Generic substitution: the use of medicinal products containing different salts and implications for safety and efficacy

In their quest to gain early entry of new generic products into the market prior to patent expiration, one of the strategies pursued by generic drug product manufacturers is to incorporate different salts of an approved active pharmaceutical ingredient (API) in a brand company's marketed dosage form and subject such dosage forms to bioequivalence assessment. These initiatives present challenges to regulatory authorities where the decision to approve bioequivalent products containing such pharmaceutical alternatives must be considered in the light of safety and efficacy, and more particularly, with respect to their substitutability. This article describes the various issues and contentions associated with the concept of pharmaceutical alternatives, specifically with respect to the uses of different salts and the implications for safety, efficacy and generic substitution

Theory and applications of free-electron vortex states

Both classical and quantum waves can form vortices: with helical phase fronts and azimuthal current densities. These features determine the intrinsic orbital angular momentum carried by localized vortex states. In the past 25 years, optical vortex beams have become an inherent part of modern optics, with many remarkable achievements and applications. In the past decade, it has been realized and demonstrated that such vortex beams or wavepackets can also appear in free electron waves, in particular, in electron microscopy. Interest in free-electron vortex states quickly spread over different areas of physics: from basic aspects of quantum mechanics, via applications for fine probing of matter (including individual atoms), to high-energy particle collision and radiation processes. Here we provide a comprehensive review of theoretical and experimental studies in this emerging field of research. We describe the main properties of electron vortex states, experimental achievements and possible applications within transmission electron microscopy, as well as the possible role of vortex electrons in relativistic and high-energy processes. We aim to provide a balanced description including a pedagogical introduction, solid theoretical basis, and a wide range of practical details. Special attention is paid to translate theoretical insights into suggestions for future experiments, in electron microscopy and beyond, in any situation where free electrons occur.Comment: 87 pages, 34 figure

M & L Jaargang 6/1

GeneriekMieke Verbeeck Van herberg tot café. [The story of beerhouses, inns and pubs in Flanders.]Heden zomaar in een café aan een tafel schuiven en de ober vragen om een kopje gelijknamige, welgeurende hete drank, getuigt voorwaar van enige stoutmoedigheid.Het café is immers lang reeds geen caffé meer, en veeleer ware bier hier op zijn plaats: maar hoe dan weer het cliché-matige, traditioneel of retro-decorum verklaard? In haar zoektocht naar het heden en verleden van taveernen, guinguettes, estaminets, herbergen en hoe zou het anders cafés, treft Mieke Verbeeck alvast één constante aan: de dorst.D. Colard Over de vergankelijke glorie van het Brusselse drankhuis. [The transient glory of the Brussels drinking-houses.]Metropolis is een hoofdstedelijk begrip, niet in het minst nu eerlang het Brussels nachtleven met weelderig iconografisch materiaal het daglicht dreigt te halen, ja voorwaar: de spotlights van een heuse tentoonstelling.De verleiding was dan ook té groot om niet voor deze stad de negentiende-eeuwse zelfingenomen opgang van café en estaminet te illustreren, tot hun jazzy nabloei halverwege de jaren 1920 met de dancing.Enige ongebruikelijke verve, wat fotos en bijwijlen schitterende ontwerptekeningen zijn helaas maar al te vaak het weinige dat overblijft om enigszins nog in verbeelding hun herinnering in stand te houden.K. Lanclus De opera van Gent. [The opera house at Ghent.]Onder dit motto schenkt M&L voortaan en systematisch 8 van kleur en illustraties ruim verzadigde bladzijden lang aandacht aan Vlaanderens meest monumentale, meest gevulgariseerde maar minst gekende, moeilijk toegankelijke monumenten. Een extra aansporing om dit tijdschrift onder de arm, de deuren-ontsluitende tips op zak nu eens bijvoorbeeld... de Opera van Gent van binnenuit te verkennen. Een gloednieuw verhaal in talrijke afleveringen, ontworpen en samengesteld door vele dames en één heer: de inventaris-teams van het Bestuurd voor Monumenten en Landschappen.SummaryM&L Binnenkran

Predictors of loss to follow-up of tuberculosis cases under the DOTS programme in Namibia

Background In Namibia, one out of every 25 cases of tuberculosis (TB) is “lost to follow-up” (LTFU). This has impacted negatively on national efforts to end the disease by 2035. The aim of this study was to determine the trends and predictors of LTFU under the directly observed treatment short-course (DOTS) programme in Namibia. Methods The study involved a retrospective longitudinal analysis of a nationwide cohort of TB cases registered under the DOTS programme in Namibia from 2006 to 2015. The trends and predictors of LTFU among cases in the National Electronic TB Register of the National TB and Leprosy Program were respectively determined by interrupted time series and multivariate logistic regression analyses using R-Studio software. Results Out of 104 203 TB cases, 3775 (3.6%) were LTFU. A quarter (26%) of cases with poor outcomes were due to LTFU. The annual decline in cases of LTFU was significant between the first (2005–2010) and second (2010–2015) medium-term plan period for TB programme implementation (p=0.002). The independent predictors of LTFU were male sex (p=0.004), 15–24 years age group (p=0.03), provider of treatment (p<0.001), intensive phase (p=0.047) and living in border/transit regions (p<0.001). HIV co-infection and TB regimen were not significant predictors of LTFU. Conclusions There were declining trends in LTFU in Namibia. DOTS programmes should integrate socioeconomic interventions for young and middle-aged adult male TB cases to reduce LTFU

Fault activity in the epicentral area of the 1580 Dover Strait (Pas-de-Calais) earthquake (northwestern Europe)

On 1580 April 6 one of the most destructive earthquakes of northwestern Europe took place in the Dover Strait (Pas de Calais). The epicentre of this seismic event, the magnitude of which is estimated to have been about 6.0, has been located in the offshore continuation of the North Artois shear zone, a major Variscan tectonic structure that traverses the Dover Strait. The location of this and two other moderate magnitude historical earthquakes in the Dover Strait suggests that the North Artois shear zone or some of its fault segments may be presently active. In order to investigate the possible fault activity in the epicentral area of the AD 1580 earthquake, we have gathered a large set of bathymetric and seismic-reflection data covering the almost-entire width of the Dover Strait. These data have revealed a broad structural zone comprising several subparallel WNW–ESE trending faults and folds, some of them significantly offsetting the Cretaceous bedrock. The geophysical investigation has also shown some indication of possible Quaternary fault activity. However, this activity only appears to have affected the lowermost layers of the sediment infilling Middle Pleistocene palaeobasins. This indicates that, if these faults have been active since Middle Pleistocene, their slip rates must have been very low. Hence, the AD 1580 earthquake appears to be a very infrequent event in the Dover Strait, representing a good example of the moderate magnitude earthquakes that sometimes occur in plate interiors on faults with unknown historical seismicity

Beyond small-scale transients: a closer look at the diffuse quiet solar corona

Within the quiet Sun corona imaged at 1 MK, much of the field of view consists of diffuse emission that appears to lack the spatial structuring that is so evident in coronal loops or bright points. We seek to determine if these diffuse regions are categorically different in terms of their intensity fluctuations and spatial configuration from the more well-studied dynamic coronal features. We analyze a time series of observations from Solar Orbiter's High Resolution Imager in the Extreme Ultraviolet to quantify the characterization of the diffuse corona at high spatial and temporal resolutions. We then compare this to the dynamic features within the field of view, mainly a coronal bright point. We find that the diffuse corona lacks visible structuring, such as small embedded loops, and that this is persistent over the 25 min duration of the observation. The intensity fluctuations of the diffuse corona, which are within +/-5%, are significantly smaller in comparison to the coronal bright point. Yet, the total intensity observed in the diffuse corona is of the same order as the bright point. It seems inconsistent with our data that the diffuse corona is a composition of small loops or jets or that it is driven by discrete small heating events that follow a power-law-like distribution. We speculate that small-scale processes like MHD turbulence might be energizing the diffuse regions, but at this point we cannot offer a conclusive explanation for the nature of this feature.Comment: Accepted for publication in A&A. 10 pages, 8 figure

Atmospheric drivers of storage water use in Scots pine

International audienceIn this study we determined the microclimatic drivers of storage water use in Scots pine (Pinus sylvestris L.) growing in a temperate climate. The storage water use was modeled using the ANAFORE model, integrating a dynamic water flow and ? storage model with a process-based transpiration model. The model was calibrated and validated with sap flow measurements for the growing season of 2000 (26 May?18 October). Because there was no severe soil drought during the study period, we were able to study atmospheric effects. Incoming radiation was the main driver of storage water use. The general trends of sap flow and storage water use are similar, and follow more or less the pattern of incoming radiation. Nevertheless, considerable differences in the day-to-day pattern of sap flow and storage water use were observed, mainly driven by vapour pressure deficit (VPD). During dry atmospheric conditions (high VPD) storage water use was reduced. This reduction was disproportionally higher than the reduction in measured sap flow. Our results suggest that the trees did not rely more on storage water during periods of atmospheric drought, without severe soil drought. A third important factor was the tree water deficit. When storage compartments were depleted beyond a threshold, storage water use was limited due to the low water potential in the storage compartments. The maximum relative contribution of storage water to daily transpiration was also constrained by an increasing tree water deficit

Earthquake geology of the Kanda fault system (Tanganyika-Rukwa rift, SW highlands of Tanzania)

The 160 km-long Kanda normal fault system is running longitudinally across the Ufipa tilted horst between the Tanganyika and Rukwa rift basins in the western branch of the East African Rift System. It is likely to have been affected the Ms 7.4 earthquake in 1910 whose instrumental epicentre was located approximately near Sumbawanga town, along the northern portion of the fault. Remote sensing, morphotectonic, and palaeoseismological investigations together with structural geology and electric resistivity profiling allow to characterise the main seismological parameters of this major active fault.In order to reconstruct the along-trend displacement profile and fault segmentation, topographic profiles were made across the fault scarp using data from differential GPS, Hand GPS and the 90 m resolution STRM DEM. Comparison of topographic profiles from the same site using the different topographic data provides some insight on the methodology and validity of topographic profiles extraction. Due to the large dimensions of the fault scarp (10-30 m high) the strong magnitude of the potential earthquakes (Ms. 7.5) and the large associated co-seismic slip (2-4 m), classical paleoseismic trenching is difficult to apply. Instead, we used existing exposures such as natural trenches, road cuts and outcrops, supplemented by a dense topographic survey (5000 points on differential GPS over less than 1 km2) to produce a 2 m resolution digital elevation model, performed detailed geological mapping, airphoto interpretation, electric resistivity profiling, small drillings, and C14 dating. Efforts were concentrated on a promising site where river sediments and peat deposits are interbedded with volcanic tephra layers and largely exposed on the footwall. Results show that the Kanda fault had different cycles of activity, separated by tectonically quite periods. The last period of activity probably started by 11 cal Ka BP, soon after the deposition of a marked tephra layer, but sedimentation on the footwall continued up to 5 Ka cal BP. Since then, the minimum offset is estimated at 17.9 m, which gives a minimum slip rate of 3.58 mm/year, of an equivalent of one earthquakes generating 3.58 m slip per 1000 years (Ms in the range of 7.0 - 7.5)