In acquired thrombotic thrombocytopenic purpura (TTP), an immune-mediated deficiency of the von Willebrand factor-cleaving protease ADAMTS13 allows unrestrained adhesion of von Willebrand factor ...multimers to platelets and microthrombosis, which result in thrombocytopenia, hemolytic anemia, and tissue ischemia. Caplacizumab, an anti-von Willebrand factor humanized, bivalent variable-domain-only immunoglobulin fragment, inhibits interaction between von Willebrand factor multimers and platelets.
In this double-blind, controlled trial, we randomly assigned 145 patients with TTP to receive caplacizumab (10-mg intravenous loading bolus, followed by 10 mg daily subcutaneously) or placebo during plasma exchange and for 30 days thereafter. The primary outcome was the time to normalization of the platelet count, with discontinuation of daily plasma exchange within 5 days thereafter. Key secondary outcomes included a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the trial treatment period; recurrence of TTP at any time during the trial; refractory TTP; and normalization of organ-damage markers.
The median time to normalization of the platelet count was shorter with caplacizumab than with placebo (2.69 days 95% confidence interval {CI}, 1.89 to 2.83 vs. 2.88 days 95% CI, 2.68 to 3.56, P=0.01), and patients who received caplacizumab were 1.55 times as likely to have a normalization of the platelet count as those who received placebo. The percentage of patients with a composite outcome event was 74% lower with caplacizumab than with placebo (12% vs. 49%, P<0.001). The percentage of patients who had a recurrence of TTP at any time during the trial was 67% lower with caplacizumab than with placebo (12% vs. 38%, P<0.001). Refractory disease developed in no patients in the caplacizumab group and in three patients in the placebo group. Patients who received caplacizumab needed less plasma exchange and had a shorter hospitalization than those who received placebo. The most common adverse event was mucocutaneous bleeding, which was reported in 65% of the patients in the caplacizumab group and in 48% in the placebo group. During the trial treatment period, three patients in the placebo group died. One patient in the caplacizumab group died from cerebral ischemia after the end of the treatment period.
Among patients with TTP, treatment with caplacizumab was associated with faster normalization of the platelet count; a lower incidence of a composite of TTP-related death, recurrence of TTP, or a thromboembolic event during the treatment period; and a lower rate of recurrence of TTP during the trial than placebo. (Funded by Ablynx; HERCULES ClinicalTrials.gov number, NCT02553317 .).
Essentials
Acquired thrombotic thrombocytopenic purpura (aTTP) is linked with significant morbidity/mortality.
Caplacizumab's effect on major thromboembolic (TE) events, exacerbations and death was ...studied.
Fewer caplacizumab‐treated patients had a major TE event, an exacerbation, or died versus placebo.
Caplacizumab has the potential to reduce the acute morbidity and mortality associated with aTTP.
Summary
Background
Acquired thrombotic thrombocytopenic purpura (aTTP) is a life‐threatening autoimmune thrombotic microangiopathy. In spite of treatment with plasma exchange and immunosuppression, patients remain at risk for thrombotic complications, exacerbations, and death. In the phase II TITAN study, treatment with caplacizumab, an anti‐von Willebrand factor Nanobody® was shown to reduce the time to confirmed platelet count normalization and exacerbations during treatment.
Objective
The clinical benefit of caplacizumab was further investigated in a post hoc analysis of the incidence of major thromboembolic events and exacerbations during the study drug treatment period and thrombotic thrombocytopenic purpura‐related death during the study.
Methods
The Standardized Medical Dictionary for Regulatory Activities (MedDRA) Query (SMQ) for ‘embolic and thrombotic events’ was run to investigate the occurrence of major thromboembolic events and exacerbations in the safety population of the TITAN study, which consisted of 72 patients, of whom 35 received caplacizumab and 37 received placebo.
Results
Four events (one pulmonary embolism and three aTTP exacerbations) were reported in four patients in the caplacizumab group, and 20 such events were reported in 14 patients in the placebo group (two acute myocardial infarctions, one ischemic stroke, one hemorrhagic stroke, one pulmonary embolism, one deep vein thrombosis, one venous thrombosis, and 13 aTTP exacerbations). Two of the placebo‐treated patients died from aTTP during the study.
Conclusion
In total, 11.4% of caplacizumab‐treated patients and 43.2% of placebo‐treated patients experienced one or more major thromboembolic events, experienced an exacerbation, or died. This analysis shows the potential for caplacizumab to reduce the risk of major thromboembolic morbidities and mortality associated with aTTP.
Understanding the temperature dependence of the direct and indirect gaps is indispensable for optimizing the applications of semiconductors. Experimentally, this temperature dependence can be very ...precisely determined by ellipsometry, by absorption or by luminescence spectroscopy. We have re-analyzed the temperature dependence of the direct and indirect gaps of some prominent tetrahedral semiconductors and improved available fits by applying a simple modified approach which uses statistical factors and the knowledge of prominent transverse-acoustic and transverse-optical bands in the measured or calculated phonon density of states of the semiconductors under consideration.
•Re-analysis of the temperature dependence of the gaps of tetrahedral semiconductors•Modeling of the temperature dependence of the gaps of tetrahedral semiconductors•Simplified modeling using statistical factors and prominent phonon bands
We have theoretically investigated, by ab initio techniques, the phonon properties of several semiconductors with chalcopyrite structure. Comparison with experiments has led us to distinguish between ...materials with d electrons in the valence band (e.g., CuGaS sub(2), AgGaS sub(2)) and those without d electrons (e.g., ZnSnAs sub(2)). The former exhibit a rather peculiar nonmonotonic temperature dependence of the energy gap which, so far, has resisted cogent theoretical description. We analyze this nonmonotonic temperature dependence by fitting two Bose-Einstein oscillators with weights of opposite sign leading to an increase at low temperatures and a decrease at higher temperatures and find that the energy of the former correlates well with characteristic peaks in the phonon density of states associated with low-energy vibrations of the d-electron elements. We hope that this work will encourage theoretical investigations of the electronphonon interaction in this direction, especially of the current ab initio type.
Intermolecular hydrogen bonds impede long-range (anti-)ferroelectric order of water. We confine H
O molecules in nanosized cages formed by ions of a dielectric crystal. Arranging them in channels at ...a distance of ~5 Å with an interchannel separation of ~10 Å prevents the formation of hydrogen networks while electric dipole-dipole interactions remain effective. Here, we present measurements of the temperature-dependent dielectric permittivity, pyrocurrent, electric polarization and specific heat that indicate an order-disorder ferroelectric phase transition at T
≈ 3 K in the water dipolar lattice. Ab initio molecular dynamics and classical Monte Carlo simulations reveal that at low temperatures the water molecules form ferroelectric domains in the ab-plane that order antiferroelectrically along the channel direction. This way we achieve the long-standing goal of arranging water molecules in polar order. This is not only of high relevance in various natural systems but might open an avenue towards future applications in biocompatible nanoelectronics.
Water is characterized by large molecular electric dipole moments and strong interactions between molecules; however, hydrogen bonds screen the dipole-dipole coupling and suppress the ferroelectric ...order. The situation changes drastically when water is confined: in this case ordering of the molecular dipoles has been predicted, but never unambiguously detected experimentally. In the present study we place separate H
O molecules in the structural channels of a beryl single crystal so that they are located far enough to prevent hydrogen bonding, but close enough to keep the dipole-dipole interaction, resulting in incipient ferroelectricity in the water molecular subsystem. We observe a ferroelectric soft mode that causes Curie-Weiss behaviour of the static permittivity, which saturates below 10 K due to quantum fluctuations. The ferroelectricity of water molecules may play a key role in the functioning of biological systems and find applications in fuel and memory cells, light emitters and other nanoscale electronic devices.
PbMn3Mn4O12 a quadruple perovskite was prepared by high pressure and high temperature synthesis. Powder X-ray diffraction (PXD) and differential scanning calorimetry reveal a structural phase ...transition at ∼380K. Rietveld refinement of the synchrotron room temperature data indicate rhombohedral symmetry (R-3) with a=6.43675(4)Å and α=109.556(2)°. Similar 423K PXD data refined in a body centered cubic cell (Im-3) with a=7.4283(9)Å. The temperature variation of magnetization, shows a magnetic field dependent antiferromagnetic-like transition at 68K, and dynamic fluctuations indicative of magnetic frustration. The semiconducting electrical behavior indicates a large decrease in the conductivity near 68K. The temperature dependence of the real part of the dielectric constant, εreal increases dramatically at ∼68K, and shows relaxor-type ferroelectric behavior as a function of frequency. The intimate coupling of magnetic, electrical and dielectric properties at 68K in PbMn3Mn4O12 suggests possible multiferroic behavior.
Resistance vs. temperature plot showing drastically increasing resistances at temperatures below 68K (a). Formation of a frequency dependency of the dielectric constant between 68K and ambient temperature (b). Sharp cusp in the magnetic susceptibility observed at 68K which is suppressed with increasing magnetic field (c) indicates coupling of magnetic, electric and dielectric effects. Display omitted
► PbMn3Mn4O12 a quadruple perovskite was prepared at high pressure. ► A structural transition is seen at 380K from space group R-3-to-Im-3. ► An antiferromagnetic transition is observed at 68K. ► It is semiconducting with a large decrease in the conductivity near 68K. ► The temperature dependence of the dielectric constant increases dramatically at 68K. ► Coupling of magnetic, electric and dielectric behavior suggests multiferroicity.
•Dy2AgIn3 is characterized by the antagonism of ferromagnetic -antiferromagnetic interactions.•Geometric frustration and crystal field effects prevent the formation of the magnetic moment on the Dy ...ions.•A cluster glass regime is recognized below 31 K and irreversibility effects are observed below 43 K.•Neutron diffraction shows No magnetic structure.
The crystallographic and magnetic properties of the polycrystalline intermetallic compound Dy2AgIn3 are presented. The compound crystallizes in the hexagonal CaIn2- type structure (space groupP63/mmc). The magnetic susceptibility data reveals a Curie–Weiss (CW) law behavior above120K, with a calculated effective magnetic moment μeff=10.63±0.29μB/Dy3+and a Curie paramagnetic temperatureθp=17.5K±0.5K, demonstrating the dominance of ferromagnetic (FM) couplings in the sample. In the temperature range of 60-120Kit exhibits a Griffith’s phase like behavior. The dc field cooled (FC) and zero field cooled (ZFC) susceptibility, show field dependent irreversible phenomena belowTr~43K, and the ZFC plots present a cusp glass like maxima at31K. The irreversibility temperatureTradopts aH2/3, field dependence of de Almeida–Thouless type line which defines the stability limits in the H-T plane withTr(0)=44.5±0.5K. The ac susceptibility data shows a relative shift in freezing temperature δTf~0.048±0.004, while near the freezing temperature it exhibits a Power- Vogel-Fulcher law dependency characterized by the dynamic exponentszν=7.4, single flip time τ0=10-6sandTg=24.5±0.65K. These values suggest the formation of cluster spin-glass states (CSG). At low angles the neutron diffraction (ND) profiles display diffuse scattering of antiferromagnetic (AFM) origin which is triggered by the ~5nm- magnetic spin clusters.
Spin-orbit coupling of as large as a half eV for electrons in 5d orbitals often gives rise to the formation of spin-orbital entangled objects, with the effective total angular momentum Jeff. Of ...particular interest are the Jeff=3/2 states realized in 5d1 transition metal ions surrounded by an anion octahedron. The pure Jeff=3/2 quartet does not have any magnetic dipolar moment (〈M〉=0) but hosts hidden pseudodipolar moments accompanied by charge quadrupoles and magnetic octupoles. Cs2TaCl6 and Rb2TaCl6 are correlated insulators with 5d1Ta4+ ions in a regular Cl octahedron. Here we demonstrate that these Ta chlorides indeed have a substantially suppressed effective magnetic dipolar moment of ∼0.2μB. Two phase transitions are observed at low temperatures that are not pronounced in the magnetization but accompanied with large electronic entropy of ∼R ln4. We ascribe the two transitions to the ordering of hidden multipoles.
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