Guidelines and considerations for the use of system suitability and quality control samples in mass spectrometry assays applied in untargeted clinical metabolomic studies

Background Quality assurance (QA) and quality control (QC) are two quality management processes that are integral to the success of metabolomics including their application for the acquisition of high quality data in any high-throughput analytical chemistry laboratory. QA defines all the planned and systematic activities implemented before samples are collected, to provide confidence that a subsequent analytical process will fulfil predetermined requirements for quality. QC can be defined as the operational techniques and activities used to measure and report these quality requirements after data acquisition. Aim of review This tutorial review will guide the reader through the use of system suitability and QC samples, why these samples should be applied and how the quality of data can be reported. Key scientific concepts of review System suitability samples are applied to assess the operation and lack of contamination of the analytical platform prior to sample analysis. Isotopically-labelled internal standards are applied to assess system stability for each sample analysed. Pooled QC samples are applied to condition the analytical platform, perform intra-study reproducibility measurements (QC) and to correct mathematically for systematic errors. Standard reference materials and long-term reference QC samples are applied for inter-study and inter-laboratory assessment of data

MUSCLE : automated multi-objective evolutionary optimization of targeted LC-MS/MS analysis:Automated multi-objective evolutionary optimization of targeted LC-MS/MS analysis

Summary: Developing liquid chromatography tandem mass spectrometry (LC-MS/MS) analyses of (bio)chemicals is both time consuming and challenging, largely because of the large number of LC and MS instrument parameters that need to be optimized. This bottleneck significantly impedes our ability to establish new (bio)analytical methods in fields such as pharmacology, metabolomics and pesticide research. We report the development of a multi-platform, user-friendly software tool MUSCLE (multi-platform unbiased optimization of spectrometry via closed-loop experimentation) for the robust and fully automated multi-objective optimization of targeted LC-MS/MS analysis. MUSCLE shortened the analysis times and increased the analytical sensitivities of targeted metabolite analysis, which was demonstrated on two different manufacturer’s LC-MS/MS instruments. Availability and implementation: Available at http://www.muscleproject.org. Contact: [email protected] Supplementary information: Supplementary data are available at Bioinformatics online

Multivariable fractional polynomial interaction to investigate continuous effect modifiers in a meta-analysis on higher versus lower PEEP for patients with ARDS.

OBJECTIVES: A recent individual patient data (IPD) meta-analysis suggested that patients with moderate or severe acute respiratory distress syndrome (ARDS) benefit from higher positive end-expiratory pressure (PEEP) ventilation strategies. However, thresholds for continuous variables (eg, hypoxaemia) are often arbitrary and linearity assumptions in regression approaches may not hold; the multivariable fractional polynomial interaction (MFPI) approach can address both problems. The objective of this study was to apply the MFPI approach to investigate interactions between four continuous patient baseline variables and higher versus lower PEEP on clinical outcomes. SETTING: Pooled data from three randomised trials in intensive care identified by a systematic review. PARTICIPANTS: 2299 patients with acute lung injury requiring mechanical ventilation. INTERVENTIONS: Higher (N=1136) versus lower PEEP (N=1163) ventilation strategy. OUTCOME MEASURES: Prespecified outcomes included mortality, time to death and time-to-unassisted breathing. We examined the following continuous baseline characteristics as potential effect modifiers using MFPI: PaO2/FiO2 (arterial partial oxygen pressure/ fraction of inspired oxygen), oxygenation index, respiratory system compliance (tidal volume/(inspiratory plateau pressure-PEEP)) and body mass index (BMI). RESULTS: We found that for patients with PaO2/FiO2 below 150 mm Hg, but above 100 mm Hg or an oxygenation index above 12 (moderate ARDS), higher PEEP reduces hospital mortality, but the beneficial effect appears to level off for patients with very severe ARDS. Patients with mild ARDS (PaO2/FiO2 above 200 mm Hg or an oxygenation index below 10) do not seem to benefit from higher PEEP and might even be harmed. For patients with a respiratory system compliance above 40 mL/cm H2O or patients with a BMI above 35 kg/m(2), we found a trend towards reduced mortality with higher PEEP, but there is very weak statistical confidence in these findings. CONCLUSIONS: MFPI analyses suggest a nonlinear effect modification of higher PEEP ventilation by PaO2/FiO2 and oxygenation index with reduced mortality for some patients suffering from moderate ARDS. STUDY REGISTRATION NUMBER: CRD42012003129

Localized modes at a D-brane--O-plane intersection and heterotic Alice strings

We study a system of $N_c$ $D3$-branes intersecting $D7$-branes and $O7$-planes in 1+1-dimensions. We use anomaly cancellation and string dualities to argue that there must be chiral fermion zero-modes on the $D3$-branes which are localized near the $O7$-planes. Away from the orientifold limit we verify this by using index theory as well as explicit construction of the zero-modes. This system is related to F-theory on K3 and heterotic matrix string theory, and the heterotic strings are related to Alice string defects in $\mathcal{N}=4$ Super-Yang-Mills. In the limit of large $N_c$ we find an $AdS_3$ dual of the heterotic matrix string CFT.Comment: 44 pages, typos corrected, version published in JHE

Revisiting soliton contributions to perturbative amplitudes

Open Access funded by SCOAP3. CP is a Royal Society Research Fellow and partly supported by the U.S. Department of Energy under grants DOE-SC0010008, DOE-ARRA-SC0003883 and DOE-DE-SC0007897. ABR is supported by the Mitchell Family Foundation. We would like to thank the Mitchell Institute at Texas A&M and the NHETC at Rutgers University respectively for hospitality during the course of this work. We would also like to acknowledge the Aspen Center for Physics and NSF grant 1066293 for a stimulating research environment

T-dualising the Deformed and Resolved Conifold

In a previous paper we used T-duality to construct a new type of 1/4-BPS solution describing a pair of NS5-branes intersecting in 1+3 dimensions and localised in all other directions except for a single transverse circle. This led to an explicit solution to a sourced Monge--Ampere equation, of which there are few known examples. In this paper we refine this formalism and apply it to two important generalisations: the resolved and deformed conifolds. In doing so we construct two new solutions describing, respectively, a pair of NS5-branes separated in a transverse direction and a pair of NS5-branes with smooth `diamond' profile. We show how the parameter of the resolved conifold (size of the S^2) maps to a transverse separation of the NS5-branes, while the modulus of the deformed conifold (size of the S^3) maps to the deformation parameter of the diamond web.Comment: 57 pages, 1 figure; v2: typos fixe

How do multi-stage, multi-arm trials compare to the traditional two-arm parallel group design – a reanalysis of 4 trials

<p>Abstract</p> <p>Background</p> <p>To speed up the evaluation of new therapies, the multi-arm, multi-stage trial design was suggested previously by the authors.</p> <p>Methods</p> <p>In this paper, we evaluate the performance of the two-stage, multi-arm design using four cancer trials conducted at the MRC CTU. The performance of the design at fictitious interim analyses is assessed using a conditional bootstrap approach.</p> <p>Results</p> <p>Two main aims are addressed: the error rate of correctly carrying on/stopping the trial at an interim analysis as well as quantifying the gains in terms of resources by employing this design. Furthermore, we make suggestions for the best timing of this interim analysis.</p> <p>Conclusion</p> <p>Multi-arm, multi-stage trials are an effective way of speeding up the therapy evaluation process. The design performs well in terms of the type I and II error rates.</p

A comprehensive computational model of sound transmission through the porcine lung

A comprehensive computational simulation model of sound transmission through the porcine lung is introduced and experimentally evaluated. This subject-specific model utilizes parenchymal and major airway geometry derived from x-ray CT images. The lung parenchyma is modeled as a poroviscoelastic material using Biot theory. A finite element (FE) mesh of the lung that includes airway detail is created and used in COMSOL FE software to simulate the vibroacoustic response of the lung to sound input at the trachea. The FE simulation model is validated by comparing simulation results to experimental measurements using scanning laser Doppler vibrometry on the surface of an excised, preserved lung. The FE model can also be used to calculate and visualize vibroacoustic pressure and motion inside the lung and its airways caused by the acoustic input. The effect of diffuse lung fibrosis and of a local tumor on the lung acoustic response is simulated and visualized using the FE model. In the future, this type of visualization can be compared and matched with experimentally obtained elastographic images to better quantify regional lung material properties to noninvasively diagnose and stage disease and response to treatment

Anomalities in the Analysis of Calibrated Data

This study examines effects of calibration errors on model assumptions and data--analytic tools in direct calibration assays. These effects encompass induced dependencies, inflated variances, and heteroscedasticity among the calibrated measurements, whose distributions arise as mixtures. These anomalies adversely affect conventional inferences, to include the inconsistency of sample means; the underestimation of measurement variance; and the distributions of sample means, sample variances, and Student's t as mixtures. Inferences in comparative experiments remain largely intact, although error mean squares continue to underestimate the measurement variances. These anomalies are masked in practice, as conventional diagnostics cannot discern irregularities induced through calibration. Case studies illustrate the principal issues

Long-Term Seizure Suppression and Optogenetic Analyses of Synaptic Connectivity in Epileptic Mice with Hippocampal Grafts of GABAergic Interneurons

Studies in rodent epilepsy models suggest that GABAergic interneuron progenitor grafts can reduce hyperexcitability and seizures in temporal lobe epilepsy (TLE). Although integration of the transplanted cells has been proposed as the underlying mechanism for these disease-modifying effects, prior studies have not explicitly examined cell types and synaptic mechanisms for long-term seizure suppression. To address this gap, we transplanted medial ganglionic eminence (MGE) cells from embryonic day 13.5 VGAT-Venus or VGAT-ChR2-EYFP transgenic embryos into the dentate gyrus (DG) of adult mice 2 weeks after induction of TLE with pilocarpine. Beginning 3–4 weeks after status epilepticus, we conducted continuous video-electroencephalographic recording until 90–100 d. TLE mice with bilateral MGE cell grafts in the DG had significantly fewer and milder electrographic seizures, compared with TLE controls. Immunohistochemical studies showed that the transplants contained multiple neuropeptide or calcium-binding protein-expressing interneuron types and these cells established dense terminal arborizations onto the somas, apical dendrites, and axon initial segments of dentate granule cells (GCs). A majority of the synaptic terminals formed by the transplanted cells were apposed to large postsynaptic clusters of gephyrin, indicative of mature inhibitory synaptic complexes. Functionality of these new inhibitory synapses was demonstrated by optogenetically activating VGAT-ChR2-EYFP-expressing transplanted neurons, which generated robust hyperpolarizations in GCs. These findings suggest that fetal GABAergic interneuron grafts may suppress pharmacoresistant seizures by enhancing synaptic inhibition in DG neural circuits