Faster, more reproducible DESI-MS for biological tissue imaging

A new, more robust sprayer for desorption electrospray ionization (DESI) mass spectrometry imaging is presented. The main source of variability in DESI is thought to be the uncontrolled variability of various geometric parameters of the sprayer, primarily the position of the solvent capillary, or more specifically, its positioning within the gas capillary or nozzle. If the solvent capillary is off-center, the sprayer becomes asymmetrical, making the geometry difficult to control and compromising reproducibility. If the stiffness, tip quality, and positioning of the capillary are improved, sprayer reproducibility can be improved by an order of magnitude. The quality of the improved sprayer and its potential for high spatial resolution imaging are demonstrated on human colorectal tissue samples by acquisition of images at pixel sizes of 100, 50, and 20 μm, which corresponds to a lateral resolution of 40-60 μm, similar to the best values published in the literature. The high sensitivity of the sprayer also allows combination with a fast scanning quadrupole time-of-flight mass spectrometer. This provides up to 30 times faster DESI acquisition, reducing the overall acquisition time for a 10 mm × 10 mm rat brain sample to approximately 1 h. Although some spectral information is lost with increasing analysis speed, the resulting data can still be used to classify tissue types on the basis of a previously constructed model. This is particularly interesting for clinical applications, where fast, reliable diagnosis is required. Graphical Abstract ᅟ

A global model perturbed parameter ensemble study of secondary organic aerosol formation

A global model perturbed parameter ensemble of 60 simulations was used to explore how combinations of six parameters related to secondary organic aerosol (SOA) formation affect particle number concentrations and organic aerosol mass. The parameters represent the formation of organic compounds with different volatilities from biogenic and anthropogenic sources. The most plausible parameter combinations were determined by comparing the simulations against observations of the number concentration of particles larger than 3 nm diameter (N3), the number concentration of particles larger than 50 nm diameter (N50), and the organic aerosol (OA) mass concentration. The simulations expose a high degree of model equifinality in which the skill of widely different parameter combinations cannot be distinguished against observations. We therefore conclude that, based on the observations we have used, a six-parameter SOA scheme is under-determined. Nevertheless, the model skill in simulating N3 and N50 is clearly determined by the low-volatility and extremely low-volatility compounds that affect new particle formation and growth, and the skill in simulating OA mass is determined by the low-volatility and semi-volatile compounds. The biogenic low-volatility class of compounds that grow nucleated clusters and condense on all particles is found to have the strongest effect on the model skill in simulating N3, N50, and OA. The simulations also expose potential structural deficiencies in the model: we find that parameter combinations that are best for N3 and N50 are worst for OA mass, and the ensemble exaggerates the observed seasonal cycle of particle concentrations – a deficiency that we conclude requires an additional anthropogenic source of either primary or secondary particles

Latent cluster analysis of ALS phenotypes identifies prognostically differing groups

BACKGROUND Amyotrophic lateral sclerosis (ALS) is a degenerative disease predominantly affecting motor neurons and manifesting as several different phenotypes. Whether these phenotypes correspond to different underlying disease processes is unknown. We used latent cluster analysis to identify groupings of clinical variables in an objective and unbiased way to improve phenotyping for clinical and research purposes. METHODS Latent class cluster analysis was applied to a large database consisting of 1467 records of people with ALS, using discrete variables which can be readily determined at the first clinic appointment. The model was tested for clinical relevance by survival analysis of the phenotypic groupings using the Kaplan-Meier method. RESULTS The best model generated five distinct phenotypic classes that strongly predicted survival (p<0.0001). Eight variables were used for the latent class analysis, but a good estimate of the classification could be obtained using just two variables: site of first symptoms (bulbar or limb) and time from symptom onset to diagnosis (p<0.00001). CONCLUSION The five phenotypic classes identified using latent cluster analysis can predict prognosis. They could be used to stratify patients recruited into clinical trials and generating more homogeneous disease groups for genetic, proteomic and risk factor research

Blood pressure variability and cardiovascular risk in the PROspective study of pravastatin in the elderly at risk (PROSPER)

Variability in blood pressure predicts cardiovascular disease in young- and middle-aged subjects, but relevant data for older individuals are sparse. We analysed data from the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) study of 5804 participants aged 70–82 years with a history of, or risk factors for cardiovascular disease. Visit-to-visit variability in blood pressure (standard deviation) was determined using a minimum of five measurements over 1 year; an inception cohort of 4819 subjects had subsequent in-trial 3 years follow-up; longer-term follow-up (mean 7.1 years) was available for 1808 subjects. Higher systolic blood pressure variability independently predicted long-term follow-up vascular and total mortality (hazard ratio per 5 mmHg increase in standard deviation of systolic blood pressure = 1.2, 95% confidence interval 1.1–1.4; hazard ratio 1.1, 95% confidence interval 1.1–1.2, respectively). Variability in diastolic blood pressure associated with increased risk for coronary events (hazard ratio 1.5, 95% confidence interval 1.2–1.8 for each 5 mmHg increase), heart failure hospitalisation (hazard ratio 1.4, 95% confidence interval 1.1–1.8) and vascular (hazard ratio 1.4, 95% confidence interval 1.1–1.7) and total mortality (hazard ratio 1.3, 95% confidence interval 1.1–1.5), all in long-term follow-up. Pulse pressure variability was associated with increased stroke risk (hazard ratio 1.2, 95% confidence interval 1.0–1.4 for each 5 mmHg increase), vascular mortality (hazard ratio 1.2, 95% confidence interval 1.0–1.3) and total mortality (hazard ratio 1.1, 95% confidence interval 1.0–1.2), all in long-term follow-up. All associations were independent of respective mean blood pressure levels, age, gender, in-trial treatment group (pravastatin or placebo) and prior vascular disease and cardiovascular disease risk factors. Our observations suggest variability in diastolic blood pressure is more strongly associated with vascular or total mortality than is systolic pressure variability in older high-risk subjects

Robust observational constraint of uncertain aerosol processes and emissions in a climate model and the effect on aerosol radiative forcing

The effect of observational constraint on the ranges of uncertain physical and chemical process parameters was explored in a global aerosol–climate model. The study uses 1 million variants of the Hadley Centre General Environment Model version 3 (HadGEM3) that sample 26 sources of uncertainty, together with over 9000 monthly aggregated grid-box measurements of aerosol optical depth, PM2.5, particle number concentrations, sulfate and organic mass concentrations. Despite many compensating effects in the model, the procedure constrains the probability distributions of parameters related to secondary organic aerosol, anthropogenic SO2 emissions, residential emissions, sea spray emissions, dry deposition rates of SO2 and aerosols, new particle formation, cloud droplet pH and the diameter of primary combustion particles. Observational constraint rules out nearly 98 % of the model variants. On constraint, the ±1σ (standard deviation) range of global annual mean direct radiative forcing (RFari) is reduced by 33 % to −0.14 to −0.26 W m−2, and the 95 % credible interval (CI) is reduced by 34 % to −0.1 to −0.32 W m−2. For the global annual mean aerosol–cloud radiative forcing, RFaci, the ±1σ range is reduced by 7 % to −1.66 to −2.48 W m−2, and the 95 % CI by 6 % to −1.28 to −2.88 W m−2. The tightness of the constraint is limited by parameter cancellation effects (model equifinality) as well as the large and poorly defined “representativeness error” associated with comparing point measurements with a global model. The constraint could also be narrowed if model structural errors that prevent simultaneous agreement with different measurement types in multiple locations and seasons could be improved. For example, constraints using either sulfate or PM2.5 measurements individually result in RFari±1σ ranges that only just overlap, which shows that emergent constraints based on one measurement type may be overconfident

The appropriateness of prescribing antibiotics in the community in Europe: study design

Contains fulltext : 97417.pdf (publisher's version ) (Open Access)ABSTRACT: BACKGROUND: Over 90% of all antibiotics in Europe are prescribed in primary care. It is important that antibiotics are prescribed that are likely to be effective; however, information about antibiotic resistance in the community is incomplete. The aim of our study is to investigate the appropriateness of antibiotic prescribing in primary care in Europe by collecting and combining patterns of antibiotic resistance patterns and antibiotic prescription patterns in primary care. We will also evaluate the appropriateness of national antibiotic prescription guidelines in relation to resistance patterns. METHODS/DESIGN: Antibiotic resistance will be studied in an opportunistic sample from the community in nine European countries. Resistance data will be collected by taking a nose swab of persons (N = 4,000 per country) visiting a primary care practice for a non-infectious disease. Staphylococcus aureus and Streptococcus pneumoniae will be isolated and tested for resistance to a range of antibiotics in one central laboratory. Data on antibiotic prescriptions over the past 5 years will be extracted from the electronic medical records of General Practitioners (GPs). The results of the study will include the prevalence and resistance data of the two species and 5 years of antibiotic prescription data in nine European countries.The odds of receiving an effective antibiotic in each country will be calculated as a measure for the appropriateness of prescribing. Multilevel analysis will be used to assess the appropriateness of prescribing. Relevant treatment guidelines of the nine participating countries will be evaluated using a standardized instrument and related to the resistance patterns in that country. DISCUSSION: This study will provide valuable and unique data concerning resistance patterns and prescription behaviour in primary care in nine European countries. It will provide evidence-based recommendations for antibiotic treatment guidelines that take resistance patterns into account which will be useful for both clinicians and policy makers. By improving antibiotic use we can move towards controlling the resistance problem globally

Obstetric and perinatal factors as predictors of child behaviour at 5 years

Objective To identify whether obstetric and perinatal factors are independent predictors of child behaviour at 5 years. Methodology The Mater University Study of Pregnancy (MUSP) is a prospective cohort study of 8556 mothers enrolled in early pregnancy. The relationship of obstetric and perinatal factors, maternal lifestyle, age and gender of the child, and social disadvantage were examined as predictors of child behaviour in 5005 children completing a modified child behaviour checklist at 5 years. This checklist contained three independent groups of behaviour: externalizng, internalizing and SAT (social, attentional and thought problems). Results In the initial analysis a limited number of associations were present. After adjusting for measures of social disadvantage, only number of antenatal admissions was associated with child behaviour in all three scales, while maternal cigarette smoking in pregnancy and male gender were associated with externalising and SAT behaviours. Conclusions Most common epidemiologic obstetric and perinatal risk factors were not independent predictors of behaviour problems in children at 5 years

The global aerosol synthesis and science project (GASSP): Measurements and modeling to reduce uncertainty

This is the final version of the article. Available from American Meteorological Society via the DOI in this record.The largest uncertainty in the historical radiative forcing of climate is caused by changes in aerosol particles due to anthropogenic activity. Sophisticated aerosol microphysics processes have been included in many climate models in an effort to reduce the uncertainty. However, the models are very challenging to evaluate and constrain because they require extensive in situ measurements of the particle size distribution, number concentration, and chemical composition that are not available from global satellite observations. The Global Aerosol Synthesis and Science Project (GASSP) aims to improve the robustness of global aerosol models by combining new methodologies for quantifying model uncertainty, to create an extensive global dataset of aerosol in situ microphysical and chemical measurements, and to develop new ways to assess the uncertainty associated with comparing sparse point measurements with low-resolution models. GASSP has assembled over 45,000 hours of measurements from ships and aircraft as well as data from over 350 ground stations. The measurements have been harmonized into a standardized format that is easily used by modelers and nonspecialist users. Available measurements are extensive, but they are biased to polluted regions of the Northern Hemisphere, leaving large pristine regions and many continental areas poorly sampled. The aerosol radiative forcing uncertainty can be reduced using a rigorous model–data synthesis approach. Nevertheless, our research highlights significant remaining challenges because of the difficulty of constraining many interwoven model uncertainties simultaneously. Although the physical realism of global aerosol models still needs to be improved, the uncertainty in aerosol radiative forcing will be reduced most effectively by systematically and rigorously constraining the models using extensive syntheses of measurements.GASSP was funded by the Natural Environment Research Council (NERC) under Grants NE/J024252/1, NE/J022624/1, and NE/J023515/1; ACID-PRUF under Grants NE/I020059/1 and NE/I020148/1; the European Union BACCHUS project under Grant 603445-BACCHUS; ACTRIS under Grants 262254 and 654109; and by the UK–China Research and Innovation Partnership Fund through the Met Office Climate Science for Service Partnership (CSSP) China as part of the Newton Fund. We made use of the N8 HPC facility funded from the N8 consortium and an Engineering and Physical Sciences Research Council Grant to use ARCHER (EP/K000225/1) and the JASMIN facility (www.jasmin.ac.uk/) via the Centre for Environmental Data Analysis funded by NERC and the UK Space Agency and delivered by the Science and Technology Facilities Council. We acknowledge the following additional funding: the Royal Society Wolfson Merit Award (Carslaw); a doctoral training grant from the Natural Environment Research Council and a CASE studentship with the Met Office Hadley Centre (Regayre); the European Research Council under the European Union’s Seventh Framework Programme (FP7/2007-2013)/ERC Grant Agreement FP7-280025 (Stier); the Department of Energy under DE-SC0007178 (Zhang); the U.S. National Science Foundation under ATM-745986 (Snider); the NOAA Global Change Program (Nenes); NASA Global Tropospheric Experiment Program, the NASA Tropospheric Composition Program, the NASA Radiation Sciences Program, and the NASA Earth Venture Suborbital Project (Anderson); the NOAA Climate Program Office (Quinn); NSF Atmospheric Chemistry Program, the NASA Global Tropospheric Experiment, and NASA Earth Science Project Office (Clarke); German Federal Ministry of Education and Research (BMBF) CLOUD12 project Grant 01LK1222B (Kristensen); Swedish Research Council (VR), the Knut and Alice Wallenberg Foundation and the Swedish Polar Research Secretariat (SPRS) for access to the icebreaker Oden and logistical support (Leck); the Department of Energy (DE-SC0007178) and the Max Planck Society (Andreae, Poeschl); the global environment research fund of the Ministry of the Environment in Japan (2-1403), the Arctic Challenge for Sustainability (ArCS) project of the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) in Japan, and the Japan Society for the Promotion of Science (JSPS) KAKENHI (Grants JP16H01770, JP26701004, and JP26241003) (Kondo, Oshima); Lufthansa for enabling CARIBIC and the German Federal Ministry of Education and Research (BMBF) for financing the CARIBIC instruments operation as part of the Joint Project IAGOS-D (Hermann); the Collaborative Innovation Center of Climate Change supported by the Jiangsu provincial government and the JirLATEST supported by the Ministry of Education, China (Ding and Chi); the Max Planck Institute for Chemistry, Mainz, Germany (Schmale); the NOAA Atmospheric Composition and Climate Program, the NASA Radiation Sciences Program, and the NASA Upper Atmosphere Research Program supporting the NOAA SP2 BC data acquisition and analysis (Schwarz); DOE (BER/ASR) DE-SC0016559 and EPA STAR 83587701-0 (the EPA has not reviewed this manuscript and no endorsement should be inferred) (Jimenez); and Environment and Climate Change Canada (Leaitch)

Circumstellar disks and planets. Science cases for next-generation optical/infrared long-baseline interferometers

We present a review of the interplay between the evolution of circumstellar disks and the formation of planets, both from the perspective of theoretical models and dedicated observations. Based on this, we identify and discuss fundamental questions concerning the formation and evolution of circumstellar disks and planets which can be addressed in the near future with optical and infrared long-baseline interferometers. Furthermore, the importance of complementary observations with long-baseline (sub)millimeter interferometers and high-sensitivity infrared observatories is outlined.Comment: 83 pages; Accepted for publication in "Astronomy and Astrophysics Review"; The final publication is available at http://www.springerlink.co