Integrated data acquisition and processing to determine metabolite contents, relaxation times, and macromolecule baseline in single examinations of individual subjects

Absolute quantitation of clinical (1)H-MR spectra is virtually always incomplete for single subjects because the separate determination of spectrum, baseline, and transverse and longitudinal relaxation times in single subjects is prohibitively long. Integrated Processing and Acquisition of Data (IPAD) based on a combined 2-dimensional experimental and fitting strategy is suggested to substantially improve the information content from a given measurement time. A series of localized saturation-recovery spectra was recorded and combined with 2-dimensional prior-knowledge fitting to simultaneously determine metabolite T(1) (from analysis of the saturation-recovery time course), metabolite T(2) (from lineshape analysis based on metabolite and water peak shapes), macromolecular baseline (based on T(1) differences and analysis of the saturation-recovery time course), and metabolite concentrations (using prior knowledge fitting and conventional procedures of absolute standardization). The procedure was tested on metabolite solutions and applied in 25 subjects (15-78 years old). Metabolite content was comparable to previously found values. Interindividual variation was larger than intraindividual variation in repeated spectra for metabolite content as well as for some relaxation times. Relaxation times were different for various metabolite groups. Parts of the interindividual variation could be explained by significant age dependence of relaxation times.

Safety of non-therapeutic atomoxetine exposures - a national poison data system study

AIMS This study's objective is to assess the safety of non-therapeutic atomoxetine exposures reported to the US National Poison Database System (NPDS). METHODS This is a retrospective database study of non-therapeutic single agent ingestions of atomoxetine in children and adults reported to the NPDS between 2002 and 2010. RESULTS A total of 20 032 atomoxetine exposures were reported during the study period, and 12 370 of these were single agent exposures. The median age was 9 years (interquartile range 3, 14), and 7380 were male (59.7%). Of the single agent exposures, 8813 (71.2%) were acute exposures, 3315 (26.8%) were acute-on-chronic, and 166 (1.3%) were chronic. In 10 608 (85.8%) cases, exposure was unintentional, in 1079 (8.7%) suicide attempts, and in 629 (5.1%) cases abuse. Of these cases, 3633 (29.4 %) were managed at health-care facilities. Acute-on-chronic exposure was associated with an increased risk of a suicidal reason for exposure compared with acute ingestions (odds ratio 1.44, 95% confidence interval 1.26-1.65). Most common clinical effects were drowsiness or lethargy (709 cases; 5.7%), tachycardia (555; 4.5%), and nausea (388; 3.1%). Major toxicity was observed in 21 cases (seizures in nine (42.9%), tachycardia in eight (38.1%), coma in six (28.6%), and ventricular dysrhythmia in one case (4.8%)). CONCLUSIONS Non-therapeutic atomoxetine exposures were largely safe, but seizures were rarely observed.

Overview of data assimilation methods

We present the data assimilation approach, which provides a framework for combining observations and model simulations of the climate system, and has led to a new field of applications for paleoclimatology. The three subsequent articles explore specific applications in more detail.

A reconstruction of radiocarbon production and total solar irradiance from the Holocene ¹⁴C and CO₂ records: implications of data and model uncertainties

Radiocarbon production, solar activity, total solar irradiance (TSI) and solar-induced climate change are reconstructed for the Holocene (10 to 0 kyr BP), and TSI is predicted for the next centuries. The IntCal09/SHCal04 radiocarbon and ice core CO2 records, reconstructions of the geomagnetic dipole, and instrumental data of solar activity are applied in the Bern3D-LPJ, a fully featured Earth system model of intermediate complexity including a 3-D dynamic ocean, ocean sediments, and a dynamic vegetation model, and in formulations linking radiocarbon production, the solar modulation potential, and TSI. Uncertainties are assessed using Monte Carlo simulations and bounding scenarios. Transient climate simulations span the past 21 thousand years, thereby considering the time lags and uncertainties associated with the last glacial termination. Our carbon-cycle-based modern estimate of radiocarbon production of 1.7 atoms cm−2 s−1 is lower than previously reported for the cosmogenic nuclide production model by Masarik and Beer (2009) and is more in-line with Kovaltsov et al. (2012). In contrast to earlier studies, periods of high solar activity were quite common not only in recent millennia, but throughout the Holocene. Notable deviations compared to earlier reconstructions are also found on decadal to centennial timescales. We show that earlier Holocene reconstructions, not accounting for the interhemispheric gradients in radiocarbon, are biased low. Solar activity is during 28% of the time higher than the modern average (650 MeV), but the absolute values remain weakly constrained due to uncertainties in the normalisation of the solar modulation to instrumental data. A recently published solar activity–TSI relationship yields small changes in Holocene TSI of the order of 1 W m−2 with a Maunder Minimum irradiance reduction of 0.85 ± 0.16 W m−2. Related solar-induced variations in global mean surface air temperature are simulated to be within 0.1 K. Autoregressive modelling suggests a declining trend of solar activity in the 21st century towards average Holocene conditions.

Justification of Data Warehousing Projects

Project justification is regarded as one of the major methodological deficits in Data Warehousing practice. As reasons for applying inappropriate methods, performing incomplete evaluations, or even entirely omitting justifications, the special nature of Data Warehousing benefits and the large portion of infrastructure-related activities are stated. In this paper, the economic justification of Data Warehousing projects is analyzed, and first results from a large academiaindustry collaboration project in the field of non-technical issues of Data Warehousing are presented. As conceptual foundations, the role of the Data Warehouse system in corporate application architectures is analyzed, and the specific properties of Data Warehousing projects are discussed. Based on an applicability analysis of traditional approaches to economic IT project justification, basic steps and responsibilities for the justification of Data Warehousing projects are derived.

Multiplicity of data in trial reports and the reliability of meta-analyses: empirical study

Objectives To examine the extent of multiplicity of data in trial reports and to assess the impact of multiplicity on meta-analysis results. Design Empirical study on a cohort of Cochrane systematic reviews. Data sources All Cochrane systematic reviews published from issue 3 in 2006 to issue 2 in 2007 that presented a result as a standardised mean difference (SMD). We retrieved trial reports contributing to the first SMD result in each review, and downloaded review protocols. We used these SMDs to identify a specific outcome for each meta-analysis from its protocol. Review methods Reviews were eligible if SMD results were based on two to ten randomised trials and if protocols described the outcome. We excluded reviews if they only presented results of subgroup analyses. Based on review protocols and index outcomes, two observers independently extracted the data necessary to calculate SMDs from the original trial reports for any intervention group, time point, or outcome measure compatible with the protocol. From the extracted data, we used Monte Carlo simulations to calculate all possible SMDs for every meta-analysis. Results We identified 19 eligible meta-analyses (including 83 trials). Published review protocols often lacked information about which data to choose. Twenty-four (29%) trials reported data for multiple intervention groups, 30 (36%) reported data for multiple time points, and 29 (35%) reported the index outcome measured on multiple scales. In 18 meta-analyses, we found multiplicity of data in at least one trial report; the median difference between the smallest and largest SMD results within a meta-analysis was 0.40 standard deviation units (range 0.04 to 0.91). Conclusions Multiplicity of data can affect the findings of systematic reviews and meta-analyses. To reduce the risk of bias, reviews and meta-analyses should comply with prespecified protocols that clearly identify time points, intervention groups, and scales of interest.

Acquisition of a multifunctional IgA+ plasma cell phenotype in the gut

The largest mucosal surface in the body is in the gastrointestinal tract, a location that is heavily colonized by microbes that are normally harmless. A key mechanism required for maintaining a homeostatic balance between this microbial burden and the lymphocytes that densely populate the gastrointestinal tract is the production and transepithelial transport of poly-reactive IgA (ref. 1). Within the mucosal tissues, B cells respond to cytokines, sometimes in the absence of T-cell help, undergo class switch recombination of their immunoglobulin receptor to IgA, and differentiate to become plasma cells. However, IgA-secreting plasma cells probably have additional attributes that are needed for coping with the tremendous bacterial load in the gastrointestinal tract. Here we report that mouse IgA(+) plasma cells also produce the antimicrobial mediators tumour-necrosis factor-α (TNF-α) and inducible nitric oxide synthase (iNOS), and express many molecules that are commonly associated with monocyte/granulocytic cell types. The development of iNOS-producing IgA(+) plasma cells can be recapitulated in vitro in the presence of gut stroma, and the acquisition of this multifunctional phenotype in vivo and in vitro relies on microbial co-stimulation. Deletion of TNF-α and iNOS in B-lineage cells resulted in a reduction in IgA production, altered diversification of the gut microbiota and poor clearance of a gut-tropic pathogen. These findings reveal a novel adaptation to maintaining homeostasis in the gut, and extend the repertoire of protective responses exhibited by some B-lineage cells.

Acquisition of complement inhibitor serine protease factor I and its cofactors C4b-binding protein and factor H by Prevotella intermedia

Infection with the Gram-negative pathogen Prevotella intermedia gives rise to periodontitis and a growing number of studies implies an association of P. intermedia with rheumatoid arthritis. The serine protease Factor I (FI) is the central inhibitor of complement degrading complement components C3b and C4b in the presence of cofactors such as C4b-binding protein (C4BP) and Factor H (FH). Yet, the significance of complement inhibitor acquisition in P. intermedia infection and FI binding by Gram-negative pathogens has not been addressed. Here we show that P. intermedia isolates bound purified FI as well as FI directly from heat-inactivated human serum. FI bound to bacteria retained its serine protease activity as shown in degradation experiments with (125)I-labeled C4b. Since FI requires cofactors for its activity we also investigated the binding of purified cofactors C4BP and FH and found acquisition of both proteins, which retained their activity in FI mediated degradation of C3b and C4b. We propose that FI binding by P. intermedia represents a new mechanism contributing to complement evasion by a Gram-negative bacterial pathogen associated with chronic diseases.

Antimicrobial use in Swiss dairy farms: quantification and evaluation of data quality

Data on antimicrobial use play a key role in the development of policies for the containment of antimicrobial resistance. On-farm data could provide a detailed overview of the antimicrobial use, but technical and methodological aspects of data collection and interpretation, as well as data quality need to be further assessed. The aims of this study were (1) to quantify antimicrobial use in the study population using different units of measurement and contrast the results obtained, (2) to evaluate data quality of farm records on antimicrobial use, and (3) to compare data quality of different recording systems. During 1 year, data on antimicrobial use were collected from 97 dairy farms. Antimicrobial consumption was quantified using: (1) the incidence density of antimicrobial treatments; (2) the weight of active substance; (3) the used daily dose and (4) the used course dose for antimicrobials for intestinal, intrauterine and systemic use; and (5) the used unit dose, for antimicrobials for intramammary use. Data quality was evaluated by describing completeness and accuracy of the recorded information, and by comparing farmers' and veterinarians' records. Relative consumption of antimicrobials depended on the unit of measurement: used doses reflected the treatment intensity better than weight of active substance. The use of antimicrobials classified as high priority was low, although under- and overdosing were frequently observed. Electronic recording systems allowed better traceability of the animals treated. Recording drug name or dosage often resulted in incomplete or inaccurate information. Veterinarians tended to record more drugs than farmers. The integration of veterinarian and farm data would improve data quality.