Androgenic effects on ventricular repolarization: A translational study from the international pharmacovigilance database to iPSC-cardiomyocytes.

BACKGROUND: Male hypogonadism, arising from a range of etiologies including androgen-deprivation therapies (ADTs), has been reported as a risk factor for acquired long-QT syndrome (aLQTS) and torsades de pointes (TdP). A full description of the clinical features of aLQTS associated with ADT and of underlying mechanisms is lacking. METHODS: We searched the international pharmacovigilance database VigiBase for men (n=6 560 565 individual case safety reports) presenting with aLQTS, TdP, or sudden death associated with ADT. In cardiomyocytes derived from induced pluripotent stem cells from men, we studied electrophysiological effects of ADT and dihydrotestosterone. RESULTS: Among subjects receiving ADT in VigiBase, we identified 184 cases of aLQTS (n=168) and/or TdP (n=68; 11% fatal), and 99 with sudden death. Of the 10 ADT drugs examined, 7 had a disproportional association (reporting odds ratio=1.4-4.7; P<0.05) with aLQTS, TdP, or sudden death. The minimum and median times to sudden death were 0.25 and 92 days, respectively. The androgen receptor antagonist enzalutamide was associated with more deaths (5430/31 896 [17%]; P<0.0001) than other ADT used for prostate cancer (4208/52 089 [8.1%]). In induced pluripotent stem cells, acute and chronic enzalutamide (25µM) significantly prolonged action potential durations (action potential duration at 90% when paced at 0.5Hz; 429.7±27.1 (control) versus 982.4±33.2 (acute, P<0.001) and 1062.3±28.9ms (chronic; P<0.001), and generated afterdepolarizations and/or triggered activity in drug-treated cells (11/20 acutely and 8/15 chronically). Enzalutamide acutely and chronically inhibited delayed rectifier potassium current, and chronically enhanced late sodium current. Dihydrotestosterone (30nM) reversed enzalutamide electrophysiological effects on induced pluripotent stem cells. CONCLUSION: QT prolongation and TdP are a risk in men receiving enzalutamide and other ADTs. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03193138.

Local-scale structures across the morphotropic phase boundary in PbZr1-x Ti x O3.

Lead zirconate titanate (PZT) is one of the most widely studied piezoelectric materials, mainly because of its 'mysterious' relationship between the so-called morphotropic phase boundary (MPB) and its strong piezoelectric coupling factor. Using results from a pair distribution function analysis, this paper examines how the complex local structure in PZT affects the long-range average structure across the MPB. A monoclinic M C type structure is discovered in PZT. A first-order transformation between the monoclinic M A and M C components in both the average and local structures explains the sudden change in piezoelectric effect around these compositions. The role of polarization rotation in the enhancement of the piezoelectric properties is discussed with respect to the composition of PZT. The structure-property relationship that is revealed by this study explains the unique properties of PZT, and may be applicable in the design of new MPB-type functional materials.

Crystallographic and optical study of LiNb1†-†xTaxO3.

Powders of lithium niobate-tantalate across the full compositional range have been made and crystals grown using a lithium vanadate flux growth technique. The Li-content of a lithium tantalate crystal has been determined using the zero-birefringence temperature and Curie measurements, confirming the Li content is between that of congruent and stoichiometric crystals. X-ray diffraction measurements show the Nb/Ta displacement and octahedral tilt both decrease as the Ta content is increased. This also results in a decrease in the lattice parameters from lithium niobate to lithium tantalate. Birefringence measurements on the crystals as a function of temperature have been used to determine the point that the crystals become zero-birefringent, and by comparison with the structural studies have confirmed that it is not related to a phase transition and the structures remain polar through the zero-birefringence points.

Crystallographic and optical study of PbHfO3 crystals.

The symmetry of the intermediate high-temperature phase of PbHfO3 has been determined unambiguously to be orthorhombic using a combination of high-resolution X-ray diffraction and birefringence imaging microscopy measurements of crystal plates. While lattice parameter measurements as a function of temperature in the intermediate phase are consistent with either orthorhombic or tetragonal symmetry, domain orientations observed in birefringence imaging microscopy measurements utilizing the Metripol system are only consistent with orthorhombic symmetry with the unit cell in the rhombic orientation of the pseudocubic unit cell.

There ain't nothing like a Dame: a commentary on Lonsdale (1947) 'Divergent beam X-ray photography of crystals'.

Prof. Dame Kathleen Lonsdale was one of the two first female Fellows of the Royal Society, having originally been a student of that great British scientist and Nobel Laureate William Henry Bragg. She came to fame initially for her solution of the crystal structure of hexamethyl benzene, thus demonstrating that the benzene ring was flat, of considerable importance to organic chemistry, where it had been proposed before but without proof. This was at a time when the solution of crystal structures was in its infancy, and in its day this work was considered a triumph. As a rare example then of a female physicist, Lonsdale became interested in various aspects of the diffraction of X-rays, and in particular published an important paper on a form of diffraction in which a strongly divergent source was used rather than the usual highly collimated beam. The photographs thus obtained showed a series of arcs and circles, whose positions were so sensitive that they could be used to determine the quality of crystals such as diamond, and even to calculate their lattice dimensions, and hence carbon-carbon bond lengths, to hitherto extraordinary precision. Lonsdale also became known not just as a scientist but as a peace activist and an active member of the Society of Friends. This commentary was written to celebrate the 350th anniversary of the journal Philosophical Transactions of the Royal Society.

Phase transitions and thermal-stress-induced structural changes in a ferroelectric Pb(Zr0.80Ti0.20)O3 single crystal.

A single crystal of lead-zirconate-titanate, composition Pb(Zr0.80Ti0.20)O3, was studied by polarized-Raman scattering as a function of temperature. Raman spectra reveal that the local structure deviates from the average structure in both ferroelectric and paraelectric phases. We show that the crystal possesses several, inequivalent complex domain boundaries which show no sign of instability even 200 K above the ferroelectric-to-paraelectric phase transition temperature TC. Two types of boundaries are addressed. The first boundary was formed between ferroelectric domains below TC. This boundary remained stable up to the highest measurement temperatures, and stabilized the domains so that they had the same orientation after repeated heating and cooling cycles. These domains transformed normally to the cubic paraelectric phase. Another type of boundary was formed at 673 K and exhibited no signs of instability up to 923 K. The boundary formation was reversible: it formed and vanished between 573 and 673 K during heating and cooling, respectively. A model in which the crystal is divided into thin slices with different Zr/Ti ratios is proposed. The physical mechanism behind the thermal-stress-induced structural changes is related to the different thermal expansion of the slices, which forces the domain to grow similarly after each heating and cooling cycle. The results are interesting for non-volatile memory development, as it implies that the original ferroelectric state can be restored after the material has been transformed to the paraelectric phase. It also suggests that a low-symmetry structure, stable up to high temperatures, can be prepared through controlled deposition of layers with desired compositions.

The missing boundary in the phase diagram of PbZr(1-x)TixO3.

PbZr(1-x)Ti(x)O3 (PZT) is one of the most important and widely used piezoelectric materials. The study of its local and average structures is of fundamental importance in understanding the origin of its high-performance piezoelectricity. Pair distribution function analysis and Rietveld refinement have been carried out to study both the short- and long-range order in the Zr-rich rhombohedral region of the PZT phase diagram. The nature of the monoclinic phase across the Zr-rich and morphotropic phase boundary area of PZT is clarified. Evidence is found that long-range average rhombohedral and both long- and short-range monoclinic regions coexist at all compositions. In addition, a boundary between a monoclinic (M(A)) structure and another monoclinic (M(B)) structure has been found. The general advantage of a particular monoclinic distortion (M(A)) for high piezoactivity is discussed from a spatial structural model of susceptibility to stress and electric field, which is applicable across the wide field of perovskite materials science.

The not so simple cubic structure of PbZr(1-x)Ti(x)O3 (PZT): complex local structural effects in perovskites.

High-resolution neutron diffraction on the important piezoelectric lead zirconate titanate (PZT) has found that oxygen disorder exists well into the cubic phase. This unexpected result shows that within this phase there persists a remnant of the tilted oxygen octahedra present within the room-temperature ferroelectric phase. The result is that the cubic phase, far from having a simple crystal structure, exhibits a more complex local structure than had hitherto been thought.

Neutron powder diffraction refinement of PbZr(1†-†x)Ti(x)O3.

Rietveld refinement of different structural models using neutron diffraction data for a series of powders of lead zirconate titanate, PbZr(1 - x)Ti(x)O(3) (PZT), is described. It is found that at all the compositions and temperatures studied the best results include contributions from more than one phase in order to fit the data. Consequently a new phase diagram is proposed.

Single crystal study of competing rhombohedral and monoclinic order in lead zirconate titanate.

Neutron diffraction data obtained on single crystals of PbZr(1-x)Ti(x)O3 with x=0.325 and x=0.460, which lie on the pseudorhombohedral side of the morphotropic phase boundary, suggest a coexistence of rhombohedral (R3m/R3c) and monoclinic (Cm) domains and that monoclinic order is enhanced by Ti substitution. A monoclinic phase with a doubled unit cell (Cc) is ruled out as the ground state.

Structures of K(0.05)Na(0.95)NbO3 (50-300 K) and K(0.30)Na(0.70)NbO3 (100-200 K).

Rietveld refinement using neutron powder diffraction data is reported for the potential lead-free piezoelectric material K(x)Na(1-x)NbO3 (x = 0.05, x = 0.3) at low temperatures. The structures were determined to be of rhombohedral symmetry, space group R3c, with the tilt system a(-)a(-)a(-) for both compositions. It was found that some of the structural parameters differ significantly in the two structures, and particularly the NbO6 octahedral strains as a function of temperature. The 300 K profile for K(0.05)Na(0.95)NbO3 shows the coexistence of rhombohedral and monoclinic phases, which indicates that the phase boundary is close to room temperature; the phase boundary for K(0.30)Na(0.70)NbO3 is found to be at approximately 180 K.

Structural study of K(x)Na(1 - x)NbO(3) (KNN) for compositions in the range x = 0.24-0.36.

The structure of the A-site substituted perovskite K(x)Na(1 - x)NbO(3), x = 0.24-0.36, where a phase boundary was previously reported, has been determined by high-resolution X-ray powder and neutron powder diffraction studies. The structure of the x = 0.3 compound was refined in the monoclinic space group Pm at 293 K and in P4mm at 523 K. The Glazer tilt system of the room-temperature monoclinic phase is a(0)b(+)c(0), which has implications for the nature of the next symmetry change with composition towards pure potassium niobate. A phase-coexistence region at the transition between monoclinic and tetragonal phases was also identified, consistent with a first-order phase boundary. There is also evidence for an intermediate oxygen-octahedra tilted tetragonal phase.

Optical birefringence study of the ferroelectric phase transition in lithium niobate tantalate mixed crystals: LiNb(1-x)Ta(x)O(3).

The optical birefringence of a complete solid-solution series of lithium niobate-tantalate crystals has been measured as a function of temperature. It is found that, irrespective of composition, the high-temperature paraelectric phase has a birefringence close to +0.063, suggesting that this value arises purely from the oxygen octahedra in the crystal structure. It is also observed that a small addition of lithium niobate to the tantalate produces a crystal that has zero birefringence at room temperature.

The macroscopic symmetry of Pb(Mg1/3Nb2/3)1-xTixO3 in the morphotropic phase boundary region (x = 0.25-0.5).

The macroscopic symmetry of Pb(Mg1/3Nb2/3)1-xTixO3 (PMN-PT) crystals with x = 0.25-0.5 has been studied by optical microscopy. Precise data on the temperature dependence of the birefringence and optical extinction directions have been obtained. Two different low-symmetry phases separating rhombohedral and tetragonal phases have been observed in the compositional range x = 0.3-0.47. The optical extinction in the range x = 0.3-0.37 is consistent with Cm space group symmetry, while for x = 0.37-0.47 Pm symmetry is appropriate. Gradual rotation of the optical indicatrix has been found at temperatures just below Tc in crystals with x = 0.27-0.3. A refined phase diagram is presented.

Observation of divergent-beam X-ray diffraction from a crystal of diamond using synchrotron radiation.

In 1947 Kathleen Lonsdale conducted a series of experiments on X-ray diffraction using a divergent beam external to a crystal sample. Unlike the Kossel technique, where divergent X-rays are excited by the presence of fluorescing atoms within the crystal, the use of an external divergent source made it possible to study non-fluorescing crystals. The resulting photographs not only illustrated the complexity of X-ray diffraction from crystals in a truly beautiful way, but also demonstrated unprecedented experimental precision. This long-forgotten work is repeated here using a synchrotron radiation source and, once again, considerable merit is found in Lonsdale's technique. The results of this experiment suggest that, through the use of modern 'third-generation' synchrotron sources, divergent-beam diffraction could soon enjoy a renaissance for high-precision lattice-parameter determination and the study of crystal perfection.

Nomenclature of magnetic, incommensurate, composition-changed morphotropic, polytype, transient-structural and quasicrystalline phases undergoing phase transitions. II. Report of an IUCr Working Group on Phase Transition Nomenclature.

A general nomenclature applicable to the phases that form in any sequence of transitions in the solid state has been recommended by an IUCr Working Group [Acta Cryst. (1998). A54, 1028-1033]. The six-field notation of the first Report, hereafter I, was applied to the case of structural phase transitions, i.e. to transformations resulting from temperature and/or pressure changes between two crystalline (strictly periodic) phases involving modifications to the atomic arrangement. Extensive examples that illustrate the recommendations were provided. This second Report considers, within the framework of a similar six-field notation, the more complex nomenclature of transitions involving magnetic phases, incommensurate phases and transitions that occur as a function of composition change. Extension of the nomenclature to the case of phases with less clearly established relevance to standard schemes of transition in equilibrium systems, namely polytype phases, radiation-induced and other transient phases, quasicrystalline phases and their transitions is recommended more tentatively. A uniform notation for the translational periodicity, propagation vector or wavevector for magnetic and/or incommensurate substances is specified. The notation adopted for incommensurate phases, relying partly on the existence of an average structure, is also consistent with that for commensurate phases in a sequence. The sixth field of the nomenclature is used to emphasize the special features of polytypes and transient phases. As in I, illustrative examples are provided for each category of phase sequence.