Models of everywhere revisited: a technological perspective

The concept ‘models of everywhere’ was first introduced in the mid 2000s as a means of reasoning about the environmental science of a place, changing the nature of the underlying modelling process, from one in which general model structures are used to one in which modelling becomes a learning process about specific places, in particular capturing the idiosyncrasies of that place. At one level, this is a straightforward concept, but at another it is a rich multi-dimensional conceptual framework involving the following key dimensions: models of everywhere, models of everything and models at all times, being constantly re-evaluated against the most current evidence. This is a compelling approach with the potential to deal with epistemic uncertainties and nonlinearities. However, the approach has, as yet, not been fully utilised or explored. This paper examines the concept of models of everywhere in the light of recent advances in technology. The paper argues that, when first proposed, technology was a limiting factor but now, with advances in areas such as Internet of Things, cloud computing and data analytics, many of the barriers have been alleviated. Consequently, it is timely to look again at the concept of models of everywhere in practical conditions as part of a trans-disciplinary effort to tackle the remaining research questions. The paper concludes by identifying the key elements of a research agenda that should underpin such experimentation and deployment

HIV Drugs Inhibit Transfer of Plasmids Carrying Extended-Spectrum β-Lactamase and Carbapenemase Genes

More and more bacterial infections are becoming resistant to antibiotics. This has made treatment of many infections very difficult. One of the reasons this is such a large problem is that bacteria are able to share their genetic material with other bacteria, and these shared genes often include resistance to a variety of antibiotics, including some of our drugs of last resort. We are addressing this problem by using a fluorescence-based system to search for drugs that will stop bacteria from sharing resistance genes. We uncovered a new role for two drugs used to treat HIV and show that they are able to prevent the sharing of two different types of resistance genes in two unique bacterial strains. This work lays the foundation for future work to reduce the prevalence of resistant infections.Antimicrobial-resistant (AMR) infections pose a serious risk to human and animal health. A major factor contributing to this global crisis is the sharing of resistance genes between different bacteria via plasmids. The WHO lists Enterobacteriaceae, such as Escherichia coli and Klebsiella pneumoniae, producing extended-spectrum β-lactamases (ESBL) and carbapenemases as “critical” priorities for new drug development. These resistance genes are most often shared via plasmid transfer. However, finding methods to prevent resistance gene sharing has been hampered by the lack of screening systems for medium-/high-throughput approaches. Here, we have used an ESBL-producing plasmid, pCT, and a carbapenemase-producing plasmid, pKpQIL, in two different Gram-negative bacteria, E. coli and K. pneumoniae. Using these critical resistance-pathogen combinations, we developed an assay using fluorescent proteins, flow cytometry, and confocal microscopy to assess plasmid transmission inhibition within bacterial populations in a medium-throughput manner. Three compounds with some reports of antiplasmid properties were tested; chlorpromazine reduced transmission of both plasmids and linoleic acid reduced transmission of pCT. We screened the Prestwick library of over 1,200 FDA-approved drugs/compounds. From this, we found two nucleoside analogue drugs used to treat HIV, abacavir and azidothymidine (AZT), which reduced plasmid transmission (AZT, e.g., at 0.25 μg/ml reduced pCT transmission in E. coli by 83.3% and pKpQIL transmission in K. pneumoniae by 80.8% compared to untreated controls). Plasmid transmission was reduced by concentrations of the drugs which are below peak serum concentrations and are achievable in the gastrointestinal tract. These drugs could be used to decolonize humans, animals, or the environment from AMR plasmids

Downgrading Recent Estimates of Land Available for Biofuel Production

Recent estimates of additional land available for bioenergy production range from 320 to 1411 million ha. These estimates were generated from four scenarios regarding the types of land suitable for bioenergy production using coarse-resolution inputs of soil productivity, slope, climate, and land cover. In this paper, these maps of land availability were assessed using high-resolution satellite imagery. Samples from these maps were selected and crowdsourcing of Google Earth images was used to determine the type of land cover and the degree of human impact. Based on this sample, a set of rules was formulated to downward adjust the original estimates for each of the four scenarios that were previously used to generate the maps of land availability for bioenergy production. The adjusted land availability estimates range from 56 to 1035 million ha depending upon the scenario and the ruleset used when the sample is corrected for bias. Large forest areas not intended for biofuel production purposes were present in all scenarios. However, these numbers should not be considered as definitive estimates but should be used to highlight the uncertainty in attempting to quantify land availability for biofuel production when using coarse-resolution inputs with implications for further policy development

Student nurse selection and predictability of academic success : the Multiple Mini Interview project

BACKGROUND: With recent reports of public enquiries into failure to care, universities are under pressure to ensure that candidates selected for undergraduate nursing programmes demonstrate academic potential as well as characteristics and values such as compassion, empathy and integrity. The Multiple Mini Interview (MMI) was used in one university as a way of ensuring that candidates had the appropriate numeracy and literacy skills as well as a range of communication, empathy, decision-making and problem-solving skills as well as ethical insights and integrity, initiative and team-work. OBJECTIVES: To ascertain whether there is evidence of bias in MMIs (gender, age, nationality and location of secondary education) and to determine the extent to which the MMI is predictive of academic success in nursing. DESIGN: A longitudinal retrospective analysis of student demographics, MMI data and the assessment marks for years 1, 2 and 3. SETTINGS: One university in southwest London. PARTICIPANTS: One cohort of students who commenced their programme in September 2011, including students in all four fields of nursing (adult, child, mental health and learning disability). METHODS: Inferential statistics and a Bayesian Multilevel Model. RESULTS: MMI in conjunction with MMI numeracy test and MMI literacy test shows little or no bias in terms of ages, gender, nationality or location of secondary school education. Although MMI in conjunction with numeracy and literacy testing is predictive of academic success, it is only weakly predictive. CONCLUSIONS: The MMI used in conjunction with literacy and numeracy testing appears to be a successful technique for selecting candidates for nursing. However, other selection methods such as psychological profiling or testing of emotional intelligence may add to the extent to which selection methods are predictive of academic success on nursing

Bone Fracture Toughness and Strength Correlate With Collagen Cross‐Link Maturity in a Dose‐Controlled Lathyrism Mouse Model

Collagen cross‐linking is altered in many diseases of bone, and enzymatic collagen cross‐links are important to bone quality, as evidenced by losses of strength after lysyl oxidase inhibition (lathyrism). We hypothesized that cross‐links also contribute directly to bone fracture toughness. A mouse model of lathyrism using subcutaneous injection of up to 500 mg/kg β‐aminopropionitrile (BAPN) was developed and characterized (60 animals across 4 dosage groups). Three weeks of 150 or 350 mg/kg BAPN treatment in young, growing mice significantly reduced cortical bone fracture toughness, strength, and pyridinoline cross‐link content. Ratios reflecting relative cross‐link maturity were positive regressors of fracture toughness (HP/[DHLNL + HLNL] r2 = 0.208, p < 0.05; [HP + LP]/[DHNL + HLNL] r2 = 0.196, p < 0.1), whereas quantities of mature pyridinoline cross‐links were significant positive regressors of tissue strength (lysyl pyridinoline r2 = 0.159, p = 0.014; hydroxylysyl pyridinoline r2 = 0.112, p < 0.05). Immature and pyrrole cross‐links, which were not significantly reduced by BAPN, did not correlate with mechanical properties. The effect of BAPN treatment on mechanical properties was dose specific, with the greatest impact found at the intermediate (350 mg/kg) dose. Calcein labeling was used to define locations of new bone formation, allowing for the identification of regions of normally cross‐linked (preexisting) and BAPN‐treated (newly formed, cross‐link‐deficient) bone. Raman spectroscopy revealed spatial differences attributable to relative tissue age and effects of cross‐link inhibition. Newly deposited tissues had lower mineral/matrix, carbonate/phosphate, and Amide I cross‐link (matrix maturity) ratios compared with preexisting tissues. BAPN treatment did not affect mineral measures but significantly increased the cross‐link (matrix maturity) ratio compared with newly formed control tissue. Our study reveals that spatially localized effects of short‐term BAPN cross‐link inhibition can alter the whole‐bone collagen cross‐link profile to a measureable degree, and this cross‐link profile correlates with bone fracture toughness and strength. Thus, cross‐link profile perturbations associated with bone disease may provide insight into bone mechanical quality and fracture risk. © 2014 American Society for Bone and Mineral Research.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/110745/1/jbmr2356.pd

Testing a model of UK growth: A role for R&D subsidies

Debate continues on the economic growth effects of direct support for business R&D. We set out aDSGE model of the UK in which direct R&D subsidies drive total factor productivity (TFP) throughtheir incentive effects on agents' optimal decisions. We estimate and test the model by IndirectInference, finding that this model can account for the joint behaviour of UK output and TFP. The model allows us to analyse the short-run impact of R&D subsidies on TFP and to quantify the longer-term impacts of R&D subsidy shocks on output. We also determine uncertainty bounds for key growth parameters using Monte Carlo analysis. Our results show that even temporary policy cuts to R&D funding have long-lasting impacts on UK economic growth. The findings are of great policy relevance given ongoing debate around the future UK innovation environment and the novel application of indirect inference to this question

Utilisation of an operative difficulty grading scale for laparoscopic cholecystectomy

Background A reliable system for grading operative difficulty of laparoscopic cholecystectomy would standardise description of findings and reporting of outcomes. The aim of this study was to validate a difficulty grading system (Nassar scale), testing its applicability and consistency in two large prospective datasets. Methods Patient and disease-related variables and 30-day outcomes were identified in two prospective cholecystectomy databases: the multi-centre prospective cohort of 8820 patients from the recent CholeS Study and the single-surgeon series containing 4089 patients. Operative data and patient outcomes were correlated with Nassar operative difficultly scale, using Kendall’s tau for dichotomous variables, or Jonckheere–Terpstra tests for continuous variables. A ROC curve analysis was performed, to quantify the predictive accuracy of the scale for each outcome, with continuous outcomes dichotomised, prior to analysis. Results A higher operative difficulty grade was consistently associated with worse outcomes for the patients in both the reference and CholeS cohorts. The median length of stay increased from 0 to 4 days, and the 30-day complication rate from 7.6 to 24.4% as the difficulty grade increased from 1 to 4/5 (both p < 0.001). In the CholeS cohort, a higher difficulty grade was found to be most strongly associated with conversion to open and 30-day mortality (AUROC = 0.903, 0.822, respectively). On multivariable analysis, the Nassar operative difficultly scale was found to be a significant independent predictor of operative duration, conversion to open surgery, 30-day complications and 30-day reintervention (all p < 0.001). Conclusion We have shown that an operative difficulty scale can standardise the description of operative findings by multiple grades of surgeons to facilitate audit, training assessment and research. It provides a tool for reporting operative findings, disease severity and technical difficulty and can be utilised in future research to reliably compare outcomes according to case mix and intra-operative difficulty

The Fitness Cost of Antibiotic Resistance in Streptococcus pneumoniae: Insight from the Field

Laboratory studies have suggested that antibiotic resistance may result in decreased fitness in the bacteria that harbor it. Observational studies have supported this, but due to ethical and practical considerations, it is rare to have experimental control over antibiotic prescription rates.We analyze data from a 54-month longitudinal trial that monitored pneumococcal drug resistance during and after biannual mass distribution of azithromycin for the elimination of the blinding eye disease, trachoma. Prescription of azithromycin and antibiotics that can create cross-resistance to it is rare in this part of the world. As a result, we were able to follow trends in resistance with minimal influence from unmeasured antibiotic use. Using these data, we fit a probabilistic disease transmission model that included two resistant strains, corresponding to the two dominant modes of resistance to macrolide antibiotics. We estimated the relative fitness of these two strains to be 0.86 (95% CI 0.80 to 0.90), and 0.88 (95% CI 0.82 to 0.93), relative to antibiotic-sensitive strains. We then used these estimates to predict that, within 5 years of the last antibiotic treatment, there would be a 95% chance of elimination of macrolide resistance by intra-species competition alone.Although it is quite possible that the fitness cost of macrolide resistance is sufficient to ensure its eventual elimination in the absence of antibiotic selection, this process takes time, and prevention is likely the best policy in the fight against resistance

Evolutionary Epidemiology of Drug-Resistance in Space

The spread of drug-resistant parasites erodes the efficacy of therapeutic treatments against many infectious diseases and is a major threat of the 21st century. The evolution of drug-resistance depends, among other things, on how the treatments are administered at the population level. “Resistance management” consists of finding optimal treatment strategies that both reduce the consequence of an infection at the individual host level, and limit the spread of drug-resistance in the pathogen population. Several studies have focused on the effect of mixing different treatments, or of alternating them in time. Here, we analyze another strategy, where the use of the drug varies spatially: there are places where no one receives any treatment. We find that such a spatial heterogeneity can totally prevent the rise of drug-resistance, provided that the size of treated patches is below a critical threshold. The range of parasite dispersal, the relative costs and benefits of being drug-resistant compared to being drug-sensitive, and the duration of an infection with drug-resistant parasites are the main factors determining the value of this threshold. Our analysis thus provides some general guidance regarding the optimal spatial use of drugs to prevent or limit the evolution of drug-resistance