Authors' Reply to Coste et al.: "Levothyrox® New and Old Formulations: Are they Switchable for Millions of Patients?"

"Authors'Reply to Coste et al"International audienc

A General Framework for Ordering Fuzzy Sets

Abstract. Orderings and rankings of fuzzy sets have turned out to play a funda-mental role in various disciplines. Throughout the previous 25 years, a lot a different approaches to this issue have been introduced, ranging from rather simple ones to quite exotic ones. The aim of this paper is to present a new framework for com-paring fuzzy sets with respect to a general class of fuzzy orderings. This approach includes several known techniques based on generalizing the crisp linear ordering of real numbers by means of the extension principle, however, in its general form, it is applicable to any fuzzy subsets of any kind of universe for which a fuzzy ordering is known – no matter whether linear or partial.

SCIAMACHY validation by aircraft remote measurements: design, execution, and first results of the SCIA-VALUE mission

International audienceFor the first time three different remote sensing instruments ? a sub-millimeter radiometer, a differential optical absorption spectrometer in the UV-visible spectral range, and a lidar ? were deployed aboard DLR's meteorological research aircraft Falcon 20 to validate a large number of SCIAMACHY level 2 and off-line data products such as O3, NO2, N2O, BrO, OClO, H2O, aerosols, and clouds. Within two main validation campaigns of the SCIA-VALUE mission (SCIAMACHY VALidation and Utilization Experiment) extended latitudinal cross-sections stretching from polar regions to the tropics as well as longitudinal cross sections at polar latitudes at about 70° N and the equator have been generated. This contribution gives an overview over the campaigns performed and reports on the observation strategy for achieving the validation goals. We also emphasize the synergetic use of the novel set of aircraft instrumentation and the usefulness of this innovative suite of remote sensing instruments for satellite validation

Stochastic climate theory and modeling

Stochastic methods are a crucial area in contemporary climate research and are increasingly being used in comprehensive weather and climate prediction models as well as reduced order climate models. Stochastic methods are used as subgrid-scale parameterizations (SSPs) as well as for model error representation, uncertainty quantification, data assimilation, and ensemble prediction. The need to use stochastic approaches in weather and climate models arises because we still cannot resolve all necessary processes and scales in comprehensive numerical weather and climate prediction models. In many practical applications one is mainly interested in the largest and potentially predictable scales and not necessarily in the small and fast scales. For instance, reduced order models can simulate and predict large-scale modes. Statistical mechanics and dynamical systems theory suggest that in reduced order models the impact of unresolved degrees of freedom can be represented by suitable combinations of deterministic and stochastic components and non-Markovian (memory) terms. Stochastic approaches in numerical weather and climate prediction models also lead to the reduction of model biases. Hence, there is a clear need for systematic stochastic approaches in weather and climate modeling. In this review, we present evidence for stochastic effects in laboratory experiments. Then we provide an overview of stochastic climate theory from an applied mathematics perspective. We also survey the current use of stochastic methods in comprehensive weather and climate prediction models and show that stochastic parameterizations have the potential to remedy many of the current biases in these comprehensive models

Why Were More Than 200 Subjects Required to Demonstrate the Bioequivalence of a New Formulation of Levothyroxine with an Old One?

At the request of French Regulatory Authorities, a new formulation of Levothyrox® was licensed in France in 2017, with the objective of avoiding the stability deficiencies of an existing licensed formulation. Before launching the new formulation, an average bioequivalence (ABE) trial was conducted, having enrolled 204 subjects and selected for interpretation a narrow a priori bioequivalence range of 0.90–1.11. Bioequivalence was concluded. In a previous publication, we questioned the ability of an ABE trial to guarantee the switchability within patients of the new and old levothyroxine formulations. It was suggested that the two formulations should be compared using the conceptual framework of individual bioequivalence. The present paper is a response to those claiming that, despite the fact that ABE analysis does not formally address the switchability of the two formulations, future patients will nevertheless be fully protected. The basis for this claim is that the ABE study was established in a large trial and analyzed using a stringent a priori acceptance interval of equivalence. These claims are questionable, because the use of a very large number of subjects nullifies the implicit precautionary intention of the European guideline when, for a Narrow Therapeutic Index drug, it recommends shortening the a priori acceptance interval from 0.80–1.25 to 0.90–1.11

Levothyrox® new and old formulations: are they switchable for millions of patients?

International audienceIn France, more than 2.5 million patients are currently treated with levothyroxine, mainly as the marketed product Levothyrox ®. In March 2017, at the request of French authorities, a new formulation of Levothyrox ® was licensed, with the objective of avoiding stability deficiencies of the old formulation. Before launching this new formulation, an average bioequivalence trial, based on European Union recommended guidelines, was performed. The implicit rationale was the assumption that the two products, being bioequivalent, would also be switchable, allowing substitution of the new for the old formulation, thus avoiding the need for individual calibration of the dosage regimen of thyroxine, using the thyroid-stimulating hormone level as the endpoint, as required for a new patient on initiating treatment. Despite the fact that both formulations were shown to be bioequivalent, adverse drug reactions were reported in several thousands of patients after taking the new formulation. In this opinion paper, we report that more than 50% of healthy volunteers enrolled in a successful regulatory average bioequivalence trial were actually outside the a priori bioequivalence range. Therefore, we question the ability of an average bioequivalence trial to guarantee the switchability within patients of the new and old levothyroxine formulations. We further propose an analysis of this problem using the conceptual framework of individual bioequivalence. This involves investigating the bioavailability of the two formulations within a subject, by comparing not only the population means (as established by average bioequivalence) but also by assessing two variance terms, namely the within-subject variance and the variance estimating subject-by-formulation interaction. A higher within individual variability for the new formulation would lead to reconsideration of the appropriateness of the new formulation. Alternatively, a possible subject-by-formulation interaction would allow a judgement on the ability, or not, of doctors to manage patients effectively during transition from the old to the new formulation

The Hard X-ray Luminosity of OB Star Populations: Implications for the Contribution of Star Formation to the Cosmic X-ray Background

We present an empirical analysis of the integrated X-ray luminosity arising from populations of OB stars. In particular, we utilize results from the All-Sky Monitor on RXTE, along with archival data from previous missions, to assess the mean integrated output of X-rays in the 2-10 keV band from accreting early-type binaries within 3 kpc of the Sun. Using a recent OB star census of the Solar neighborhood, we then calculate the specific X-ray luminosity per O star from accretion-powered systems. We also assess the contribution to the total X-ray luminosity of an OB population from associated T Tauri stars, stellar winds, and supernovae. We repeat this exercise for the major Local Group galaxies, concluding that the total X-ray luminosity per O star spans a broad range from 2 to 20e34 erg/s. Contrary to previous results, we do not find a consistent trend with metallicity; in fact, the specific luminosities for M31 and the SMC are equal, despite having metallicities which differ by an order of magnitude. In light of these results, we assess the fraction of the observed 2-10 keV emission from starburst galaxies that arises directly from their OB star populations, concluding that, while binaries can explain most of the hard X-ray emission in many local starbursts, a significant additional component or components must be present in some systems. A discussion of the nature of this additional emission, along with its implications for the contribution of starbursts to the cosmic X-ray background, concludes our report.Comment: aastex, 30 pages including 2 tables and 1 figure. To appear in Ap

Brain Structural Networks Associated with Intelligence and Visuomotor Ability

Increasing evidence indicates that multiple structures in the brain are associated with intelligence and cognitive function at the network level. The association between the grey matter (GM) structural network and intelligence and cognition is not well understood. We applied a multivariate approach to identify the pattern of GM and link the structural network to intelligence and cognitive functions. Structural magnetic resonance imaging was acquired from 92 healthy individuals. Source-based morphometry analysis was applied to the imaging data to extract GM structural covariance. We assessed the intelligence, verbal fluency, processing speed, and executive functioning of the participants and further investigated the correlations of the GM structural networks with intelligence and cognitive functions. Six GM structural networks were identified. The cerebello-parietal component and the frontal component were significantly associated with intelligence. The parietal and frontal regions were each distinctively associated with intelligence by maintaining structural networks with the cerebellum and the temporal region, respectively. The cerebellar component was associated with visuomotor ability. Our results support the parieto-frontal integration theory of intelligence by demonstrating how each core region for intelligence works in concert with other regions. In addition, we revealed how the cerebellum is associated with intelligence and cognitive functions