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Objectives Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC. Patients and Methods This was a multicenter, single-arm, open-label, phase II trial involving treatment-naive patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan. Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated. Results The median age of patients was 70 years (range: 37–85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7–14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7–78.5) and 92.5% (95% CI: 81.8–97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib. Conclusion Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC.

Objectives The aim of this AFIRE (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease) trial subgroup analysis was to examine rivaroxaban monotherapy benefits and their relation to the time between stenting and enrollment among patients after coronary stenting. Background Of 2,215 patients with atrial fibrillation and stable coronary artery disease in the AFIRE trial, rivaroxaban monotherapy was noninferior to rivaroxaban plus antiplatelet therapy (combination therapy) in terms of efficacy and superior for safety endpoints. However, thrombotic risk after antiplatelet therapy cessation remained a concern among 1,444 patients who had undergone coronary stenting >1 year before enrollment. Methods The benefits of rivaroxaban monotherapy in coronary stenting subgroups were assessed for efficacy (a composite of stroke, systemic embolism, myocardial infarction, unstable angina requiring revascularization, or death of any cause), safety (major bleeding defined according to International Society on Thrombosis and Haemostasis criteria), ischemic endpoints, net adverse clinical event, and time between stenting and enrollment. Results Efficacy and safety endpoints for monotherapy were superior to combination therapy, with HRs of 0.70 for efficacy (95% CI: 0.50-0.98; P = 0.036) and 0.55 for safety (95% CI: 0.33-0.92; P = 0.019). For ischemic endpoints, the HR was 0.82 (95% CI: 0.58-1.15; P = 0.240). The HR became smaller with longer time between stenting and enrollment (efficacy, P for interaction = 0.158; safety, P = 0.097). Conclusions In patients with atrial fibrillation after coronary stenting, the benefits of rivaroxaban monotherapy for efficacy and safety endpoints were consistent with those in the whole AFIRE trial population. The benefits became apparent with longer time between stenting and enrollment. (Atrial Fibrillation and Ischemic Events With Rivaroxaban in Patients With Stable Coronary Artery Disease Study [AFIRE]; UMIN000016612 , NCT02642419 )

Both cuprates and iron-based superconductors demonstrate nematicity, defined as the spontaneous breaking of rotational symmetry in electron systems. The nematic state can play a role in the high-transition-temperature superconductivity of these compounds. However, the microscopic mechanism responsible for the transport anisotropy in iron-based compounds remains debatable. Here, we investigate the electronic anisotropy of CaFeAsF by measuring its interlayer resistivity under magnetic fields with varying field directions. Counterintuitively, the interlayer resistivity was larger in the longitudinal configuration ($B \parallel I \parallel c$) than in the transverse one ($B \perp I \parallel c$). The interlayer resistivity exhibited a so-called coherence peak under in-plane fields and was highly anisotropic with respect to the in-plane field direction. At $T$ = 4 K and $B$ = 14 T, the magnetoresistance $\Delta\rho/\rho_0$ was seven times larger in the $B \parallel b_o$ than in the $B \parallel a_o$ configuration. Our theoretical calculations of the conductivity based on the first-principles electronic band structure qualitatively reproduced the above observations but underestimated the magnitudes of the observed features. The proposed methodology can be a powerful tool for probing the nematic electronic state in various materials., Comment: 25 pages, 5 figures

In this study, we succeeded in synthesizing new antiperovskite phosphides MPd3P (M = Ca, Sr, Ba) and discovered the appearance of a superconducting phase (0.17 ≤ x ≤ 0.55) in a solid solution (Ca1-xSrx)Pd3P. Three perovskite-related crystal structures were identified in (Ca1-xSrx)Pd3P, and a phase diagram was built on the basis of experimental results. The first phase transition from centrosymmetric (Pnma) to noncentrosymmetric orthorhombic (Aba2) occurred in CaPd3P near room temperature. The phase transition temperature decreased as Ca2+ was replaced with a larger-sized isovalent Sr2+. Bulk superconductivity at a critical temperature (Tc) of approximately 3.5 K was observed in a range of x = 0.17-0.55; this was associated with the centrosymmetric orthorhombic phase. Thereafter, a noncentrosymmetric tetragonal phase (I41md) remained stable for 0.6 ≤ x ≤ 1.0, and superconductivity was significantly suppressed as samples with x = 0.75 and 1.0 showed Tc values as low as 0.32 K and 57 mK, respectively. For further substitution with a larger-sized isovalent Ba2+, namely, (Sr1-yBay)Pd3P, the tetragonal phase continued throughout the composition range. BaPd3P no longer showed superconductivity down to 20 mK. Since the inversion symmetry of structure and superconductivity can be precisely controlled in (Ca1-xSrx)Pd3P, this material may offer a unique opportunity to study the relationship between inversion symmetry and superconductivity.

Antiperovskites are a promising candidate structure for the exploration of new materials. We discovered an antiperovskite phosphide, LaPd

Topological insulators with broken time-reversal symmetry and the Fermi level within the magnetic gap at the Dirac cone provides exotic topological magneto-electronic phenomena. Here, we introduce an improved magnetically doped topological insulator, Fe-doped BiSbTe2Se (Fe-BSTS) bulk single crystal, with an ideal Fermi level. Scanning tunneling microscopy and spectroscopy (STM/STS) measurements revealed that the surface state possesses a Dirac cone with the Dirac point just below the Fermi level by 12 meV. The normalized dI/dV spectra suggest a gap opening with Δmag ∼55 meV, resulting in the Fermi level within the opened gap. Ionic-liquid gated-transport measurements also support the Dirac point just below the Fermi level and the presence of the magnetic gap. The chemical potential of the surface state can be fully tuned by ionic-liquid gating, and thus the Fe-doped BSTS provides an ideal platform to investigate exotic quantum topological phenomena.

Topological insulators with broken time-reversal symmetry and the Fermi level within the magnetic gap at the Dirac cone provides exotic topological magneto-electronic phenomena. Here, we introduce an improved magnetically doped topological insulator, Fe-doped BiSbTe

• Here we analysed the effects of CO

Background Blood pressure (BP) variability has reportedly been a risk factor for various clinical events. To clarify the influence of BP visit‐to‐visit variability on adverse events in patients with nonvalvular atrial fibrillation, a post hoc analysis of the J‐RHYTHM Registry was performed. Methods and Results Of 7406 outpatients with nonvalvular atrial fibrillation from 158 institutions, 7226 (age, 69.7±9.9 years; men, 70.7%), in whom BP was measured 4 times or more (14.6±5.0 times) during the 2‐year follow‐up period or until occurrence of an event, constituted the study group. SD and coefficient of variation of BP values were calculated as BP variability. Thromboembolism, major hemorrhage, and all‐cause death occurred in 110 (1.5%), 121 (1.7%), and 168 (2.3%) patients, respectively. When patients were divided into quartiles of systolic BP‐SD (P =0.015 for thromboembolism; HR, 2.60, 95% CI, 1.36–4.97, P =0.004 for major hemorrhage; and HR, 1.85, 95% CI, 1.11–3.07, P =0.018 for all‐cause death) after adjusting for components of the CHA 2 DS 2 ‐VASc score, warfarin and antiplatelet use, atrial fibrillation type, BP measurement times, and others. These findings were consistent when BP‐coefficient of variation was used instead of BP‐SD. Conclusions Systolic BP visit‐to‐visit variability was significantly associated with all adverse events in patients with nonvalvular atrial fibrillation. Further studies are needed to clarify the causality between BP variability and adverse outcomes in patients with nonvalvular atrial fibrillation. Registration URL: https://www.umin.ac.jp/ctr/ ; Unique Identifier: UMIN000001569.

Antiperovskites are a promising candidate structure for the exploration of new materials. We discovered an antiperovskite phosphide, LaPd$_{3}$P, following our recent synthesis of $A$Pd$_{3}$P ($A$ = Ca, Sr, Ba). While $A$Pd$_{3}$P and (Ca,Sr)Pd$_{3}$P were found to be tetragonal or orthorhombic systems, LaPd$_{3}$P is a new prototype cubic system ($a$ = 9.0317(1) A) with a noncentrosymmetric space group ($I-43m$). LaPd$_{3}$P exhibited superconductivity with a transition temperature ($T_\mathrm{c}$) of 0.28 K. The upper critical field, Debye temperature, and Sommerfeld constant ($\gamma$) were determined as 0.305(8) kOe, 267(1) K, 6.06(4) mJ mol-1 K-2 f.u.-1, respectively. We performed first-principles electronic band structure calculations for LaPd$_{3}$P and compared the theoretical and experimental results. The calculated Sommerfeld constant (2.24 mJ mol-1 K-2 f.u.-1) was much smaller than the experimental value of $\gamma$ because the Fermi energy ($E_\mathrm{F}$) was located slightly below the density of states (DOS) pseudogap. This difference was explained by the increase in the DOS at $E_\mathrm{F}$ due to the approximately 5 at.% La deficiency (hole doping) in the sample. The observed Tc value was much lower than that estimated using the Bardeen-Cooper-Schrieffer equation. To explain the discrepancy, we examined the possibility of an unconventional superconductivity in LaPd$_{3}$P arising from the lack of space inversion symmetry., Comment: 13 pages, 5 figures, 4 tables

In the recently discovered antiperovskite phosphide (Ca,Sr)Pd$_3$P, centrosymmetric (CS) and non-centrosymmetric (NCS) superconducting phases appear depending on the Sr concentration, and their transition temperatures ($T_\mathrm{c}$) differ by as much as one order of magnitude. In this study, we investigated the superconducting properties and electronic band structures of CS orthorhombic (CSo) (Ca$_{0.6}$Sr$_{0.4}$)Pd$_3$P ($T_\mathrm{c}$ = 3.5 K) and NCS tetragonal (NCSt) (Ca$_{0.25}$Sr$_{0.75}$)Pd$_3$P ($T_\mathrm{c}$ = 0.32 K) samples with a focus on explaining their large $T_\mathrm{c}$ difference. Specific heat measurements indicated that CSo (Ca$_{0.6}$Sr$_{0.4}$)Pd$_3$P was an s-wave superconductor in a moderate-coupling regime with a 2$\Delta$$_0$/k$_B$$T_\mathrm{c}$ value of 4.0. Low-lying phonons leading to the strong coupling in the structurally analogous SrPt$_3$P were unlikely to be present in CSo (Ca$_{0.6}$Sr$_{0.4}$)Pd$_3$P. Given that CSo (Ca$_{0.6}$Sr$_{0.4}$)Pd$_3$P and NCSt (Ca$_{0.25}$Sr$_{0.75}$)Pd$_3$P exhibited similar Debye temperatures ($\Theta$$_D$) of approximately 200 K, the large $T_\mathrm{c}$ difference could not be attributed to $\Theta$$_D$.$T_\mathrm{c}$ of each phase was accurately reproduced based on the Bardeen-Cooper-Schrieffer (BCS) theory using experimental data and the density of states of the Fermi level $N$(0) calculated from their band structures. We concluded that the considerable suppression of $T_\mathrm{c}$ in NCSt (Ca$_{0.25}$Sr$_{0.75}$)Pd$_3$P can be primarily attributed to the decrease in $N$(0) associated with the structural phase transition without considering the lack of inversion symmetry., Comment: 14 pages, 8 figures

The osmate pyrochlore Cd2Os2O7 supports an antiferromagnet insulator ground state with an all-in/all-out (AIAO) spin ordering at low temperature. Above 225 K, Cd2Os2O7 becomes a paramagnetic metal whereas the mechanism of this metal-to-insulator transition (MIT) remains elusive. In this letter, we use cryogenic near-field technique operating at terahertz frequencies to study the evolution of low-energy response across the MIT. We observed a systematic variation of the magnitude of nano-THz signal across the transition, consistent with the trend in the direct-current conductivity. Conducting domain walls that dominate the nano-scale landscape of the conductivity of a closely related AIAO system Nd2Ir2O7 are not apparent in Cd2Os2O7.

Magnetic torque measurements in the spin-orbit coupled metal ${\mathrm{Cd}}_{2}{\mathrm{Re}}_{2}{\mathrm{O}}_{7}$ have been performed to investigate unique multipole orders associated with inversion symmetry breaking. The torque curves as a function of field angle are decomposed into two terms, a fourfold symmetry term (${\ensuremath{\tau}}_{4}\ensuremath{\propto}{H}^{4}$), corresponding to an electric quadrupole order, and a twofold symmetry term (${\ensuremath{\tau}}_{2}\ensuremath{\propto}{H}^{2}$), likely corresponding to an electric toroidal quadrupole order at low temperatures. Below 20 K, a strong enhancement of the fourfold symmetry term following a large phase change is observed toward the superconducting transition whereas no such behavior is evident in the twofold symmetry term. The results show anomalous changes of the electric quadrupole order at the low temperatures.

The cubic Kondo lattice ${\mathrm{YbCo}}_{2}{\mathrm{Zn}}_{20}$ is one of the heaviest known Fermi liquids. We have measured the low-temperature electrical resistivity $\ensuremath{\rho}(T)$, magnetic susceptibility $\ensuremath{\chi}(T)$, and heat capacity $C(T)$ in single crystals of $\mathrm{Yb}{({\mathrm{Co}}_{1\ensuremath{-}x}{\mathrm{Ni}}_{x})}_{2}{\mathrm{Zn}}_{20}$ ($x\ensuremath{\le}0.126$) and $\mathrm{Yb}{({\mathrm{Co}}_{1\ensuremath{-}x}{\mathrm{Fe}}_{y})}_{2}{\mathrm{Zn}}_{20}$ ($y\ensuremath{\le}0.07$). While pure ${\mathrm{YbCo}}_{2}{\mathrm{Zn}}_{20}$ displays maxima in $\ensuremath{\rho}(T)$ and $\ensuremath{\chi}(T)$, ascribed to an enhanced crystal electric field (CEF) degeneracy, the maxima are suppressed by small amounts ($\ensuremath{\approx}6$ at.%) of substitutions of the Co atoms. This goes along with a suppression of superheavy Fermi liquid behavior as manifested in the divergence of $C/T$. We ascribe the observations to local distortions at the Yb site due to the chemical disorder in the environment, rather than to a chemical pressure effect. This fragileness to the local distortion indicates that superheavy Fermion behavior in ${\mathrm{YbCo}}_{2}{\mathrm{Zn}}_{20}$ is closely linked to an enhanced CEF degeneracy.

Magnetic torque measurements have been performed to investigate the phase transitions of the metallic pyrochlore compound $\mathrm{C}{\mathrm{d}}_{2}\mathrm{R}{\mathrm{e}}_{2}{\mathrm{O}}_{7}$, in which a spin-orbit (SO) interaction leads to unique multipole orders associated with an inversion symmetry breaking. We find that the magnetic torque signals with a fourfold symmetry (${\ensuremath{\tau}}_{4}\ensuremath{\propto}{H}^{4}$) as well as a twofold symmetry (${\ensuremath{\tau}}_{2}\ensuremath{\propto}{H}^{2}$) are significantly enhanced at low temperatures below a structural phase transition temperature (\ensuremath{\sim}200 K). The analyses of the torque curve symmetries show that the ${\ensuremath{\tau}}_{4}$ term arises from an even-parity order parameter (OP) with the irreducible representation ${E}_{\mathrm{g}}$, whereas the ${\ensuremath{\tau}}_{2}$ term from an odd-parity OP with ${E}_{\mathrm{u}}$, ${T}_{1\mathrm{u}}$ or ${T}_{2\mathrm{u}}$. The parity mixing of the primary OPs shows a peculiar phase transition in the SO coupled $\mathrm{C}{\mathrm{d}}_{2}\mathrm{R}{\mathrm{e}}_{2}{\mathrm{O}}_{7}$. The coexistence of the two OPs provides important insights into the origin of the multipole orders induced by the SO interaction.

We present the topology of spin-split Fermi surface of CaAgAs as determined by de Haas-van Alphen (dHvA) effect measurements combined with ab initio calculations. We have determined the torus-shaped nodal-line Fermi surface from the dHvA oscillations of $\beta$ and $\gamma$ orbits. The former orbit encircles the nodal-line, while the latter does not. Nevertheless, a nontrivial Berry phase is found for both orbits. The nontrivial phase of $\beta$ arises from the orbital characters, which can be expressed as a pseudospin rotating around the nodal-line. On the other hand, the phase of $\gamma$ is attributed to the vortex of real spin texture induced by an antisymmetric spin-orbit interaction. Our result demonstrates that both the real- and pseudo-spin textures are indispensable in interpreting the electronic topology in noncentrosymmetric nodal-line semimetals., Comment: 11 pages, 7 figures

Purpose Cardiac allograft tolerance in non-human primates (NHPs) has been achieved by our group using a mixed chimerism model with allogeneic bone marrow transplant after non-myeloablative conditioning but not without kidney co-transplantation. B cell lymphoma 2 (Bcl2) inhibition has allowed for durable mixed chimerism with reduced conditioning in the murine skin transplant model. We investigated whether the Bcl2 inhibitor ABT199 could enhance mixed chimerism and induce cardiac allograft tolerance in the absence of kidney cotransplantation. Methods Fifteen cynomolgus recipients underwent mixed chimerism conditioning (ATGAM, total body and thymic irradiation) then organ and bone marrow transplantation. Group 1 recipients received heart alone (n=5), Group 2 recipients received heart and kidney cotransplants (n=7), and in Group 3, heart recipients received ABT199 in lieu of kidney cotransplants (n=3).Group 1 and 2 received 3Gy total body irradiation (TBI) while Group 3 received 1.5Gy TBI. All recipients underwent a 28-day course of immunosuppression with a calcineurin inhibitor and anti-CD154 mAb after which all immunosuppression was stopped. Results All five Group 1 recipients demonstrated cellular rejection (ISHLT 3R) by 96 days post bone marrow transplant (pBMTx). In contrast, no Group 2 recipients showed early rejection and 6/7 survived >400 days pBMTx. The first two Group 3 recipients developed GvHD and succumbed by days 59 and 68 pBMTx without evidence of rejection. However, after reducing the size of the donor BMT, the third recipient is now 76 days pBMTx with excellent allograft contractility and no evidence of GVHD. Mean peak lymphoid chimerism was 10% on day 26 pBMTx for Group 1, 26% on day 33 pBMTx for Group 2, and 57% on day 54 pBMTx for Group 3. (Figure 1) Conclusion After further refinement of the conditioning regimen, ABT199 may allow for the induction of heart allograft tolerance without the need for kidney co-transplantation and with a reduction in TBI thereby improving safety.

A spin–orbit coupled metal Cd2Re2O7 is known to show two structural phase transitions at Ts1 ≈ 200 K and Ts2 ≈ 115 K, which are likely of an electronic origin. The magnetic torque curves have been ...

Objective:To report the clinical features of myasthenia gravis (MG) induced by treatment with immune checkpoint inhibitors using 2-year safety databases based on postmarketing surveys in Japan.Methods:We studied 10,277 patients with cancer who had received monotherapy with either nivolumab or ipilimumab between September 2014 and August 2016. As the control group, 105 patients with idiopathic MG were used.Results:There were 12 MG cases (0.12%) among 9,869 patients with cancer who had been treated with nivolumab, but none among 408 patients treated with ipilimumab. These 12 patients included 6 men and 6 women with a mean age of 73.5 ± 6.3 years. MG onset occurred in the early phase after nivolumab treatment and rapidly deteriorated. Nivolumab-related MG (nivoMG) included 4 patients with mild involvement and 8 patients with severe involvement. Bulbar symptoms and myasthenic crisis were observed more frequently in nivoMG than idiopathic MG. Ten patients were positive for anti–acetylcholine receptor antibodies. Serum creatine kinase levels were markedly elevated to an average level of 4,799 IU/L. Among the 12 patients with nivoMG, 4 had myositis and 3 had myocarditis, with 1 of these patients having both. Immunosuppressive therapy was effective. Postintervention status showed that pharmacologic remission or minimal manifestations were obtained in 4 patients; however, 2 patients died. Immune-related adverse events triggered by nivolumab impaired the patients' daily living activity.Conclusions:The prompt and correct recognition of MG following treatment with immune checkpoint inhibitors in patients with cancer is important.