bluuebunny/crossref_metadata_2025_split huggingface dataset:
Electrospray ionization tandem mass spectrometric and electron impact mass spectrometric characterization of mycosporine‐like amino acids
Authors: Whitehead Kenia , Hedges John I. 
Published: September 2003

AbstractPositive‐ion mass spectral fragmentations of seven mycosporine‐like amino acids (MAAs) are reported and discussed. The MAAs studied are small compounds composed of a cycloheximine ring substituted with amino acid or amino alcohol units. Techniques used include electron impact (EI) and electrospray ionization (ESI) with tandem mass spectrometry (MS/MS). ESI‐MS/MS showed unusual small radical losses, generally resulting from the loss of a methyl group with the exception of shinorine and porphyra for which the initial losses were 30 and 44 Da, respectively. As expected from structural similarities, porphyra, shinorine and palythinol displayed similar fragmentation patterns, while palythenic acid and palythene fragmented in a similar manner. Overall, the ESI‐MS/MS fragmentations at m/z <200 exhibited a distinctive pattern for all seven MAAs with characteristic ions at m/z 137, 168, 186, and 197 or 199. Several ions were observed for each of the MAAs analyzed, and together provide a useful and potentially diagnostic pattern for identification of MAAs and as an aid in structure elucidation of novel MAAs. For GC/EI‐MS analysis, trimethylsilyl (TMS) derivatives were made. The EI‐MS fragmentation patterns of TMS‐MAAs showed many features typical of TMS‐derivatized α‐amines. The precursor TMS‐MAA ion was not detected, but a [M–90]+. ion was the highest‐mass intense peak observed for palythine, palythinol and shinorine, while palythene gave a [M–116]+. ion. Besides determining the number of acidic hydrogens, EI‐MS of TMS‐derivatized MAAs will aid in structure elucidation of novel MAAs. Copyright © 2003 John Wiley & Sons, Ltd.
Studies on azaspiracid biotoxins. III. Instrumental validation for rapid quantification of AZA 1 in complex biological matrices
Authors: Blay Pearl K. S. , Brombacher Stephan , Volmer Dietrich A. 
Published: September 2003

AbstractAzaspiracids are neurotoxins produced by marine algae that have been detected in harvested mussels since 1995. They pose a significant threat to human health through the consumption of contaminated shellfish, and negatively impact the economy of areas where shellfish are harvested and processed. Regulatory agencies are beginning to advocate instrumental assays over traditional mouse bioassay methods. The development and validation of an assay method for AZA 1, the predominant azaspiracid toxin, and the production of a calibration standard and reference material will therefore be vital for quality control in monitoring laboratories worldwide. This report demonstrates a rapid and reproducible liquid chromatography/mass spectrometry (LC/MS) method for separation of all twelve known azaspiracids. Using a triple‐quadrupole mass spectrometer, ultra‐high sensitivity was obtained at the low‐femtogram level injected on‐column. At the same time, a linear response of three orders of magnitude was observed. We compared the results with those measured on an ion‐trap mass spectrometer. The triple‐quadrupole instrument was more sensitive, reliable and reproducible than the ion‐trap instrument. The detection limit obtained on the ion‐trap mass spectrometer was ten times higher than that obtained on the triple quadrupole. During the study, a new azaspiracid analog (AZA 7c) was discovered. Copyright © 2003 John Wiley & Sons, Ltd.
Higher‐throughput screening for Caco‐2 permeability utilizing a multiple sprayer liquid chromatography/tandem mass spectrometry system
Authors: Fung Eliza N. , Chu Inhou , Li Cheng , Liu Tongtong , Soares Anthony , Morrison Richard , Nomeir Amin A. 
Published: September 2003

AbstractIn the current drug discovery environment, higher‐throughput analytical assays have become essential to keep pace with the screening demands for drug metabolism and pharmacokinetics (DMPK) attributes. This has been dictated by advances primarily in chemical procedures, notably combinatorial and parallel syntheses, which has resulted in many‐fold increases in the number of compounds requiring DMPK evaluation. Because of its speed and specificity, liquid chromatography/tandem mass spectrometry (LC/MS/MS) has become the dominant technology for sample analysis in the DMPK screening assays. For higher‐throughput assays, analytical speed as well as other factors such as method development, data processing, quality control, and report generation, must be optimized. The four‐way multiplexed electrospray interface (MUX®), which allows for the analysis of four LC eluents simultaneously, has been adopted to maximize the rate of sample introduction into the mass spectrometer. Generic fast‐gradient HPLC methods that are suitable for approximately 80% of the new chemical entities encountered have been developed. In‐house‐written software programs have been used to streamline information flow within the system, and for quality control by automatically identifying analytical anomalies. By integrating these components together with automated method development and data processing, a system capable of screening 100 compounds per week for Caco‐2 permeability has been established. Copyright © 2003 John Wiley & Sons, Ltd.
Electrospray mass spectrometric studies of noncovalent complexes of buspirone hydrochloride and other serotonin 5‐HT1A receptor ligands containing arylpiperazine moieties
Authors: Kowalski Piotr , Suder Piotr , Kowalska Teresa , Silberring Jerzy , Duszyńska Beata , Bojarski Andrzej J. 
Published: September 2003

AbstractNoncovalent complexes consisting of two protonated amines and a chloride anion were observed under electrospray ionization mass spectrometry (ESI‐MS) conditions. The observed phenomenon was investigated for the hydrochlorides of buspirone, a well‐known anxiolytic drug, and 23 other arylpiperazine derivatives that had been developed as serotonin 5‐HT1A receptor ligands. Due to the major role of ionic interactions in a vacuum, it was proposed that the detected complexes were formed by NH+···Cl−···NH+ bridges. It was found that complexation depended on structural features of the analyzed compounds. For derivatives with a shorter linker (three methylene groups) containing a terminal cyclic amide fragment, complex ions were not observed. It was postulated that, in the latter case, steric hindrance due to a terminal group could disturb ionic bridge formation. Since both the observed complexation and ligand‐binding processes are driven by noncovalent forces, and a qualitative relationship between them was found (compounds with a 4‐carbon chain always display higher affinity for 5‐HT1A receptors than do their 3‐carbon analogues), such ESI‐MS studies may yield valuable information on ligand–receptor interactions. Copyright © 2003 John Wiley & Sons, Ltd.
Assessing individual bioequivalence with high‐order cross‐over designs: a unified procedure
Authors: Hsuan Francis C. , Reeve Russell 
Published: September 2003

AbstractThe U.S. FDA's newly issued guidance on bioequivalence recommends the use of individual bioequivalence (IBE) for highly variable drugs and possibly for modified release dosage forms. The recommended approach to the analysis is to follow the methodology of Hyslop, Hsuan and Holder (HHH), based on a linear mixed model. A limitation of the HHH method is that it works only for uniform designs, such as RTRT/TRTR. In this paper, we present an alternative approach based on a multivariate model. The multivariate model is shown to be a strict superset of the linear mixed model and can successfully model data where the mixed model fails. Our multivariate approach coincides with the HHH method where the HHH method applies, but generalizes to any high‐order cross‐over design, such as the Balaam design, RTR/TRT, and TRSS/RSTT/STRR. We present numerical examples to demonstrate the proposed method, and examine its properties with a simulation study. Copyright © 2003 John Wiley & Sons, Ltd.
Three methods for analysing correlated ROC curves: a comparison in real data sets from multi‐reader, multi‐case studies with a factorial design
Authors: Toledano Alicia Y. 
Published: September 2003

AbstractThis paper compares three published methods for analysing multiple correlated ROC curves: a method using generalized estimating equations with marginal non‐proportional ordinal regression models; a method using jackknifed pseudovalues of summary statistics; a method using a corrected F‐test from analysis of variance of summary statistics. Use of these methods is illustrated through six real data examples from studies with the common factorial design, that is, multiple readers interpreting images obtained with each test modality on each study subject. The issue of the difference between typical summary statistics and summary statistics from typical ROC curves is explored. The examples also address similarities and differences among the analytical methods. In particular, while point estimates of differences between test modalities are similar, the standard errors of these differences do not agree for all three methods. A simulation study supports the standard errors provided by the generalized estimating equations with marginal non‐proportional ordinal regression models. Copyright ©2003 John Wiley & Sons, Ltd.
Quality control and the identification of vaccine responders using ELISA‐derived antibody data
Authors: Le Chap T. , Grambsch Patricia M. , Giebink G. Scott 
Published: September 2003

AbstractFirst vaccines are traditionally licensed after showing favourable results from phase III efficacy trials. Subsequent competing vaccines, however, have been licensed primarily on the basis of immunogenicity data rather than clinical efficacy. Focusing on pneumococcal vaccines where optical densities are measured and serum antibody concentrations are ‘estimated’ (from a statistical model) using an immunoglobulin (IgG) enzyme‐linked immunosorbent assay (ELISA), the focus of this paper will centre on two highly related issues: the determination of an upper limit for quality control used in the assay methodology (let us call it the maximum tolerated limit or MTL) and the identification of vaccine responders. The goal is to show that these two issues are inter‐related, so that investigators could reduce misclassification which would interfere with the eventual comparison of immunogenicity results. Copyright © 2003 John Wiley & Sons, Ltd.
‘Online’ monitoring and retrospective analysis of hospital outcomes based on a scan statistic
Authors: Ismail Noor Azina , Pettitt A. N. , Webster R. A. 
Published: September 2003

AbstractStatistical tests based on the scan statistic are introduced for detecting possible increases in the occurrence of hospital events. The tests use a moving window and the theoretical aspects of the tests are investigated using Markov chain theory. The main objective of this study is to provide a statistical technique to assist hospital staff in deciding whether the variation they observe is greater than usually expected under random variation. In this paper we develop the test for Poisson data and apply the theory to monitor the occurrence of orthopaedic wound infection and Methicillin‐resistant Staphylo‐ coccus aureus colonization. We find that this method is sensitive in detecting the change in the process parameter which may not be detected by standard control chart methods. Both online and retrospective analyses are considered. Copyright © 2003 John Wiley & Sons, Ltd.
Lead‐time and overdiagnosis estimation in neuroblastoma screening
Authors: Spix Claudia , Michaelis Jörg , Berthold Frank , Erttmann Rudolf , Sander Johannes , Schilling Freimut H. 
Published: September 2003

AbstractIn Germany, neuroblastoma is the most frequent extracranial solid childhood tumour. Its properties made it seem an ideal candidate for screening. A German trial assessed the effect of screening at one year of age from 1995–2001 in a nationwide project. We present here the methods developed for the estimation of lead‐time and overdiagnosis in this project. Follow up on 1.5 million screened children and 2.1 million control children is currently available until June 2002. Ascertainment of control cohort cases and false negative cases is complete up to this date. A method for determining an empirical lead‐time distribution and overdiagnosis estimate from comparing the age specific incidences in the control group and the study group is presented. Lead‐time leads to an excess of cases in the screening group at the screening age and cases missing at higher age. If more cases are observed at the screening age than can be explained by lead‐time, the difference is attributed to overdiagnosis. The width of the screening age window and the empirical maximum lead‐time have to be chosen from graphs. About 1.0/100000 cases (20 per cent of the possible cases) experienced lead‐time while 6.8/100000 cases were overdiagnosed. The mean lead‐time was estimated to be about 15 months. The number of cases who might benefit is much smaller than was expected before the study while the overdiagnosed group is much larger. The method is robust against the choices that have to be made in the estimation process. Copyright © 2003 John Wiley & Sons, Ltd.
Measuring spatial effects in time to event data: a case study using months from angiography to coronary artery bypass graft (CABG)
Authors: Crook Angela M. , Knorr‐Held Leonhard , Hemingway Harry 
Published: September 2003

AbstractThe application of Bayesian hierarchical models to measure spatial effects in time to event data has not been widely reported. This case study aims to estimate the effect of area of residence on waiting times to coronary artery bypass graft (CABG) and to assess the role of important individual specific covariates (age, sex and disease severity). The data involved all patients with definite coronary artery disease who were referred to one cardiothoracic unit from five contiguous health authorities covering 488 electoral wards (areas). Time to event was the waiting time in months from angiography (diagnosis) to CABG (event). A number of discrete time survival models were fitted to the data. A discrete baseline hazard was estimated by fitting waiting time non‐parametrically into the models. Ward was fitted as a spatial effect using a Gaussian Markov random field prior. Individual specific covariates considered were age, sex and number of diseased vessels. The recently proposed DIC criteria was used for comparing models. Results showed a marked spatial effect on time to bypass surgery after including age, sex and disease severity in the model. Notably this spatial effect was not apparent when these covariates were not included in the model. The observed small area spatial variation in time to CABG warrants further investigation. Copyright © 2003 John Wiley & Sons, Ltd.
Design and sample size estimation in clinical trials with clustered survival times as the primary endpoint
Authors: Xie Tailiang , Waksman Joel 
Published: September 2003

AbstractMany clinical trials involve the collection of data on the time to occurrence of the same type of multiple events within sample units, in which ordering of events is arbitrary and times are usually correlated. To design a clinical trial with this type of clustered survival times as the primary endpoint, estimating the number of subjects (sampling units) required for a given power to detect a specified treatment difference is an important issue. In this paper we derive a sample size formula for clustered survival data via Lee, Wei and Amato's marginal model. It can be easily used to plan a clinical trial in which clustered survival times are of primary interest. Simulation studies demonstrate that the formula works very well. We also discuss and compare cluster survival time design and single survival time design (for example, time to the first event) in different scenarios. Copyright © 2003 John Wiley & Sons, Ltd.
A comparison of recent methods for the analysis of small‐sample cross‐over studies
Authors: Chen Xun , Wei Lynn 
Published: September 2003

AbstractThe standard analysis of variance (ANOVA) method is usually applied to analyse continuous data from cross‐over studies. The method, however, has been known to be not robust for general variance–covariance structure. The simple empirical generalized least squares (EGLS) method, proposed in an attempt to improve the precision of the standard ANOVA method for general variance–covariance structure, is usually insufficient for small‐sample cross‐over trials. In this paper we compare the following commonly used or recent approaches: standard ANOVA; simple EGLS; modified ANOVA method derived from a modified approximate F‐distribution; and a modified EGLS method adjusted by the Kenward and Roger procedure in terms of robustness and power while applying to small‐sample cross‐over studies (say, the sample size is less than 40) over a variety of variance–covariance structures by simulation. We find that the unconditional modified ANOVA method has robust performance for all of the simulated small‐sample cross‐over studies over the various variance–covariance structures, and has comparable power with the standard ANOVA method whenever they are comparable in type I error rate. The EGLS method (simple or modified) is not reliable when the sample size of a cross‐over study is too small, say, less than 24 in the simulation, unless a simple covariance structure is correctly assumed. Given a relatively larger sample size, the modified EGLS method, assuming an unstructured covariance matrix, demonstrates robust performance over the various variance–covariance structures in the simulation and provides more powerful tests than those of the modified (or standard) ANOVA method. Copyright © 2003 John Wiley & Sons, Ltd.
General linear contrasts on latent variable means: structural equation hypothesis tests for multivariate clinical trials
Authors: Donaldson Gary W. 
Published: September 2003

AbstractStructural equation models articulate the assumed measurement and causal relations among variables, imposing discipline on otherwise unstructured and redundant associations that arise in correlational studies. Biomedical research has eschewed such methods, relying on the generally superior causal inference afforded by randomized controlled trials. Increasingly, however, clinical trials incorporate numerous covariates that are measured but unmanipulated. Most clinical trials now also include multiple correlated endpoints, which can generate ambiguous outcome patterns refractory to simple statistical analysis and interpretation. Modern clinical trials are really multivariate longitudinal studies with at best a component of randomized control; as such, structural equation approaches can add rigour and clarity. The analysis of latent variance (LANOVA) conception combines structural equation and experimental analysis of variance legacies. It allows, for any design that can be decomposed into between‐group and within‐person models, tests on latent means (that is, the means of the unobserved factors) that are directly analogous to their analysis of variance counterparts. LANOVA variables are either outcomes (which may have a time structure), varying covariates (which may have a time structure), or background covariates (which are static). Allowable causal relations are set‐recursive: background covariates can affect all other variables; varying covariates can affect current outcomes and later outcomes and covariates; outcomes can affect only later outcomes. All standard ANOVA and ANCOVA hypotheses can then be tested by proper restrictions among the means and intercepts of these latent variables. Structural equation modelling programs can be used to estimate the models and test the hypotheses. I demonstrate the approach by expressing and testing hypotheses appropriate for two clinical studies that evaluate patient‐reported outcomes in populations with solid and haematological malignancies. Copyright © 2003 John Wiley & Sons, Ltd.
O QUELLE ARMONYE: DIALOGUE SINGING IN LATE RENAISSANCE FRANCE
Authors: Brooks Jeanice 
Published: September 2003

François de Billon’s Fort inexpugnable de l’honneur du sexe feminin (1555) was among the most extensive contributions to the sixteenth-century polemic on the nature of women known as the querelle des femmes. In keeping with the military connotations of its title, Billon’s ‘impregnable fortress’ is an exercise in bellicose rhetoric; his sallies are illustrated with woodcuts of roaring lions and fire-spitting cannons to heighten the effect of bravado. In the section on women’s musical gifts, he vaunts the ‘angelic sweetness’ of the female singing voice, and claims that although male musicians more often win fame, women have always been better singers:In [singing] nevertheless women have always been the very best. Whatever may be said by Sandrin, Arcadelt or Janequin, the most renowned musicians of Europe in our time, whom I would willingly ask, ‘Where is it that one can find sweetness of vocal harmony, in general, if not in the musical throat of Woman, even if she puts forth only a little warbling?’ And if they answered that in some men one finds more, could I not rightly reply, ‘What is the reason, my friends, that so few men of your profession are married and that you all flee marriage, if not that through propriety [honnesteté] you would be forced to bring your wives (instead of choirboys) into princely chambers to sing with you, or without you, which would be found so much sweeter than any childish voice? O what harmony, if you were all married in the normal fashion to beautiful women; if they were well instructed by you in the rules of music; and if in the aforementioned manner, you tuned yourselves well with them. The pleasure of listening to you would be double, the advantage triple, and thus, frequently nothing would be sung except in duo’.
LABOURING IN THE MIDST OF WOLVES: READING A GROUP OF FAUVEL MOTETS
Authors: Roesner Edward H. 
Published: September 2003

Il finera car touz iourz vivreNe pourra pas.(He will meet his end, for he cannot live for ever)The ensemble of texts brought together in the celebrated MS 146 of the fonds français in the Bibliothèque nationale de France, Paris, makes up a complex and many-sided essay on government and kingship, one directed to the French monarch Philip V (1317–22) at or near the beginning of his reign. Its various elements reflect on the problem-laden final years of the rule of his father, Philip IV ‘le Bel’ (1285-1314), and the troubled succession that followed in 1315 and 1316. Each fascicle of the manuscript, the so-called Roman de Fauvel, the dits of Geffroi de Paris, the collection of songs and dits ascribed to Jehannot de Lescurel, and the anonymous verse chronicle of the years 1300–16, interacts with the others in myriad ways and on many levels to yield a collective commentary on the state of the monarchy and the realm, and an admonitio on wise rule.
Solutions for Space Operations with a Star Finder
Authors: Chianese S. , Lucarelli G. , Troisi S. 
Published: September 2003

This paper shows a possible new use of a common or computerised star finder for a rapid and easy solution to some space problems such as:
– launch windows;– satellite fly-over;– the rise and setting of a satellite;– Earth or Moon satellite surveys;– the eclipse of a satellite.