Validation of the Valve Academic Research Consortium Bleeding Definition in Patients With Severe Aortic Stenosis Undergoing Transcatheter Aortic Valve Implantation.

BACKGROUND The Valve Academic Research Consortium (VARC) has proposed a standardized definition of bleeding in patients undergoing transcatheter aortic valve interventions (TAVI). The VARC bleeding definition has not been validated or compared to other established bleeding definitions so far. Thus, we aimed to investigate the impact of bleeding and compare the predictivity of VARC bleeding events with established bleeding definitions. METHODS AND RESULTS Between August 2007 and April 2012, 489 consecutive patients with severe aortic stenosis were included into the Bern-TAVI-Registry. Every bleeding complication was adjudicated according to the definitions of VARC, BARC, TIMI, and GUSTO. Periprocedural blood loss was added to the definition of VARC, providing a modified VARC definition. A total of 152 bleeding events were observed during the index hospitalization. Bleeding severity according to VARC was associated with a gradual increase in mortality, which was comparable to the BARC, TIMI, GUSTO, and the modified VARC classifications. The predictive precision of a multivariable model for mortality at 30 days was significantly improved by adding the most serious bleeding of VARC (area under the curve [AUC], 0.773; 95% confidence interval [CI], 0.706 to 0.839), BARC (AUC, 0.776; 95% CI, 0.694 to 0.857), TIMI (AUC, 0.768; 95% CI, 0.692 to 0.844), and GUSTO (AUC, 0.791; 95% CI, 0.714 to 0.869), with the modified VARC definition resulting in the best predictivity (AUC, 0.814; 95% CI, 0.759 to 0.870). CONCLUSIONS The VARC bleeding definition offers a severity stratification that is associated with a gradual increase in mortality and prognostic information comparable to established bleeding definitions. Adding the information of periprocedural blood loss to VARC may increase the sensitivity and the predictive power of this classification.

Analysis of Phenotypic Variation in Childhood Wheezing Disorders

Recurrent wheezing or asthma is a common problem in children that has increased considerably in prevalence in the past few decades. The causes and underlying mechanisms are poorly understood and it is thought that a numb er of distinct diseases causing similar symptoms are involved. Due to the lack of a biologically founded classification system, children are classified according to their observed disease related features (symptoms, signs, measurements) into phenotypes. The objectives of this PhD project were a) to develop tools for analysing phenotypic variation of a disease, and b) to examine phenotypic variability of wheezing among children by applying these tools to existing epidemiological data. A combination of graphical methods (multivariate co rrespondence analysis) and statistical models (latent variables models) was used. In a first phase, a model for discrete variability (latent class model) was applied to data on symptoms and measurements from an epidemiological study to identify distinct phenotypes of wheezing. In a second phase, the modelling framework was expanded to include continuous variability (e.g. along a severity gradient) and combinations of discrete and continuo us variability (factor models and factor mixture models). The third phase focused on validating the methods using simulation studies. The main body of this thesis consists of 5 articles (3 published, 1 submitted and 1 to be submitted) including applications, methodological contributions and a review. The main findings and contributions were: 1) The application of a latent class model to epidemiological data (symptoms and physiological measurements) yielded plausible pheno types of wheezing with distinguishing characteristics that have previously been used as phenotype defining characteristics. 2) A method was proposed for including responses to conditional questions (e.g. questions on severity or triggers of wheezing are asked only to children with wheeze) in multivariate modelling.ii 3) A panel of clinicians was set up to agree on a plausible model for wheezing diseases. The model can be used to generate datasets for testing the modelling approach. 4) A critical review of methods for defining and validating phenotypes of wheeze in children was conducted. 5) The simulation studies showed that a parsimonious parameterisation of the models is required to identify the true underlying structure of the data. The developed approach can deal with some challenges of real-life cohort data such as variables of mixed mode (continuous and categorical), missing data and conditional questions. If carefully applied, the approach can be used to identify whether the underlying phenotypic variation is discrete (classes), continuous (factors) or a combination of these. These methods could help improve precision of research into causes and mechanisms and contribute to the development of a new classification of wheezing disorders in children and other diseases which are difficult to classify.

A rapid and efficient ion-exchange chromatography for Lu–Hf, Sm–Nd, and Rb–Sr geochronology and the routine isotope analysis of sub-ng amounts of Hf by MC-ICP-MS

The development and improvement of MC-ICP-MS instruments have fueled the growth of Lu–Hf geochronology over the last two decades, but some limitations remain. Here, we present improvements in chemical separation and mass spectrometry that allow accurate and precise measurements of 176Hf/177Hf and 176Lu/177Hf in high-Lu/Hf samples (e.g., garnet and apatite), as well as for samples containing sub-nanogram quantities of Hf. When such samples are spiked, correcting for the isobaric interference of 176Lu on 176Hf is not always possible if the separation of Lu and Hf is insufficient. To improve the purification of Hf, the high field strength elements (HFSE, including Hf) are first separated from the rare earth elements (REE, including Lu) on a first-stage cation column modified after Patchett and Tatsumoto (Contrib. Mineral. Petrol., 1980, 75, 263–267). Hafnium is further purified on an Ln-Spec column adapted from the procedures of Münker et al. (Geochem., Geophys., Geosyst., 2001, DOI: 10.1029/2001gc000183) and Wimpenny et al. (Anal. Chem., 2013, 85, 11258–11264) typically resulting in Lu/Hf < 0.0001, Zr/Hf < 1, and Ti/Hf < 0.1. In addition, Sm–Nd and Rb–Sr separations can easily be added to the described two-stage ion-exchange procedure for Lu–Hf. The isotopic compositions are measured on a Thermo Scientific Neptune Plus MC-ICP-MS equipped with three 1012 Ω resistors. Multiple 176Hf/177Hf measurements of international reference rocks yield a precision of 5–20 ppm for solutions containing 40 ppb of Hf, and 50–180 ppm for 1 ppb solutions (=0.5 ng sample Hf 0.5 in ml). The routine analysis of sub-ng amounts of Hf will facilitate Lu–Hf dating of low-concentration samples.

Evaluation of 3-dimensional superimposition techniques on various skeletal structures of the head using surface models.

OBJECTIVES To test the applicability, accuracy, precision, and reproducibility of various 3D superimposition techniques for radiographic data, transformed to triangulated surface data. METHODS Five superimposition techniques (3P: three-point registration; AC: anterior cranial base; AC + F: anterior cranial base + foramen magnum; BZ: both zygomatic arches; 1Z: one zygomatic arch) were tested using eight pairs of pre-existing CT data (pre- and post-treatment). These were obtained from non-growing orthodontic patients treated with rapid maxillary expansion. All datasets were superimposed by three operators independently, who repeated the whole procedure one month later. Accuracy was assessed by the distance (D) between superimposed datasets on three form-stable anatomical areas, located on the anterior cranial base and the foramen magnum. Precision and reproducibility were assessed using the distances between models at four specific landmarks. Non parametric multivariate models and Bland-Altman difference plots were used for analyses. RESULTS There was no difference among operators or between time points on the accuracy of each superimposition technique (p>0.05). The AC + F technique was the most accurate (D<0.17 mm), as expected, followed by AC and BZ superimpositions that presented similar level of accuracy (D<0.5 mm). 3P and 1Z were the least accurate superimpositions (0.79precision of each superimposition technique (p>0.05), the detected structural changes differed significantly between different techniques (p<0.05). Bland-Altman difference plots showed that BZ superimposition was comparable to AC, though it presented slightly higher random error. CONCLUSIONS Superimposition of 3D datasets using surface models created from voxel data can provide accurate, precise, and reproducible results, offering also high efficiency and increased post-processing capabilities. In the present study population, the BZ superimposition was comparable to AC, with the added advantage of being applicable to scans with a smaller field of view.

CAD/CAM fabrication accuracy of long- vs. short-span implant-supported FDPs

OBJECTIVE To compare the precision of fit of long-span vs. short-span implant-supported screw-retained fixed dental prostheses (FDPs) made from computer-aided-design/computer-aided-manufactured (CAD/CAM) titanium and veneered with ceramic. The null hypothesis was that there is no difference in the vertical microgap between long-span and short-span FDPs. MATERIALS AND METHODS CAD/CAM titanium frameworks for an implant-supported maxillary FDP on implants with a flat platform were fabricated on one single master cast. Group A consisted of six 10-unit FDPs connected to six implants (FDI positions 15, 13, 11, 21, 23, 25) and group B of six 5-unit FDPs (three implants, FDI positions 21, 23, 25). The CAD/CAM system from Biodenta Swiss AG (Berneck, Switzerland) was used for digitizing (laser scanner) the master cast and anatomical CAD of each framework separately. The frameworks were milled (CAM) from a titanium grade V monobloc and veneered with porcelain. Median vertical distance between implant and FDP platforms from the non-tightened implants (one-screw test on implant 25) was calculated from mesial, buccal, and distal scanning electron microscope measurements. RESULTS All measurements showed values <40 μm. Total median vertical microgaps were 23 μm (range 2-38 μm) for group A and 7 μm (4-24 μm) for group B. The difference between the groups was statistically significant at implant 21 (P = 0.002; 97.5% CI -27.3 to -4.9) and insignificant at implant 23 (P = 0.093; -3.9 to 1.0). CONCLUSIONS CAD/CAM fabrication including laboratory scanning and porcelain firing was highly precise and reproducible for all long- and short-span FDPs. While all FDPs showed clinically acceptable values, the short-span FDPs were statistically more precise at the 5-unit span distance.

Real-time analysis of δ13C- and δD-CH4 in ambient air with laser spectroscopy: method development and first intercomparison results

In situ and simultaneous measurement of the three most abundant isotopologues of methane using mid-infrared laser absorption spectroscopy is demonstrated. A field-deployable, autonomous platform is realized by coupling a compact quantum cascade laser absorption spectrometer (QCLAS) to a preconcentration unit, called trace gas extractor (TREX). This unit enhances CH4 mole fractions by a factor of up to 500 above ambient levels and quantitatively separates interfering trace gases such as N2O and CO2. The analytical precision of the QCLAS isotope measurement on the preconcentrated (750 ppm, parts-per-million, µmole mole−1) methane is 0.1 and 0.5 ‰ for δ13C- and δD-CH4 at 10 min averaging time. Based on repeated measurements of compressed air during a 2-week intercomparison campaign, the repeatability of the TREX–QCLAS was determined to be 0.19 and 1.9 ‰ for δ13C and δD-CH4, respectively. In this intercomparison campaign the new in situ technique is compared to isotope-ratio mass spectrometry (IRMS) based on glass flask and bag sampling and real time CH4 isotope analysis by two commercially available laser spectrometers. Both laser-based analyzers were limited to methane mole fraction and δ13C-CH4 analysis, and only one of them, a cavity ring down spectrometer, was capable to deliver meaningful data for the isotopic composition. After correcting for scale offsets, the average difference between TREX–QCLAS data and bag/flask sampling–IRMS values are within the extended WMO compatibility goals of 0.2 and 5 ‰ for δ13C- and δD-CH4, respectively. This also displays the potential to improve the interlaboratory compatibility based on the analysis of a reference air sample with accurately determined isotopic composition.

Oxygen isotopes of lake marl at Gerzensee and Leysin (Switzerland), covering the Younger Dryas and two minor oscillations, and their correlation to the GRIP ice core

The ratio of oxygen isotopes is a temperature proxy both in precipitation and in the calcite of lacustrine sediments. The very similar oxygen-isotope records from Greenland ice cores and European lake sediments during the Last Glacial Termination suggest that the drastic climatic changes occurred quasi-simultaneously on an extra-regional, probably hemispheric scale. In order to study temporal relations of the different parameters recorded in lake sediments, for example biotic response times to rapid climatic changes, a precise chronology is required. In unlaminated lake sediments there is not yet available a method to provide a high-resolution chronology, especially for periods with radiocarbon plateaux. Alternatively, an indirect time scale can be constructed by linking the lake stratigraphy with other well-dated climate records. New oxygen-isotope records from Gerzensee and Leysin, with an estimated sampling resolution of between 15 and 40 years, match the Greenlandic isotope record in many details. Under the assumption that the main variations in temperature and thus in oxygen isotopes occurred about simultaneously in Greenland and Switzerland, we have assigned a time scale to the lake sediments of Gerzensee and Leysin by wiggle-matching their stable-isotope records with those of Greenland ice cores, which are among the best dated climatic archives. We estimate a precision of 20 to 100 years during the Last Glacial Termination.

Calibration of cosmogenic noble gas production based on ³⁶Cl-³⁶Ar ages. Part 2. The ⁸¹Kr-Kr dating technique

We calibrated the ⁸¹Kr-Kr dating system for ordinary chondrites of different sizes using independent shielding-corrected ³⁶Cl-³⁶Ar ages. Krypton concentrations and isotopic compositions were measured in bulk samples from 14 ordinary chondrites of high petrologic type and the cosmogenic Kr component was obtained by subtracting trapped Kr from phase Q. The thus-determined average cosmogenic ⁷⁸Kr/⁸³Kr, ⁸⁰Kr/⁸³Kr, ⁸²Kr/⁸³Kr, and ⁸4Kr/⁸³Kr ratiC(Lavielle and Marti 1988; Wieler 2002). The cosmogenic ⁷⁸Kr/⁸³Kr ratio is correlated with the cosmogenic 22Ne/21Ne ratio, confirming that ⁷⁸Kr/⁸³Kr is a reliable shielding indicator. Previously, ⁸¹Kr-Kr ages have been determined by assuming the cosmogenic production rate of ⁸¹Kr, P(⁸¹Kr)c, to be 0.95 times the average of the cosmogenic production rates of ⁸⁰Kr and ⁸²Kr; the factor Y = 0.95 therefore accounts for the unequal production of the various Kr isotopes (Marti 1967a). However, Y should be regarded as an empirical adjustment. For samples whose ⁸⁰Kr and ⁸²Kr concentrations may be affected by neutron-capture reactions, the shielding-dependent cosmogenic (⁷⁸Kr/⁸³Kr)c ratio has been used instead to calculate P(⁸¹Kr)/P(⁸³Kr), as for some lunar samples, this ratio has been shown to linearly increase with (⁷⁸Kr/⁸³Kr)c (Marti and Lugmair 1971). However, the ⁸¹Kr-Kr ages of our samples calculated with these methods are on average ~30% higher than their ³⁶Cl-³⁶Ar ages, indicating that most if not all the ⁸¹Kr-Kr ages determined so far are significantly too high. We therefore re-evaluated both methods to determine P(⁸¹Kr)c/P(⁸³Kr)c. Our new Y value of 0.70 ± 0.04 is more than 25% lower than the value of 0.95 used so far. Furthermore, together with literature data, our data indicate that for chondrites, P(⁸¹Kr)c/P(⁸³Kr)c is rather constant at 0.43 ± 0.02, at least for the shielding range covered by our samples ([⁷⁸Kr/⁸³Kr]c = 0.119–0.185; [22Ne/21Ne]c = 1.083–1.144), in contrast to the observations on lunar samples. As expected considering the method used, ⁸¹Kr-Kr ages calculated either directly with this new P(⁸¹Kr)c/P(⁸³Kr)c value or with our new Y value both agree with the corresponding ³⁶Cl-³⁶Ar ages. However, the average deviation of 2% indicates the accuracy of both new ⁸¹Kr-Kr dating methods and the precision of the new dating systems of ~10% is demonstrated by the low scatter in the data. Consequently, this study indicates that the ⁸¹Kr-Kr ages published so far are up to 30% too high.

Investigation of arterial spin labeling MRI for quantitative cerebral blood flow measurement

Arterial spin labeling (ASL) is a technique for noninvasively measuring cerebral perfusion using magnetic resonance imaging. Clinical applications of ASL include functional activation studies, evaluation of the effect of pharmaceuticals on perfusion, and assessment of cerebrovascular disease, stroke, and brain tumor. The use of ASL in the clinic has been limited by poor image quality when large anatomic coverage is required and the time required for data acquisition and processing. This research sought to address these difficulties by optimizing the ASL acquisition and processing schemes. To improve data acquisition, optimal acquisition parameters were determined through simulations, phantom studies and in vivo measurements. The scan time for ASL data acquisition was limited to fifteen minutes to reduce potential subject motion. A processing scheme was implemented that rapidly produced regional cerebral blood flow (rCBF) maps with minimal user input. To provide a measure of the precision of the rCBF values produced by ASL, bootstrap analysis was performed on a representative data set. The bootstrap analysis of single gray and white matter voxels yielded a coefficient of variation of 6.7% and 29% respectively, implying that the calculated rCBF value is far more precise for gray matter than white matter. Additionally, bootstrap analysis was performed to investigate the sensitivity of the rCBF data to the input parameters and provide a quantitative comparison of several existing perfusion models. This study guided the selection of the optimum perfusion quantification model for further experiments. The optimized ASL acquisition and processing schemes were evaluated with two ASL acquisitions on each of five normal subjects. The gray-to-white matter rCBF ratios for nine of the ten acquisitions were within ±10% of 2.6 and none were statistically different from 2.6, the typical ratio produced by a variety of quantitative perfusion techniques. Overall, this work produced an ASL data acquisition and processing technique for quantitative perfusion and functional activation studies, while revealing the limitations of the technique through bootstrap analysis. ^

Assessment of the performance of 3m 3500 organic vapor monitors over extended sampling durations

The purpose of this study was to assess the accuracy and precision of airborne volatile organic compound (VOC) concentrations measured using passive air samplers (3M 3500 organic vapor monitors) over extended sampling durations (9 and 15 days). A total of forty-five organic vapor monitor samples were collected at a State of Texas air monitoring site during two different sampling periods (July/August and November 2008). The results of this study indicate that for most of the tested compounds, there was no significant difference between long-term (9 or 15 days) sample concentrations and the means of parallel consecutive short-term (3 days) sample concentrations. Biases of 9 or 15-day measurements vs. consecutive 3-day measurements showed considerable variability. Those compounds that had percent bias values of <10% are suggested as acceptable for long-term sampling (9 and 15 days). Of the twenty-one compounds examined, 10 compounds are classified as acceptable for long-term sampling; these include m,p-xylene, 1,2,4-trimethylbenzene, n-hexane, ethylbenzene, benzene, toluene, o-xylene, d-limonene, dimethylpentane and methyl tertbutyl ether. The ratio of sampling procedure variability relative to variability within days was approximately 1.89 for both sampling periods for the 3-day vs. 9-day comparisons and approximately 2.19 for both sampling periods for the 3-day vs. 15-day comparisons. Considerably higher concentrations of most VOCs were measured during the November sampling period compared to the July/August period. These differences may be a result of varying meteorological conditions during these two time periods, e.g., the differences in wind direction, and wind speed. Further studies are suggested to further evaluate the accuracy and precision of 3M 3500 organic vapor monitors over extended sampling durations. ^

Zircons, isotope ratios and element analyses from tonalite and oxide gabbro of the mid-ocean ridge from ODP Hole 176-735B

A limiting factor in the accuracy and precision of U/Pb zircon dates is accurate correction for initial disequilibrium in the 238U and 235U decay chains. The longest-lived-and therefore most abundant-intermediate daughter product in the 235U isotopic decay chain is 231Pa (T1/2 = 32.71 ka), and the partitioning behavior of Pa in zircon is not well constrained. Here we report high-precision thermal ionization mass spectrometry (TIMS) U-Pb zircon data from two samples from Ocean Drilling Program (ODP) Hole 735B, which show evidence for incorporation of excess 231Pa during zircon crystallization. The most precise analyses from the two samples have consistent Th-corrected 206Pb/238U dates with weighted means of 11.9325 ± 0.0039 Ma (n = 9) and 11.920 ± 0.011 Ma (n = 4), but distinctly older 207Pb/235U dates that vary from 12.330 ± 0.048 Ma to 12.140 ± 0.044 Ma and 12.03 ± 0.24 to 12.40 ± 0.27 Ma, respectively. If the excess 207Pb is due to variable initial excess 231Pa, calculated initial (231Pa)/(235U) activity ratios for the two samples range from 5.6 ± 1.0 to 9.6 ± 1.1 and 3.5 ± 5.2 to 11.4 ± 5.8. The data from the more precisely dated sample yields estimated DPazircon/DUzircon from 2.2-3.8 and 5.6-9.6, assuming (231Pa)/(235U) of the melt equal to the global average of recently erupted mid-ocean ridge basaltic glasses or secular equilibrium, respectively. High precision ID-TIMS analyses from nine additional samples from Hole 735B and nearby Hole 1105A suggest similar partitioning. The lower range of DPazircon/DUzircon is consistent with ion microprobe measurements of 231Pa in zircons from Holocene and Pleistocene rhyolitic eruptions (Schmitt (2007; doi:10.2138/am.2007.2449) and Schmitt (2011; doi:10.1146/annurev-earth-040610-133330)). The data suggest that 231Pa is preferentially incorporated during zircon crystallization over a range of magmatic compositions, and excess initial 231Pa may be more common in zircons than acknowledged. The degree of initial disequilibrium in the 235U decay chain suggested by the data from this study, and other recent high precision datasets, leads to resolvable discordance in high precision dates of Cenozoic to Mesozoic zircons. Minor discordance in zircons of this age may therefore reflect initial excess 231Pa and does not require either inheritance or Pb loss.

Strontium isotope ratios of pore waters and planktonic foraminifera from DSDP holes

A detailed record of the strontium-87 to strontium-86 ratio in seawater during the last 100 million years was determined by measuring this ratio in 137 well-preserved and well-dated fossil foraminifera samples. Sample preservation was evaluated from scanning electron microscopy studies, measured strontium-calcium ratios, and pore water strontium isotope ratios. The evolution of the strontium isotopic ratio in seawater offers a means to evaluate long-term changes in the global strontium isotope mass balance. Results show that the marine strontium isotope composition can be used for correlating and dating well-preserved authigenic marine sediments throughout much of the Cenozoic to a precision of +/- 1 million years. The strontium-87 to strontium-86 ratio in seawater increased sharply across the Cretaceous/Tertiary boundary, but this feature is not readily explained as strontium input from a bolide impact on land.

Northwards and eastwards velocities extracted from a historical run (for the year 2000) of the UVic Earth System Climate Model of Weaver et al. (2001)

This study provides a theoretical assessment of the potential bias due to differential lateral transport on multi-proxy studies based on a range of marine microfossils. Microfossils preserved in marine sediments are at the centre of numerous proxies for paleoenvironmental reconstructions. The precision of proxies is based on the assumption that they accurately represent the overlying watercolumn properties and faunas. Here we assess the possibility of a syn-depositional bias in sediment assemblages caused by horizontal drift in the water column, due to differential settling velocities of sedimenting particles based on their shape, size and density, and due to differences in current velocities. Specifically we calculate the post-mortem lateral transport undergone by planktic foraminifera and a range of other biological proxy carriers (diatoms, radiolaria and fecal pellets transporting coccolithophores) in several regions with high current velocities. We find that lateral transport of different planktic foraminiferal species is minimal due to high settling velocities. No significant shape- or size-dependent sorting occurs before reaching the sediment, making planktic foraminiferal ideal proxy carriers. In contrast, diatoms, radiolaria and fecal pellets can be transported up to 500km in some areas. For example in the Agulhas current, transport can lead to differences of up to 2°C in temperature reconstructions between different proxies in response to settling velocities. Therefore, sediment samples are likely to contain different proportions of local and imported particles, decreasing the precision of proxies based on these groups and the accuracy of the temperature reconstruction.

Determination of polybrominated diphenyl ethers in water samples from Mendoza River Basin by HS-SPME-GC-MS/MS

Polybrominated diphenyl ethers (PBDEs) are considered persistent organic pollutants because of their ubiquity, persistence and bioaccumulation. Its harmful effects on human health and the environment, has led to its inclusion of the Stockholm Convention. Little information is found about PBDEs in abiotic systems of the South America in open literature. This paper reports the presence and concentration level of four PBDEs congeners in Mendoza River, Argentina. The selected PBDEs were: 2,2',4,4'-tetrabromodiphenyl ether (BDE-47), 2,2',4,4',5-pentabromodiphenyl ether (BDE-99), 2,2',4,4',6-pentabromodiphenyl ether (BDE- 100) and 2,2',4,4',5,5'-hexabromodiphenyl ether (BDE-153). The analytical methodology used was head space-solid phase micro extraction combined with gas chromatographymass spectrometry (HS-SPME-GC-MS/MS). Several variables, including pH, salting out, extraction technique type and extraction time were studied and optimized over the relative response the target analytes. The precision of HS-SPME-GC-MS/MS evaluated over five replicate, leading RSDs values <13%, detection limits (S/N=3) ranging from 0.03 pg ml-1 to 0.12 pg ml-1 and the calibration graph was linear with r2=0.9959. BDE-47 and BDE-100 were the predominant congeners found in the analyzed samples. Their concentrations ranged from not detected to 1.9 pg ml-1 and to 0.5 pg ml-1, respectively.