Microevolution during the emergence of a monophasic Salmonella Typhimurium epidemic in the United Kingdom

Microevolutionary events associated with the emergence and clonal expansion of new 27 epidemic clones of bacterial pathogens hold the key to understanding the drivers of 28 epidemiological success. We describe a comparative whole genome sequence and 29 phylogenomic analysis of monophasic Salmonella Typhimurium isolates from the UK 30 and Italy from 2005-2012. Monophasic isolates from this time formed a single clade 31 distinct from recent monophasic epidemic clones described previously from North 32 America and Spain. The current UK monophasic epidemic clones encode a novel 33 genomic island encoding resistance to heavy metals (SGI-3), and composite transposon 34 encoding antibiotic resistance genes not present in other Typhimurium isolates, that 35 may have contributed to the epidemiological success. We also report a remarkable 36 degree of genotypic variation that accumulated during clonal expansion of a UK 37 epidemic including multiple independent acquisitions of a novel prophage carrying the 38 sopE gene and multiple deletion events affecting the phase II flagellin locus

Social gradient in the cost of oral pain and related dental service utilisation among South African adults

Background: Oral pain affects people's daily activities and quality of life. The burden of oral pain may vary across socio-economic positions. Currently, little is known about the social gradient in the cost of oral pain among South Africans. This study therefore assessed the social gradient in the cost of oral pain and the related dental service utilisation pattern among South African adults. Methods: Data were obtained from a nationally representative cross-sectional survey of South African adults ?16 year-old (n = 2651) as part of the South African Social Attitudes Survey conducted by the South African Human Sciences Research Council. The survey included demographic data, individual-level socio-economic position (SEP), self-reported oral health status, past six months' oral pain experience and cost. The area-level SEP was obtained from the 2010 General Household Survey (n = 25,653 households) and the 2010/2011Quarterly Labour Force Survey conducted in South Africa. The composite indices used for individual-level SEP (? = 0.76) and area-level SEP (? = 0. 88) were divided into tertiles. Data analysis was done using t-tests and ANOVA. Significance was set at p < 0.05. Results: The prevalence of oral pain among the adult South Africans was 19.4 % (95 % CI = 17.2-21.9). The most commonly reported form of oral pain was 'toothache' (78.9 %). The majority of the wealthiest participants sought care from private dental clinics (64.7 %), or from public dental clinics (19.7 %), while the poorest tended to visit a public dental clinic (45 %) or nurse/general medical practitioner (17.4 %). In the poorest areas, 21 % responded to pain by 'doing nothing'. The individual expenditure for oral pain showed a social gradient from an average of ZAR61.44 spent by those of lowest SEP to ZAR433.83 by the wealthiest (national average ZAR170.92). Average time lost from school/work was two days over the six-month period, but days lost was highest for those living in middle class neighbourhoods (3.41), while those from the richest neighbourhood had lost significantly fewer days from oral pain (0.64). Conclusions: There is a significant social gradient in the burden of oral pain. Improved access to dental care, possibly through carefully planned universal National Health Insurance (NHI), may reduce oral health disparities in South Africa.Scopus 201

Conformational changes during pore formation by the perforin-related protein pleurotolysin

Membrane attack complex/perforin-like (MACPF) proteins comprise the largest superfamily of pore-forming proteins, playing crucial roles in immunity and pathogenesis. Soluble monomers assemble into large transmembrane pores via conformational transitions that remain to be structurally and mechanistically characterised. Here we present an 11 Å resolution cryo-electron microscopy (cryo-EM) structure of the two-part, fungal toxin Pleurotolysin (Ply), together with crystal structures of both components (the lipid binding PlyA protein and the pore-forming MACPF component PlyB). These data reveal a 13-fold pore 80 Å in diameter and 100 Å in height, with each subunit comprised of a PlyB molecule atop a membrane bound dimer of PlyA. The resolution of the EM map, together with biophysical and computational experiments, allowed confident assignment of subdomains in a MACPF pore assembly. The major conformational changes in PlyB are a ~70° opening of the bent and distorted central β-sheet of the MACPF domain, accompanied by extrusion and refolding of two α-helical regions into transmembrane β-hairpins (TMH1 and TMH2). We determined the structures of three different disulphide bond-trapped prepore intermediates. Analysis of these data by molecular modelling and flexible fitting allows us to generate a potential trajectory of β-sheet unbending. The results suggest that MACPF conformational change is triggered through disruption of the interface between a conserved helix-turn-helix motif and the top of TMH2. Following their release we propose that the transmembrane regions assemble into β-hairpins via top down zippering of backbone hydrogen bonds to form the membrane-inserted β-barrel. The intermediate structures of the MACPF domain during refolding into the β-barrel pore establish a structural paradigm for the transition from soluble monomer to pore, which may be conserved across the whole superfamily. The TMH2 region is critical for the release of both TMH clusters, suggesting why this region is targeted by endogenous inhibitors of MACPF function

A novel TOPSIS–CBR goal programming approach to sustainable healthcare treatment

Cancer is one of the most common diseases worldwide and its treatment is a complex and time-consuming process. Specifically, prostate cancer as the most common cancer among male population has received the attentions of many researchers. Oncologists and medical physicists usually rely on their past experience and expertise to prescribe the dose plan for cancer treatment. The main objective of dose planning process is to deliver high dose to the cancerous cells and simultaneously minimize the side effects of the treatment. In this article, a novel TOPSIS case based reasoning goal-programming approach has been proposed to optimize the dose plan for prostate cancer treatment. Firstly, a hybrid retrieval process TOPSIS–CBR [technique for order preference by similarity to ideal solution (TOPSIS) and case based reasoning (CBR)] is used to capture the expertise and experience of oncologists. Thereafter, the dose plans of retrieved cases are adjusted using goal-programming mathematical model. This approach will not only help oncologists to make a better trade-off between different conflicting decision making criteria but will also deliver a high dose to the cancerous cells with minimal and necessary effect on surrounding organs at risk. The efficacy of proposed method is tested on a real data set collected from Nottingham City Hospital using leave-one-out strategy. In most of the cases treatment plans generated by the proposed method is coherent with the dose plan prescribed by an experienced oncologist or even better. Developed decision support system can assist both new and experienced oncologists in the treatment planning process

The Prevalence of Visual Impairment in People with Dementia (the PrOVIDe study): a cross-sectional study of people aged 60–89 years with dementia and qualitative exploration of individual, carer and professional perspectives

Background: The prevalence of visual impairment (VI) and dementia increases with age and these conditions may coexist, but few UK data exist on VI among people with dementia. Objectives: To measure the prevalence of eye conditions causing VI in people with dementia and to identify/describe reasons for underdetection or inappropriate management. Design: Stage 1 – cross-sectional prevalence study. Stage 2 – qualitative research exploring participant, carer and professional perspectives of eye care. Setting: Stage 1 – 20 NHS sites in six English regions. Stage 2 – six English regions. Participants: Stage 1 – 708 participants with dementia (aged 60–89 years): 389 lived in the community (group 1) and 319 lived in care homes (group 2). Stage 2 – 119 participants. Interventions: Stage 1 gathered eye examination data following domiciliary sight tests complying with General Ophthalmic Services requirements and professional guidelines. Cognitive impairment was assessed using the Standardised Mini-Mental State Examination (sMMSE) test, and functional ability and behavior were assessed using the Bristol Activities of Daily Living Scale and Cambridge Behavioural Inventory – Revised. Stage 2 involved individual interviews (36 people with dementia and 11 care workers); and separate focus groups (34 optometrists; 38 family and professional carers). Main outcome measures.: VI defined by visual acuity (VA) worse than 6/12 or worse than 6/18 measured before and after refraction. Results: Stage 1 – when participants wore their current spectacles, VI prevalence was 32.5% [95% confidence interval (CI) 28.7% to 36.5%] and 16.3% (95% CI 13.5% to 19.6%) for commonly used criteria for VI of VA worse than 6/12 and 6/18, respectively. Of those with VI, 44% (VA 80% of participants. There was no evidence that the management of VI in people with dementia differed from that in older people in general. Exploratory analysis suggested significant deficits in some vision-related aspects of function and behaviour in participants with VI. Stage 2 key messages – carers and care workers underestimated how much can be achieved in an eye examination. People with dementia and carers were unaware of domiciliary sight test availability. Improved communication is needed between optometrists and carers; optometrists should be informed of the person’s dementia. Tailoring eye examinations to individual needs includes allowing extra time. Optometrists wanted training and guidance about dementia. Correcting VI may improve the quality of life of people with dementia but should be weighed against the risks and burdens of undergoing examinations and cataract surgery on an individual basis. Limitations: Sampling bias is possible owing to quota-sampling and response bias. Conclusions: The prevalence of VI is disproportionately higher in people with dementia living in care homes. Almost 50% of presenting VI is correctable with spectacles, and more with cataract surgery. Areas for future research are the development of an eye-care pathway for people with dementia; assessment of the benefits of early cataract surgery; and research into the feasibility of specialist optometrists for older people

Population ecology of the sea lamprey (Petromyzon marinus) as an invasive species in the Laurentian Great Lakes and an imperiled species in Europe

The sea lamprey Petromyzon marinus (Linnaeus) is both an invasive non-native species in the Laurentian Great Lakes of North America and an imperiled species in much of its native range in North America and Europe. To compare and contrast how understanding of population ecology is useful for control programs in the Great Lakes and restoration programs in Europe, we review current understanding of the population ecology of the sea lamprey in its native and introduced range. Some attributes of sea lamprey population ecology are particularly useful for both control programs in the Great Lakes and restoration programs in the native range. First, traps within fish ladders are beneficial for removing sea lampreys in Great Lakes streams and passing sea lampreys in the native range. Second, attractants and repellants are suitable for luring sea lampreys into traps for control in the Great Lakes and guiding sea lamprey passage for conservation in the native range. Third, assessment methods used for targeting sea lamprey control in the Great Lakes are useful for targeting habitat protection in the native range. Last, assessment methods used to quantify numbers of all life stages of sea lampreys would be appropriate for measuring success of control in the Great Lakes and success of conservation in the native range

Modelling of the effect of ELMs on fuel retention at the bulk W divertor of JET

Effect of ELMs on fuel retention at the bulk W target of JET ITER-Like Wall was studied with multi-scale calculations. Plasma input parameters were taken from ELMy H-mode plasma experiment. The energetic intra-ELM fuel particles get implanted and create near-surface defects up to depths of few tens of nm, which act as the main fuel trapping sites during ELMs. Clustering of implantation-induced vacancies were found to take place. The incoming flux of inter-ELM plasma particles increases the different filling levels of trapped fuel in defects. The temperature increase of the W target during the pulse increases the fuel detrapping rate. The inter-ELM fuel particle flux refills the partially emptied trapping sites and fills new sites. This leads to a competing effect on the retention and release rates of the implanted particles. At high temperatures the main retention appeared in larger vacancy clusters due to increased clustering rate

On the mechanisms governing gas penetration into a tokamak plasma during a massive gas injection

A new 1D radial fluid code, IMAGINE, is used to simulate the penetration of gas into a tokamak plasma during a massive gas injection (MGI). The main result is that the gas is in general strongly braked as it reaches the plasma, due to mechanisms related to charge exchange and (to a smaller extent) recombination. As a result, only a fraction of the gas penetrates into the plasma. Also, a shock wave is created in the gas which propagates away from the plasma, braking and compressing the incoming gas. Simulation results are quantitatively consistent, at least in terms of orders of magnitude, with experimental data for a D 2 MGI into a JET Ohmic plasma. Simulations of MGI into the background plasma surrounding a runaway electron beam show that if the background electron density is too high, the gas may not penetrate, suggesting a possible explanation for the recent results of Reux et al in JET (2015 Nucl. Fusion 55 093013)

Erratum to: 36th International Symposium on Intensive Care and Emergency Medicine

[This corrects the article DOI: 10.1186/s13054-016-1208-6.]