Cytotoxics compounded sterile preparation control by HPLC during a 16-month assessment in a French university hospital: importance of the mixing bags step

The Centralized Chemotherapy Reconstitution Unit (CCRU) of Paul Brousse Hospital Pharmacy Department assessed the reliability of its Cytotoxics Compounded Sterile Products (CCSP) preparation method in order to improve its CCSP quality assurance system. Five cytotoxic drugs — gemcitabine, 5-fluorouracil, docetaxel, paclitaxel, and oxaliplatin — were assayed by high performance liquid chromatography (HPLC) to determine CCSP concentration. During the observation period, 23,892 CCSP were prepared. Overall, 12,964 preparations contained one of the five analyzed drugs; 7382 (56.9%) out of 12,964 CCSP were analyzed by HPLC; 646 (8.8%) out of 7382 concentrations were outside ± 20% of the prescribed dose; 544 (84.2%) out of 646 were post-administration results and could not be verified. Out of 102 (15.8%) pre-administration results that were re-tested after re-shaking, 94 (92.2%) were found to be acceptable upon re-testing, and 8 (7.8%) were confirmed to be unacceptable and needed to be re-compounded. The 8.8% of tested CCSP were outside ± 20% of the prescribed dose, but extrapolating the results on re-tested CCSP, we can say that our CCSP preparation is reliable with an estimation of only 0.7% of 7382 CCSP analyzed, confirmed as being ± 20% outside the prescribed dose. Nevertheless, this ± 20% magnitude of error should be reduced. Based on pre-administration results, the primary cause of concentration errors appeared to be insufficient mixing of the finished product. Most CCSP dosages occurred after it had been administered, the organization should, therefore, be improved to include testing all CCSP prior to administration. Pharmaceutical companies should endeavor to manufacture compounded injectible drugs in a ‘ready to use’ form and provide vehicles in accurate volumes in order to improve compounding precision

Multinuclear solid-state NMR investigation of Hexaniobate and Hexatantalate compounds

This work determines the potential of solid-state NMR techniques to probe proton, alkali, and niobium environments in Lindqvist salts. Na7HNb6O19·15H2O (1), K8Nb6O19·16H2O (2), and Na8Ta6O19·24.5H2O (3) have been studied by solid-state static and magic angle spinning (MAS) NMR at high and ultrahigh magnetic field (16.4 and 19.9 T). 1H MAS NMR was found to be a convenient and straightforward tool to discriminate between protonated and nonprotonated clusters AxH8–xM6O19·nH2O (A = alkali ion; M = Nb, Ta). 93Nb MAS NMR studies at different fields and MAS rotation frequencies have been performed on 1. For the first time, the contributions of NbO5Oμ2H sites were clearly distinguished from those assigned to NbO6 sites in the hexaniobate cluster. The strong broadening of the resonances obtained under MAS was interpreted by combining chemical shift anisotropy (CSA) with quadrupolar effects and by using extensive fitting of the line shapes. In order to obtain the highest accuracy for all NMR parameters (CSA and quadrupolar), 93Nb WURST QCPMG spectra in the static mode were recorded at 16.4 T for sample 1. The 93Nb NMR spectra were interpreted in connection with the XRD data available in the literature (i.e., fractional occupancies of the NbO5Oμ2H sites). 1D 23Na MAS and 2D 23Na 3QMAS NMR studies of 1 revealed several distinct sodium sites. The multiplicity of the sites was again compared to structural details previously obtained by single-crystal X-ray diffraction (XRD) studies. The 23Na MAS NMR study of 3 confirmed the presence of a much larger distribution of sodium sites in accordance with the 10 sodium sites predicted by XRD. Finally, the effect of Nb/Ta substitutions in 1 was also probed by multinuclear MAS NMR (1H, 23Na, and 93Nb)

From crystalline to amorphous calcium pyrophosphates:a solid state Nuclear Magnetic Resonance perspective

Hydrated calcium pyrophosphates (CPP, Ca2P2O7·nH2O) are a fundamental family of materials among osteoarticular pathologic calcifications. In this contribution, a comprehensive multinuclear NMR (Nuclear Magnetic Resonance) study of four crystalline and two amorphous phases of this family is presented. 1H, 31P and 43Ca MAS (Magic Angle Spinning) NMR spectra were recorded, leading to informative fingerprints characterizing each compound. In particular, different 1H and 43Ca solid state NMR signatures were observed for the amorphous phases, depending on the synthetic procedure used. The NMR parameters of the crystalline phases were determined using the GIPAW (Gauge Including Projected Augmented Wave) DFT approach, based on first-principles calculations. In some cases, relaxed structures were found to improve the agreement between experimental and calculated values, demonstrating the importance of proton positions and pyrophosphate local geometry in this particular NMR crystallography approach. Such calculations serve as a basis for the future ab initio modeling of the amorphous CPP phases. Statement of significance The general concept of NMR crystallography is applied to the detailed study of calcium pyrophosphates (CPP), whether hydrated or not, and whether crystalline or amorphous. CPP are a fundamental family of materials among osteoarticular pathologic calcifications. Their prevalence increases with age, impacting on 17.5% of the population after the age of 80. They are frequently involved or associated with acute articular arthritis such as pseudogout. Current treatments are mainly directed at relieving the symptoms of joint inflammation but not at inhibiting CPP formation nor at dissolving these crystals. The combination of advanced NMR techniques, modeling and DFT based calculation of NMR parameters allows new original insights in the detailed structural description of this important class of biomaterials

Formation of convective cells in the scrape-off layer of the CASTOR tokamak

Understanding of the scrape-off layer (SOL) physics in tokamaks requires diagnostics with sufficient temporal and spatial resolution. This contribution describes results of experiments performed in the SOL of the CASTOR tokamak (R=40 cm, a = 6 cm) by means of a ring of 124 Langmuir probes surrounding the whole poloidal cross section. The individual probes measure either the ion saturation current of the floating potential with the spatial resolution up to 3 mm. Experiments are performed in a particular magnetic configuration, characterized by a long parallel connection length in the SOL, L_par ~q2piR. We report on measurements in discharges, where the edge electric field is modified by inserting a biased electrode into the edge plasma. In particular, a complex picture is observed, if the biased electrode is located inside the SOL. The poloidal distribution of the floating potential appears to be strongly non-uniform at biasing. The peaks of potential are observed at particular poloidal angles. This is interpreted as formation of a biased flux tube, which emanates from the electrode along the magnetic field lines and snakes q times around the torus. The resulting electric field in the SOL is 2-dimensional, having the radial as well as the poloidal component. It is demonstrated that the poloidal electric field E_pol convects the edge plasma radially due to the E_pol x B_T drift either inward or outward depending on its sign. The convective particle flux is by two orders of magnitude larger than the fluctuation-induced one and consequently dominates.Comment: 12th International Congress on Plasma Physics, 25-29 October 2004, Nice (France

Identification of inter- and intra-species variation in cereal grains through geometric morphometric analysis, and its resilience under experimental charring

The application of morphometric analysis in archaeobotany has the potential to refine quantitatively identifications of ancient plant material recovered from archaeological sites, most commonly preserved through charring due to exposure to heat. This paper uses geometric morphometrics, first, to explore variation in grain shape between three domesticated cereal species, einkorn (Triticum monococcum), emmer (Triticum dicoccum) and barley (Hordeum vulgare), both before and after experimental charring at 230 and 260oC. Results demonstrate that outline analysis reliably reflects known variations in grain shape between species and differences due to charring observed in previous experimental work, and is capable of distinguishing the species, with near-perfect results, both before and after charring. Having established this, the same method was applied to different accessions of the same species, which indicated that three different grain morphotypes of einkorn and two, possibly three, of emmer could be identified in the uncharred material, and that at least two different morphotypes for each species could be distinguished even after charring at temperatures up to 260oC. This opens up the possibility of tracking evolutionary change in crops, both chronologically and geographically, through morphometric analysis

Fixed Effect Estimation of Large T Panel Data Models

This article reviews recent advances in fixed effect estimation of panel data models for long panels, where the number of time periods is relatively large. We focus on semiparametric models with unobserved individual and time effects, where the distribution of the outcome variable conditional on covariates and unobserved effects is specified parametrically, while the distribution of the unobserved effects is left unrestricted. Compared to existing reviews on long panels (Arellano and Hahn 2007; a section in Arellano and Bonhomme 2011) we discuss models with both individual and time effects, split-panel Jackknife bias corrections, unbalanced panels, distribution and quantile effects, and other extensions. Understanding and correcting the incidental parameter bias caused by the estimation of many fixed effects is our main focus, and the unifying theme is that the order of this bias is given by the simple formula p/n for all models discussed, with p the number of estimated parameters and n the total sample size.Comment: 40 pages, 1 tabl

The first shoots of a modern morphometrics approach to the origins of agriculture

The transition from a mobile hunter-gatherer lifestyle to one of settled agriculture is arguably the most fundamental change in the development of human society (Lev-Yadun et al., 2000). The establishment of agricultural economies, emerging initially in the Fertile Crescent of the Near East (Nesbitt, 2002), required the domestication of crops; ancient plant remains recovered from early farming sites provide direct evidence for this process of domestication. Archaeobotanical remains are typically preserved through charring (partial to complete carbonisation through exposure to heat) and recovered during archaeological excavation (Charles et al., 2015). Seeds of the same species, recovered from different sites and periods, can sometimes be seen to exhibit morphological differences, which may have arisen owing to variations in cultivation practices, climate, soils and altitude, etc. To explore these possibilities, morphological variation in seeds of wheat and barley between archaeological sites was recorded and mapped both in time and space. Results presented here suggest that modern morphometric approaches may help to test some long-debated hypotheses and pave the way for new insights into the evolutionary origins of agriculture in western Asia