The cornerstone of life-saving therapy in immune mediated thrombotic thrombocytopenic purpura (iTTP) has been plasma exchange (PEX) combined with immunomodulatory strategies. Caplacizumab, a novel anti-von Willebrand factor nanobody, trialled in two multicentre, randomised-placebo-controlled trials leading to EU and FDA approval, has been available in the UK through a patient-access scheme. Data was collected retrospectively from 2018-2020 for 85 patients receiving caplacizumab, including 4 children, from 22 UK hospitals. Patient characteristics and outcomes in the real-world clinical setting were compared with caplacizumab trial endpoints and historical outcomes in the pre-caplacizumab era. 84/85 patients received steroid and rituximab alongside PEX; 26% required intubation. Median time to platelet count normalisation (3 days), duration of PEX (7 days) and hospital stay (12 days) was comparable with RCT data. Median duration of PEX and time from PEX initiation to platelet count normalisation was favourable compared with historical outcomes (p<0.05). TTP recurrence occurred in 5/85 patients; all with persistent ADAMTS13 activity <5iu/dL. Of 31 adverse events in 26 patients, 17/31 (55%) were bleeding episodes and 5/31 (16%) were thrombotic events (two unrelated to caplacizumab); mortality was 6% (5/85), with no deaths attributed to caplacizumab. In 4/5 deaths caplacizumab was introduced >48 hours after PEX initiation (3-21 days). This real-world evidence represents the first and largest series of TTP patients receiving caplacizumab outside clinical trials, including paediatric patients. Representative of true clinical practice, the findings provide valuable information for clinicians treating TTP globally.
The low energy spin excitation spectrum of the breathing pyrochlore Ba 3 Yb 2 Zn 5 O 11 has been investigated with inelastic neutron scattering. Several nearly resolution limited modes with no observable dispersion are observed at 250 mK while, at elevated temperatures, transitions between excited levels become visible. To gain deeper insight, a theoretical model of isolated Yb 3+ tetrahedra parametrized by four anisotropic exchange constants is constructed. The model reproduces the inelastic neutron scattering data, specific heat, and magnetic susceptibility with high fidelity. The fitted exchange parameters reveal a Heisenberg antiferromagnet with a very large Dzyaloshinskii-Moriya interaction. Using this model, we predict the appearance of an unusual octupolar paramagnet at low temperatures and speculate on the development of inter-tetrahedron correlations.Frustrated or competing interactions have been repeatedly found to be at the root of many unusual phenomena in condensed matter physics [1][2][3][4][5]. By destabilizing conventional long-range order down to low temperature, frustration in magnetic systems can lead to many exotic phases; from unconventional multipolar [6,7] and valence bond solid orders [1,4] to disordered phases such as classical and quantum spin liquids [1,4]. Significant attention has been devoted to understanding geometric frustration where it is the connectivity of the lattice that hinders the formation of order. Recently, however, magnets frustrated not by geometry but by competing interactions have become prominent for the novel behaviors that they host. Such competing interactions might be additional isotropic exchange acting beyond nearest neighbors [8-10], biquadratic or other multipolar interactions [11]. One possibility attracting ever increasing interest is that competing strongly anisotropic interactions may stabilize a wide range of unusual phenomena.An exciting research direction in the latter context concerns itself with so-called "quantum spin ice" [12]. This quantum spin liquid can be stabilized by perturbing classical spin ice with additional anisotropic transverse exchange interactions that induce quantum fluctuations. Particularly interesting is the potential realization of such physics in the rare-earth pyrochlores R 2 M 2 O 7 [13][14][15], where R is a trivalent 4 f rare-earth ion, and M is a non-magnetic tetravalent transition metal ion, such as M=Ti, Sn or Zr. These materials can be described in terms of pseudo spin-1/2 degrees of freedom interacting via anisotropic exchanges [12,15], where the effective spin-1/2 maps the states of the crystal-electric field ground doublet of the rare-earth ion. These materials display a wealth of interesting phenomena, from the possibility of quantum [16][17][18] ion is part of a large and small tetrahedron in the breathing pyrochlore lattice.liquids [22,23]. In many of these compounds, the physics is very delicate, showing strong sample to sample variations [24] or sensitivity to very small amounts of disorder [25,26]. Consequen...
Entanglement of spin and orbital degrees of freedom drives the formation of novel quantum and topological physical states. Discovering new spinorbit entangled ground states and emergent phases of matter requires both experimentally probing the relevant energy scales and applying suitable theoretical models. Here we report resonant inelastic x-ray scattering measurements of the transition metal oxides Ca 3 LiOsO 6 and Ba 2 YOsO 6 . We invoke an intermediate coupling approach that incorporates both spin-orbit coupling and electron-electron interactions on an even footing and reveal the ground state of 5d 3 based compounds, which has remained elusive in previously applied models, is a novel spin-orbit entangled J=3/2 electronic ground state. This work reveals the hidden diversity of spin-orbit controlled ground states in 5d systems and introduces a new arena in the search for spin-orbit controlled phases of matter. Main Text:The electronic ground state adopted by an ion is a fundamental determinant of manifested physical properties. Recently, the importance of spin-orbit coupling (SOC) in creating the electronic ground state in 5d-based compounds has come to the fore and arXiv:1610.02375v1 [cond-mat.str-el] systems, and the influence of SOC has now been observed in the macroscopic properties of numerous systems. However, beyond the J eff = 1/2 case such as that found in Sr 2 IrO 4 (3)-which is a single-hole state that applies only to idealised 5d 5 ions in cubic materialsquestions abound concerning the electronic ground states which govern 5d ion interactions.In this context 5d 3 materials present a particularly intriguing puzzle, because octahedral d 3 configurations are expected to be orbitally-quenched S = 3/2 states -in which case SOC enters only as a 3rd order perturbation (4) -yet there is clear experimental evidence that SOC influences the magnetic properties in 5d 3 transition metal oxides (TMOs). This includes the observations of large, SOC-induced spin-gaps in their magnetic excitation spectra (5-7) and x-ray absorption branching ratios which deviate from BR = I L3 /I L2 = 2 (8, 9).Despite this, no description beyond the S = 3/2 state had been established. synchrotron x-ray and neutron diffraction. Figure 1 presents the x-ray energy loss, E, versus incident energy, E i , RIXS spectra of Ca 3 LiOsO 6 at 300 K. Four lines are present at E < 2 eV, which are enhanced at E i = 10.874 keV, whereas the feature at E ≈ 4.5 eV is enhanced at E i = 10.878 keV. This indicates that the E < 2 eV features are intra-t 2g excitations, whereas the higher energy feature is from t 2g to e g excited states, as has been observed in many 5d oxides (7,(18)(19)(20). Subsequent measurements were optimised to probe the t 2g excitations by fixing E i = 10.874 keV.Figure 2 presents the detailed RIXS spectra of Ca 3 LiOsO 6 and Ba 2 YOsO 6 at temperatures of 300 K and 6 K. In each spectrum there are 5 peaks in addition to the elastic line:four peaks with E < 2 eV, labeled a, b, c and d ( Fig. 2c and d) which we associa...
The breathing pyrochlore lattice material Ba 3 Yb 2 Zn 5 O 11 exists in the nearly decoupled limit, in contrast to most other well-studied breathing pyrochlore compounds. As a result, it constitutes a useful platform to benchmark theoretical calculations of exchange interactions in insulating Yb 3+ magnets. Here we study Ba 3 Yb 2 Zn 5 O 11 at low temperatures in applied magnetic fields as a further probe of the physics of this model system. Experimentally, we consider the behavior of polycrystalline samples of Ba 3 Yb 2 Zn 5 O 11 with a combination of inelastic neutron scattering and heat capacity measurements down to 75 mK and up to fields of 10 T. Consistent with previous work, inelastic neutron scattering finds a level crossing near 3 T, but no significant dispersion of the spin excitations is detected up to the highest applied fields. Refinement of the theoretical model previously determined at zero field can reproduce much of the inelastic neutron scattering spectra and specific heat data. A notable exception is a low temperature peak in the specific heat at ∼ 0.1 K. This may indicate the scale of interactions between tetrahedra or may reflect undetected disorder in Ba 3 Yb 2 Zn 5 O 11 . a
The perovskite (Pv) SrIrO 3 is an exotic narrow-band metal owing to a confluence of the strengths of the spin-orbit coupling (SOC) and the electron-electron correlations. It has been proposed that topological and magnetic insulating phases can be achieved by tuning the SOC, Hubbard interactions, and/or lattice symmetry. Here, we report that the substitution of nonmagnetic, isovalent Sn 4+ for Ir 4+ in the SrIr 1-x Sn x O 3 perovskites synthesized under high pressure leads to a metal-insulator transition to an antiferromagnetic phase at T N ≥ 225 K. The continuous change of the cell volume as detected by X-ray diffraction and the λ-shape transition of the specific heat oncooling through T N demonstrate that the metal-insulator transition is of second-order. Neutron powder diffraction results indicate that the Sn substitution enlarges an octahedral-site distortion that reduces the SOC relative to the spin-spin exchange interaction and results in the type-G AF spin ordering below T N . Measurement of high-temperature magnetic susceptibility shows the evolution of magnetic coupling in the paramagnetic phase typical of weak itinerant-electron magnetism in the Sn-substituted samples. A reduced structural symmetry in the magnetically ordered phase leads to an electron gap opening at the Brillouin zone boundary below T N in the same way as proposed by Slater. 17, 18However, the temperature dependence of thermoelectric power does not follow the Mott diffusive formula for a metal. An enhancement of |S| that peaks at ~175 K cannot be rationalized by the phonon-drag effect, which should occur at a small fraction of the Debye temperature. 33The resistivity shows an anomaly at approximately the same temperature. In metallic PV SrRhO 3where the SOC effect is relatively weak, an enhancement near 180 K can still be discerned in S(T), but the enhancement is much smaller than that found in SrIrO 3 . This comparison highlights the possible SOC effect on the thermoelectric power, which deserves a further study. Introducing Back to the case of SrIr 1-x Sn x O 3 , the origin of the magnetism in the Sn-substituted samples is rooted in the parent oxide SrIrO 3 although it is a paramagnetic metal. The EEC effect can be probed through the ratio of γ/γ 0 , where γ is the Sommerfeld coefficient of the specific heat (see Fig. S3 and Table S1 for details) and γ 0 is the calculated electronic contribution from the band structure. 21 For SrIrO 3 , a ratio γ/γ 0 ≈ 1.1 indicates a modest correlation enhancement. However, the ratio of the temperature-independent term χ 0 obtained from the magnetic susceptibility of Determining how the Sn 4+ substitution in SrIr 1-x Sn x O 3 further enhances the interatomic magnetic coupling so as to eventually trigger the magnetic transition relies on our understanding of (1) the substitution effect on the crystal structure and (2) the explicit role of SOC on the spin-spin exchange interaction. Depending on the strength of SOC, the electronic state can be governed by either the crystal field splitting o...
*We regret to note that Dr Roberto Stasi, one of our co-authors, has very sadly passed away since the time of original data collection. We would like to acknowledge his valuable contribution to this work SummarySevere immune thrombocytopenia purpura (ITP) presents a clinical challenge. Second-line treatment options are variable without a precise protocol. We present 46 severe ITP patients treated with mycophenolate mofetil (MMF), retrospectively identified from three London teaching hospitals. Data was collected on patient demographics, co-morbidities and previous treatment strategies. Our key interest was whether there was a sustained response in platelet count to MMF. Patients included 27 males and 19 females whose ages ranged from 19 to 93 years old (median 52Á5 years). Twenty-nine had primary ITP and 17 had secondary ITP, a third of whom had viral-associated disease. The standard dose of MMF was 1 g/day. Twenty-four patients (52%) responded with 15 (33%) achieving a complete response. No active viral-associated ITP patients demonstrated a response to MMF, although numbers were small (n = 4). We were not able to demonstrate a difference between responders and non-responders based on gender, age, previous therapies or time since diagnosis of ITP. Three of four previously splenectomized patients responded, two achieving complete response. We conclude that MMF is a useful steroid-sparing immunosuppressant to be considered in the second-line or later treatment of ITP.
The influence of spin-orbit coupling (SOC) on the physical properties of the 5d2 system Sr2MgOsO6 is probed via a combination of magnetometry, specific heat measurements, elastic and inelastic neutron scattering, and density functional theory calculations. Although a significant degree of frustration is expected, we find that Sr2MgOsO6 orders in a type I antiferromagnetic structure at the remarkably high temperature of 108 K. The measurements presented allow for the first accurate quantification of the size of the magnetic moment in a 5d2 system of 0.60(2) μB –a significantly reduced moment from the expected value for such a system. Furthermore, significant anisotropy is identified via a spin excitation gap, and we confirm by first principles calculations that SOC not only provides the magnetocrystalline anisotropy, but also plays a crucial role in determining both the ground state magnetic order and the size of the local moment in this compound. Through comparison to Sr2ScOsO6, it is demonstrated that SOC-induced anisotropy has the ability to relieve frustration in 5d2 systems relative to their 5d3 counterparts, providing an explanation of the high TN found in Sr2MgOsO6.
Acute ischemic stroke (IS) and transient ischemic attack (TIA) are associated with raised von Willebrand factor (VWF) and decreased ADAMTS13 activity (ADAMTS13Ac). Their impact on mortality and morbidity is unclear. We conducted a prospective investigation of the VWF-ADAMTS13 axis in 292 adults (acute IS, n = 103; TIA, n = 80; controls, n = 109) serially from presentation until >6 weeks. The National Institutes of Health Stroke Score (NIHSS) and modified Rankin scale (mRS) were used to assess stroke severity. Presenting median VWF antigen (VWF:Ag)/ADAMTS13Ac ratios were: IS, 2.42 (range, 0.78-9.53); TIA, 1.89 (range, 0.41-8.14); and controls, 1.69 (range, 0.25-15.63). Longitudinally, the median VWF:Ag/ADAMTS13Ac ratio decreased (IS, 2.42 to 1.66; P = .0008; TIA, 1.89 to 0.65; P < .0001). The VWF:Ag/ADAMTS13Ac ratio was higher at presentation in IS patients who died (3.683 vs 2.014; P < .0001). A presenting VWF:Ag/ADAMTS13Ac ratio >2.6 predicted mortality (odds ratio, 6.33; range, 2.22-18.1). Those with a VWF:Ag/ADAMTS13Ac ratio in the highest quartile (>3.091) had 31% increased risk mortality. VWF:Ag/ADAMTS13Ac ratio at presentation of ischemic brain injury was associated with higher mRS (P = .021) and NIHSS scores (P = .029) at follow-up. Thrombolysis resulted in prompt reduction of the VWF:Ag/ADAMTS13Ac ratio and significant improvement in mRS on follow-up. A raised VWF:Ag/ADAMTS13Ac ratio at presentation of acute IS or TIA is associated with increased mortality and poorer functional outcome. A ratio of 2.6 seems to differentiate outcome. Prompt reduction in the ratio in thrombolysed patients was associated with decreased mortality and morbidity. The VWF:Ag/ADAMTS13Ac ratio is a biomarker for the acute impact of an ischemic event and longer-term outcome.
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