ABSTRACT
Allergen immunotherapy (AIT) has been performed for 112 years. In this article we summarize regulatory standards and challenges based on scientific evidence on AIT. Most crucial and timely aspects concerning AIT are addressed from the regulatory perspective of the authors as employees of a national competent authority in Europe: (1) product specificity; (2) clinical efficacy; (3) treatment for adults and children (needs for extrapolation); (4) allergen exposure chambers; (5) biomarkers; (6) standardization; (7) real-world evidence; (8) independent official batch release (benefit and challenges); (9) harmonization on the EU level. The Paul-Ehrlich-Institut (PEI), the Federal Institute for Vaccines and Biomedicines, in Langen near Frankfurt/Main in Germany, examines and evaluates the benefits and risks of AIT products within the course of clinical development, marketing authorization, and subsequently throughout their entire life cycle to ensure high-quality, safe, and effective AIT products.
ABSTRACT
The magnetic structure of chromium arsenide CrAs is studied with neutron powder diffraction at ambient pressure in the temperature range 1.5-300â K as well as with neutron single-crystal diffraction at 2â K and 0.12â GPa. The material undergoes an anti-isostructural phase transition at TN = 267â K and atmospheric conditions, in which both orthorhombic phases have the same space-group symmetry (Pnma, Z = 4) but different distortions of the parent hexagonal structure of the NiAs type (P63/mmc, Z = 2). The magnetic structure below TN is incommensurate with the propagation vector k = (0, 0, kc). At ambient pressure, the component kc decreases from kc = 0.3807â (7) at 260â K to kc = 0.3531â (6) at 50â K. Below this temperature, it is basically constant. With increasing pressure at 2â K, kc is also constant within standard uncertainties [kc = 0.353â (2)]. For the analysis of the magnetic structure, a group-theoretical approach based on the space group of the nuclear structure and its subgroups is used. To avoid falling into false minima in the refinements, a random search for magnetic moments in the models is implemented. In the literature, the magnetic structure has been determined on the basis of powder diffraction data as a double helix propagating along the c axis. Although this double-helical model leads to satisfactory agreement factors for our powder data, it does not reproduce the intensities of the magnetic satellite reflections measured on single-crystal data in a satisfactory way and can therefore be discarded. Instead, several other models are found that lead to better agreement. Each of them is spiral-like with directional components in all three directions and with no spin-density wave character that would cause a non-constant magnetic moment. In all these models, the ordering of the spins is neither a pure helix nor a pure cycloid. Instead, the unit vectors of the spin rotation planes make an angle α, 0° < α < 90°, with respect to the c* direction. The model in superspace group P21.1'(α0γ)0s yields the best agreement factors in the refinements of the neutron single-crystal and powder diffraction data. This model is unique as it is the only one in which all the magnetic moments rotate with the same chirality.
ABSTRACT
The structures and phase transitions to incommensurate structures in Rb2V3O8 and K2V3O8 mixed-valence vanadate fresnoites are studied with synchrotron single-crystal diffraction at low temperatures and ambient pressure. Although mixed satellite reflections are absent, the modulated structure of K2V3O8 below 115â K is better described in (3â +â 2)- than in (3â +â 1)-dimensional space. The geometries of the VO4 and VO5 building units are rigid and it is mainly slight rotations of these polyhedra and small variation of the intermediate K-O distances that are modulated. Prolonged exposure to the high-brilliance synchrotron beam suppresses the incommensurate phase. The previously postulated phase transition to the incommensurate phase in Rb2V3O8 at 270â K was not observed. One of the reasons could be that the intense radiation also affects the modulation in this material. Strategies to collect and analyse single-crystal diffraction data measured with very intense synchrotron radiation using modern low-noise pixel area detectors are discussed.
ABSTRACT
The nuclear and magnetic structures of Mn3Fe2Si3 are investigated in the temperature range from 20 to 300â K. The magnetic properties of Mn3Fe2Si3 were measured on a single crystal. The compound undergoes a paramagnetic to antiferromagnetic transition at T N2 ≃ 120â K and an antiferromagnetic to antiferromagnetic transition at T N1 ≃ 69â K. A similar sequence of magnetic phase transitions is found for the parent compound Mn5Si3 upon temperature variation, but the field-driven transition observed in Mn5Si3 is not found in Mn3Fe2Si3, resulting in a strongly reduced magnetocaloric effect. Structurally, the hexagonal symmetry found for both compounds under ambient conditions is preserved in Mn3Fe2Si3 through both magnetic transitions, indicating that the crystal structure is only weakly affected by the magnetic phase transition, in contrast to Mn5Si3 where both transitions distort the nuclear structure. Both compounds feature a collinear high-temperature magnetic phase AF2 and transfer into a non-collinear phase AF1 at low temperature. While one of the distinct crystallographic sites remains disordered in the AF2 phase in the parent compound, the magnetic structure in the AF2 phase involves all magnetic atoms in Mn3Fe2Si3. These observations imply that the distinct sites occupied by the magnetic atoms play an important role in the magnetocaloric behaviour of the family.
ABSTRACT
Chemical reactions and phase stabilities in the Si-Te system at high pressures were explored using in situ angle-dispersive synchrotron powder diffraction in a large-volume multianvil press together with density functional theory-based calculations. Cubic and rhombohedrally distorted clathrates, with the general formula Te8@(Si38Te8) and wide compositional range, preceded by a hexagonal phase with the composition Si0.14Te, are formed for different mixtures of Si and Te as starting materials. Si0.14Te, with the structural formula Te2(Te0.74Si0.26)3(Te0.94Si0.06)3, is the very first chalcogenide with the Mn5Si3-type structure. Silicon sesquitelluride α-Si2Te3 decomposes into a mixture of phases that includes the clathrate and hexagonal phases at high pressures and high temperatures. The higher the pressure, the lower the temperature for the two phases to occur. Regardless of the starting compositions, only the clathrate is quenched to atmospheric conditions, while the hexagonal phase amorphizes on decompression. The rhombohedral clathrates Te8@(Si38Te8) form on quenching of the cubic phases to ambient conditions. There is a high degree of interchangeability of Si and Te not only in the clathrates but also in the Mn5Si3-type structure. The theoretical calculations of enthalpies indicate that the reported decomposition of α-Si2Te3 is energetically favorable over its transformation to another polymorph of the A2X3 type at extreme conditions.
ABSTRACT
It is shown that it is possible to perform combined X-ray and neutron single-crystal studies in the same diamond anvil cell (DAC). A modified Merrill-Bassett DAC equipped with an inflatable membrane filled with He gas has been developed. It can be used on laboratory X-ray and synchrotron diffractometers as well as on neutron instruments. The data processing procedures and a joint structural refinement of the high-pressure synchrotron and neutron single-crystal data are presented and discussed for the first time.
ABSTRACT
The capability to perform high-pressure low-temperature nuclear inelastic scattering on 125Te and 121Sb with a sapphire backscattering monochromator is presented. This technique was applied to measure nuclear inelastic scattering in TeO2 at pressures up to 10 GPa and temperatures down to 25 K. The evaluated partial Te densities of phonon states were compared with theoretical calculations and with Raman scattering measured under the same conditions. The high-pressure cell developed in this work can also be used for other techniques at pressures up to at least 100 GPa.
ABSTRACT
The high-pressure and low-temperature behaviour of the GeSexTe1-x system (x = 0, 0.2, 0.5, 0.75, 1) was studied using a combination of powder diffraction measurements and first-principles calculations. Compounds in the stability field of the GeTe structure type (x = 0, 0.2, 0.5) follow the high-pressure transition pathway: GeTe-I (R3m) â GeTe-II (f.c.c.) â GeTe-III (Pnma). The newly determined GeTe-III structure is isostructural to ß-GeSe, a high-pressure and high-temperature polymorph of GeSe. Pressure-dependent formation enthalpies and stability regimes of the GeSexTe1-x polymorphs were studied by DFT calculations. Hexagonal Ge4Se3Te is stable up to at least 25â GPa. Significant differences in the high-pressure and low-temperature behaviour of the GeTe-type structures and the hexagonal phase are highlighted. The role of Ge...Ge interactions is elucidated using the crystal orbital Hamilton population method. Finally, a sketch of the high-pressure phase diagram of the system is provided.
ABSTRACT
As required by the European Medicines Agency and the US Food and Drug Administration for pivotal trials involving allergen immunotherapy (AIT) products, clinical efficacy assessment is currently based on double-blind, placebo-controlled field studies with natural allergen exposure during the allergen season. However, this study design is associated with several drawbacks, such as the high variability of allergen exposure in different trial sites or seasons and the presence of confounding environmental factors. On the contrary, environmental exposure chambers (EECs) aim to operate with a stable and reproducible allergen exposure under highly standardized environmental conditions. Technical validation parameters for different EECs worldwide have been published by several groups. However, full clinical validation of EEC study outcomes is required for their classification as an appropriate alternative to natural allergen exposure for AIT product efficacy assessment. Some clinical validation parameters have already been addressed for EEC units. The reliability of provoked symptoms in repeated EEC sessions is high, but the predictive power of EEC settings for the clinical response on natural exposure and the impact of seasonal priming on test results still have to be validated systematically, as does the inter-EEC variability. Thus the authors recommend a continued in-depth validation of EECs to exploit the potential of this technology for future AIT product development.
Subject(s)
Allergens/immunology , Atmosphere Exposure Chambers/standards , Environmental Exposure , Pollen/immunology , Rhinitis, Allergic, Seasonal/therapy , Clinical Trials as Topic , Desensitization, Immunologic/methods , Europe , Humans , Rhinitis, Allergic, Seasonal/diagnosis , Rhinitis, Allergic, Seasonal/immunology , Rhinitis, Allergic, Seasonal/physiopathology , United States , Validation Studies as TopicABSTRACT
Crystal structures of pure and doped KLnF(4) (Ln = Y, Ho, Er, Tm, Yb) grown hydrothermally were studied with synchrotron single-crystal and powder diffraction as a function of temperature and pressure. At atmospheric conditions, KHoF(4) and KErF(4) crystallize in space group P3(1), while KTmF(4), Er:KYbF(4), and KYF(4) crystallize in space group P3(2). In both enantiomorphic structures, the K(+) and Ln(3+) cations are completely ordered. The pseudo-symmetry of the structures with respect to the two minimal supergroups k = 3 (P3(1) and P3(2)) and t = 2 (P3(1)12 and P3(2)12) increases with decreasing radius of the Ln(3+) cation, respectively. No phase transition is detected in KYF(4) at low temperatures down to 100 K at atmospheric pressure. Er:KYbF(4) and KYF(4) undergo irreversible pressure-induced phase transitions at about 4 GPa. In each case, the single crystals become fragmented into several crystallites as observed during single-crystal measurements in diamond anvil cells. Up to the phase transitions, both Er:KYbF(4) and KYF(4) are more compressible along the c axis and their bulk compressibility predominantly results from the contraction of the KF(8) polyhedra. The application of pressure does not affect the distribution of the cations in the crystal structures of Er:KYbF(4) and KYF(4) up to the phase transitions at about 4 GPa.
ABSTRACT
Crystal structures of the NaLnF(4) materials (Ln = La, Ce, Pr, Nd, Sm or Gd) were studied with synchrotron single-crystal and powder diffraction. The materials with Ln = La, Ce, Nd, Sm and Gd have the average ß structure (P6, Z = 1) with partial ordering of the cations. A new type of a superstructure due to ordering of the cations and vacancies was found in NaPrF(4) (P3, Z = 6). It could be described using the group-subgroup relationships P6âP3. Our observations suggest that the ß structure is unstable and that the ordering is a slow process at ambient conditions. Upon compression, ß-NaNdF(4), ß-NaGdF(4) and the superstructure NaPrF(4) are stable to at least 8 GPa with no evidence for any pressure-induced disorder-order phenomena.
ABSTRACT
The high-pressure behaviour of (NH(4))(2)V(3)O(8) with the fresnoite structure (P4bm, Z = 2) has been studied at room temperature with single-crystal X-ray diffraction in diamond anvil cells using laboratory and synchrotron facilities. At ambient conditions, the crystal structure is composed of layers of corner-sharing V(5+)O(4) tetrahedra and V(4+)O(5) square pyramids separated by layers of the NH(4)(+) cations. At about 3 GPa, there occurs a reversible first-order phase transition to a three-dimensional structure (P4/mbm, Z = 2) built of corner-sharing V(5+)O(5) trigonal bipyramids and V(4+)O(6) octahedra. The NH(4)(+) cations fill up the interstitial sites in the tunnels formed by the vanadate framework. Up to the phase transition, the a lattice parameter of the low-pressure polymorph does not change while the contraction perpendicular to the stacking of the V(3)O(8) slabs accounts entirely for the bulk compressibility. Above the phase transition, the a lattice parameter slightly expands. The structural features of the high-pressure phase of (NH(4))(2)V(3)O(8) are compared to those of other vanadium oxides.
ABSTRACT
The incommensurately modulated structure of a natural nepheline of composition K(0.54)Na(3.24)Ca(0.03)Al(3.84)Si(4.16)O(16) has been determined in superspace. The compound crystallizes in the trigonal centered superspace group X3(00γ)0 with γ = 0.2048 (10), X = (0, 0, 0, 0), (1/3, 2/3, 0, 2/3), (2/3, 1/3, 0, 1/3), a = 17.2889 (8) and c = 8.3622 (10) Å. The structure is characterized by a framework of corner-connected (Al,Si)O(4) tetrahedra. The additional cations are incorporated in two different types of channels of the framework. All atoms in the structure are displacively modulated with amplitudes below 0.1 Å. The modulation can be well described taking into account harmonics of first order only. Atomic positions in the smaller channels of the framework are fully occupied by Na(+). Cationic positions in the larger channel are occupationally modulated, yet the variation of electron density as a function of the internal coordinate t is very small and indicates that the incorporation of different types of cations (K(+), Na(+), Ca(2+)) and vacancies is realised in a highly disordered way. Average T-O distances indicate a nearly complete Al/Si ordering in the tetrahedral framework. A large part of the O atoms are approximated by split-atom positions, which are additionally affected by occupational modulation resulting in a high degree of disorder in the modulated structure. Occupational probabilities for the split-atom positions are complementary. Occupational modulations of the cations in the larger channels and the O atoms of the tetrahedral framework are coupled and correlations between occupational and displacive modulations exist.
ABSTRACT
The structure of BaThF(6) has been investigated as a function of temperature and pressure with single-crystal X-ray diffraction using synchrotron radiation. The compound crystallizes in the tysonite structure, space group P6(3)/mmc (a = 4.296(1) Å and c = 7.571(1) Å at ambient conditions). It is stable at least down to 150 K and up to 4 GPa. In the entire range of pressures and temperatures studied here, the compound is characterized by a high degree of disorder, both on the cationic and anionic positions. Despite the different valence states and sizes, both cations occupy the same crystallographic site in the ideal tysonite structure. The cationic disorder is described by two alternative approaches. The first model corresponds to a split-atom position model in which Ba(2+) is maintained on a special position with site symmetry 6m2, while Th(4+) is slightly displaced from the respective position. In the second model, both cations are maintained on the ideal position and anharmonic displacement parameters using a tensor of third order are introduced. Anharmonic displacement parameters have been refined from high-pressure single-crystal X-ray data measured in situ in a diamond anvil cell for the first time. The feasibility and general problems of anharmonic refinements of high-pressure X-ray data are further commented.
ABSTRACT
The crystal structure of the bismuth silicon oxide Bi(12)SiO(20) was determined by single-crystal x-ray diffraction at ambient conditions and at high pressure. Single-crystal intensity data between 0.0001 and 16.8(3) GPa were collected in house with Mo Kα radiation and with synchrotron radiation (λ = 0.45 Å) at HASYLAB (D3), while lattice parameters were measured up to 23.0(3) GPa. The large cavities which exist in the crystal structure and host the lone electron pairs of the Bi(3 + ) ions are considerably compressed at high pressure. The crystal structure, however, remains stable and the lone electron pair is stereochemically active up to at least 16.8 GPa. A larger compression in the direction of the lone electron pairs by shear deformation was not observed. Raman spectra of Bi(12)SiO(20) were measured on powder samples during pressure decrease from 39.1(1) GPa down to ambient pressure and on single crystals during pressure increase up to 12.50(3) GPa. Density functional perturbation theory was used to compute Raman frequencies and intensities at ambient pressure and to investigate pressure-induced changes up to 50 GPa.
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The pressure-induced crystal structure of lead sulfide (PbS) above 2.2 GPa has been studied with single-crystal x-ray diffraction in a diamond anvil cell at room temperature. It has been found to be twinned and of the TlI type (Cmcm, Z=4), in which the Pb atoms are surrounded by seven S atoms in a capped trigonal prism coordination. The twin laws in relation to the parent B1 (NaCl) type structure (Fm Ì3m, Z=4) at atmospheric pressure have been discussed.
ABSTRACT
High-pressure behaviours of isomorphous HoMn(2)O(5) and BiMn(2)O(5) (Pbam, Z = 4) were studied, using Raman spectroscopy and single-crystal x-ray diffraction, with the samples in diamond anvil cells pressurized to 10.09 GPa and 8.54 GPa, respectively, at room temperature. No phase transition was detected in either material. The two manganates are most compressible along the a axis with the lattice contractions along the b and c directions nearly the same. Their P-V data fitted with the second-order Birch-Murnaghan equation of state (B' = 4.0) give the bulk moduli B(0) = 138(2) GPa for BiMn(2)O(5) and B(0) = 173(3) GPa for HoMn(2)O(5). The difference in bulk moduli results from BiMn(2)O(5) being more compressible than HoMn(2)O(5) along the a axis. Our study shows that the Mn-O frameworks in isomorphous RMn(2)O(5) compounds (R = Bi and rare earth) are not rigid at high pressures, but rather adapt to the behaviour of the coordination spheres around the R atoms. Bond valence calculations indicate that the pressure-induced charge transfers between the two Mn sites have different characters for the two compounds.
ABSTRACT
Ternary fluorides BaMF4 (M = Zn, Mg, Mn) have been studied in the temperature range from 300 to 10 K using synchrotron and laboratory powder and single-crystal diffraction. The first two compounds are stable down to 10 K, while the third one undergoes a phase transition to an incommensurately modulated structure at approximately 250 K. The modulated phase is stable down to 10 K. The magnetic anomalies at 45 and 27 K observed previously in BaMnF4 are exclusively reflected in the behavior of the gamma component of the q vector, which assumes an irrational value of approximately 0.395 A(-1) at the temperature corresponding to the onset of the magnetic ordering and then stays constant down to 10 K. Mn-Mn distances do not indicate any structural response to the magnetic ordering. The formation of the modulated phase can be explained on the basis of simple geometrical criteria. The incorporation of the large Mn cation in the octahedral sheets implies an increase of the cavity in which the Ba ion is incorporated. This leads to the formation of the modulated structure to adapt the coordination sphere around Ba in such a way that the bond-valence sums can be kept close to the ideal value of two. With further lowering of the temperature, the charge balance around the Ba ion requires an increasingly anharmonic character of the modulation function of Ba, until finally at 10 K a crenel-like shape is assumed for the modulation of this atom.
ABSTRACT
The pressure dependence of the structure of the mixed-valence vanadate BaV6O11 was studied with single-crystal X-ray diffraction in a diamond-anvil cell. The compressibility data could be fitted with a Murnaghan equation of state with the zero-pressure bulk modulus B0 = 161 (7) GPa and the unit-cell volume at ambient pressure = 387.1 (3) A3 (B' = 4.00). A phase transition involving a symmetry reduction from P6(3)/mmc to P6(3)mc can be reliably detected in the high-pressure data. The estimated transition pressure lies in the range 1.18 < P(c) < 3.09 GPa. The transition leads to a breaking of the regular Kagomé net formed by part of the V ions. While in the ambient pressure structure all V-V distances in the Kagomé net are equal, they split into inter-trimer and intra-trimer distances in the high-pressure phase. In general, these changes are comparable to those observed in the corresponding low-temperature transition. However, the pressure-induced transition takes place at a lower unit-cell volume compared with the temperature-induced transition. Furthermore, overall trends for inter-trimer and intra-trimer V-V distances as a function of the unit-cell volume are clearly different for datapoints obtained by variation of pressure and temperature. The behavior of BaV6O11 is compared with that of NaV6O11. While in the latter compound the transition can be explained as a pure volume effect, in BaV6O11 an additional degree of freedom related to the valence distribution among the symmetrically independent vanadium sites has to be taken into account.
ABSTRACT
Rb(2)ZnCl(4) in the normal phase (T = 308-313 K) has been studied under pressure by means of single-crystal x-ray diffraction up to 3.84 GPa and Raman spectroscopy up to 5.9 GPa. No pressure-induced phase transition has been observed but an orientational disorder of the tetrahedra is enhanced with the pressure. At the same time a partial one-dimensional correlation of some chlorine atoms might be favoured at high pressures. Raman spectra in the incommensurate phase (T = 293 K) were collected to higher pressure (24.2 GPa) varying the pressure-transmitting medium. The hydrostaticity during the compression is shown to affect drastically the broadness of the Raman peaks, leading to an amorphous-like spectrum in the least hydrostatic case.