatory protein in the asthmatic subjects, although no individual protein was identified as being significantly increased in the asthmatic subjects. Quantification of the bacterial protein, endotoxin, was observed to be decreased in the asthmatic subjects. Comparison of the circulatory microbiome in atopic and non-atopic subjects revealed that atopic disease was associated with significant changes to the circulatory microbiome composition and function potential. Moreover, characterisation of the murine gut and airway microbiome in an experimental model of atopic asthma found that HDM-induced pulmonary inflammation significantly altered the composition and function potential of the airway and gut microbiomes, thus demonstrating that atopic disease can actively induce changes to the microbiome. In conclusion, this study provides a valuable insight into the systemic changes that occur in HDM-associated asthma. A number of circulatory molecules were identified that were condition-specific and have biomarker potential, and clear changes in the atopic microbiome were detected

Pre-analytical mysteries: A case of severe hypervitaminosis D and mild hypercalcaemia

We describe a case of severe hypervitaminosis D and mild hypercalcaemia in a 68-year-old woman who presented with fatigue and weight loss. Her 25-hydroxy vitamin D (25OHD) was > 400 nmol/L (50-150) and corrected serum calcium was 2.83 mmol/L (2.1-2.6). Her intact parathyroid hormone (PTH) was 4.9 pmol/L (2.0-9.5). Further investigation revealed an IgM kappa paraprotein, and a bone marrow aspirate confirmed a diagnosis of lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (LPL/WM). As the vitamin D level was discordant with the patient’s other results and presentation, the presence of an assay interferent was suspected. A 1-in-2 dilution of the sample returned a 25OHD result of 84 nmol/L in keeping with the presence of an interferent. Testing for rheumatoid factor was negative. The sample was treated with an antibody blocking reagent (Scantibodies) and results were not consistent with heterophile antibody interference. The sample was then analysed using liquid chromatography tandem mass spectrometry (LC-MS/MS), which returned a 25OHD result of 82 nmol/L. Testing on an alternative immunoassay platform produced a 25OHD result of 75 nmol/L. Reapeted testing on the original platform following reduction of the monoclonal paraprotein with chemotherapy, returned a result of 64 nmol/L. The patient’s mild hypercalcaemia persisted following resolution of the monoclonal paraprotein, in keeping with a diagnosis of primary hyperparathyroidism. This case highlights the potential for paraproteins to cause assay interference, and the importance of considering interference when results are incongruous with the clinical presentation

“Be the change” — how Cheltenham Science Festival used a central theme to centre social change within the festival

‘Be the change’ (BTC) was the theme for Cheltenham Science Festival. BTC set out to empower audiences as individuals and as a collective to enact positive change across a wide range of global issues linked to the UN Sustainable Development Goals. We examine the role of theming within festivals and analyse how BTC centred social change within the science festival. We conclude by noting that science festivals do not have to have science, technology, engineering or maths (STEM) themes, but can instead be themed around global social issues

AI Ethics Principles in Practice: Perspectives of Designers and Developers

As consensus across the various published AI ethics principles is approached, a gap remains between high-level principles and practical techniques that can be readily adopted to design and develop responsible AI systems. We examine the practices and experiences of researchers and engineers from Australia's national scientific research agency (CSIRO), who are involved in designing and developing AI systems for many application areas. Semi-structured interviews were used to examine how the practices of the participants relate to and align with a set of high-level AI ethics principles proposed by the Australian Government. The principles comprise: (1) privacy protection and security, (2) reliability and safety, (3) transparency and explainability, (4) fairness, (5) contestability, (6) accountability, (7) human-centred values, (8) human, social and environmental wellbeing. Discussions on the gained insights from the interviews include various tensions and trade-offs between the principles, and provide suggestions for implementing each high-level principle. We also present suggestions aiming to enhance associated support mechanisms.Comment: submitted to IEEE Transactions on Technology & Societ

The value of teaching increases with tool complexity in cumulative cultural evolution

Human cumulative cultural evolution (CCE) is recognized as a powerful ecological and evolutionary force, but its origins are poorly understood. The long-standing view that CCE requires specialized social learning processes such as teaching has recently come under question, and cannot explain why such processes evolved in the first place. An alternative, but largely untested, hypothesis is that these processes gradually coevolved with an increasing reliance on complex tools. To address this, we used large-scale transmission chain experiments (624 participants), to examine the role of different learning processes in generating cumulative improvements in two tool types of differing complexity. Both tool types increased in efficacy across experimental generations, but teaching only provided an advantage for the more complex tools. Moreover, while the simple tools tended to converge on a common design, the more complex tools maintained a diversity of designs. These findings indicate that the emergence of cumulative culture is not strictly dependent on, but may generate selection for, teaching. As reliance on increasingly complex tools grew, so too would selection for teaching, facilitating the increasingly open-ended evolution of cultural artefacts

Long-term effects of flooding on mortality in England and Wales, 1994-2005: controlled interrupted time-series analysis

BACKGROUND: Limited evidence suggests that being flooded may increase mortality and morbidity among affected householders not just at the time of the flood but for months afterwards. The objective of this study is to explore the methods for quantifying such long-term health effects of flooding by analysis of routine mortality registrations in England and Wales. METHODS: Mortality data, geo-referenced by postcode of residence, were linked to a national database of flood events for 1994 to 2005. The ratio of mortality in the post-flood year to that in the pre-flood year within flooded postcodes was compared with that in non-flooded boundary areas (within 5 km of a flood). Further analyses compared the observed number of flood-area deaths in the year after flooding with the number expected from analysis of mortality trends stratified by region, age-group, sex, deprivation group and urban-rural status. RESULTS: Among the 319 recorded floods, there were 771 deaths in the year before flooding and 693 deaths in the year after (post-/pre-flood ratio of 0.90, 95% CI 0.82, 1.00). This ratio did not vary substantially by age, sex, population density or deprivation. A similar post-flood 'deficit' of deaths was suggested by the analyses based on observed/expected deaths. CONCLUSIONS: The observed post-flood 'deficit' of deaths is counter-intuitive and difficult to interpret because of the possible influence of population displacement caused by flooding. The bias that might arise from such displacement remains unquantified but has important implications for future studies that use place of residence as a marker of exposure

Individual differences in susceptibility to online influence: A theoretical review

© 2017 The Authors Scams and other malicious attempts to influence people are continuing to proliferate across the globe, aided by the availability of technology that makes it increasingly easy to create communications that appear to come from legitimate sources. The rise in integrated technologies and the connected nature of social communications means that online scams represent a growing issue across society, with scammers successfully persuading people to click on malicious links, make fraudulent payments, or download malicious attachments. However, current understanding of what makes people particularly susceptible to scams in online contexts, and therefore how we can effectively reduce potential vulnerabilities, is relatively poor. So why are online scams so effective? And what makes people particularly susceptible to them? This paper presents a theoretical review of literature relating to individual differences and contextual factors that may impact susceptibility to such forms of malicious influence in online contexts. A holistic approach is then proposed that provides a theoretical foundation for research in this area, focusing on the interaction between the individual, their current context, and the influence message itself, when considering likely response behaviour

A qualitative investigation of lived experiences of long-term health condition management with people who are food insecure.

Background: As more people are living with one or more chronic health conditions, supporting patients to become activated, self-managers of their conditions has become a key health policy focus both in the UK and internationally. There is also growing evidence in the UK that those with long term health conditions have an increased risk of being food insecure. While international evidence indicates that food insecurity adversely affects individual's health condition management capability, little is known about how those so affected manage their condition(s) in this context. An investigation of lived experience of health condition management was undertaken with food insecure people living in north east Scotland. The study aimed to explore the challenges facing food insecure people in terms of, i. their self-care condition management practices, and ii. disclosing and discussing the experience of managing their condition with a health care professional, and iii. Notions of the support they might wish to receive from them. Methods: Twenty in-depth interviews were conducted with individuals attending a food bank and food pantry in north east Scotland. Interview audio recordings were fully transcribed and thematically analysed. Results: Individuals reporting multiple physical and mental health conditions, took part in the study. Four main themes were identified i.e.: 1. food practices, trade-offs and compromises, that relate to economic constraints and lack of choice; 2. illness experiences and food as they relate to physical and mental ill-health; 3. (in) visibility of participants' economic vulnerability within health care consultations; and 4. perceptions and expectations of the health care system. Conclusions: This study, the first of its kind in the UK, indicated that participants' health condition management aspirations were undermined by the experience of food insecurity, and that their health care consultations in were, on the whole, devoid of discussions of those challenges. As such, the study indicated practical and ethical implications for health care policy, practice and research associated with the risk of intervention-generated health inequalities that were suggested by this study. Better understanding is needed about the impact of household food insecurity on existing ill health, wellbeing and health care use across the UK

Global patient outcomes after elective surgery: prospective cohort study in 27 low-, middle- and high-income countries.

BACKGROUND: As global initiatives increase patient access to surgical treatments, there remains a need to understand the adverse effects of surgery and define appropriate levels of perioperative care. METHODS: We designed a prospective international 7-day cohort study of outcomes following elective adult inpatient surgery in 27 countries. The primary outcome was in-hospital complications. Secondary outcomes were death following a complication (failure to rescue) and death in hospital. Process measures were admission to critical care immediately after surgery or to treat a complication and duration of hospital stay. A single definition of critical care was used for all countries. RESULTS: A total of 474 hospitals in 19 high-, 7 middle- and 1 low-income country were included in the primary analysis. Data included 44 814 patients with a median hospital stay of 4 (range 2-7) days. A total of 7508 patients (16.8%) developed one or more postoperative complication and 207 died (0.5%). The overall mortality among patients who developed complications was 2.8%. Mortality following complications ranged from 2.4% for pulmonary embolism to 43.9% for cardiac arrest. A total of 4360 (9.7%) patients were admitted to a critical care unit as routine immediately after surgery, of whom 2198 (50.4%) developed a complication, with 105 (2.4%) deaths. A total of 1233 patients (16.4%) were admitted to a critical care unit to treat complications, with 119 (9.7%) deaths. Despite lower baseline risk, outcomes were similar in low- and middle-income compared with high-income countries. CONCLUSIONS: Poor patient outcomes are common after inpatient surgery. Global initiatives to increase access to surgical treatments should also address the need for safe perioperative care. STUDY REGISTRATION: ISRCTN5181700

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice