Using strain to uncover the interplay between two- and three-dimensional charge density waves in high-temperature superconducting YBa2Cu3Oy.

Uniaxial pressure provides an efficient approach to control charge density waves in YBa2Cu3Oy. It can enhance the correlation volume of ubiquitous short-range two-dimensional charge-density-wave correlations, and induces a long-range three-dimensional charge density wave, otherwise only accessible at large magnetic fields. Here, we use x-ray diffraction to study the strain dependence of these charge density waves and uncover direct evidence for a form of competition between them. We show that this interplay is qualitatively described by including strain effects in a nonlinear sigma model of competing superconducting and charge-density-wave orders. Our analysis suggests that strain stabilizes the 3D charge density wave in the regions between disorder-pinned domains of 2D charge density waves, and that the two orders compete at the boundaries of these domains. No signatures of discommensurations nor of pair density waves are observed. From a broader perspective, our results underscore the potential of strain tuning as a powerful tool for probing competing orders in quantum materials.

Real-world analysis of teclistamab in 123 RRMM patients from Germany.

Teclistamab, a B-cell maturation antigen (BCMA) × CD3 directed bispecific antibody, has shown high response rates and durable remissions in the MAJESTEC-1 trial in patients with relapsed and refractory multiple myeloma (RRMM). We retrospectively assessed efficacy and tolerability in 123 patients treated at 18 different German centers to determine whether outcome is comparable in the real-world setting. Most patients had triple-class (93%) or penta-drug (60%) refractory disease, 37% of patients had received BCMA-directed pretreatment including idecabtagene vicleucel (ide-cel) CAR-T cell therapy (21/123, 17.1%). With a follow-up of 5.5 months, we observed an overall response rate (ORR) of 59.3% and a median progression-free survival (PFS) of 8.7 months. In subgroup analyses, we found significantly lower ORR and median PFS in patients with extramedullary disease (37%/2.1 months), and/or an ISS of 3 (37%/1.3 months), and ide-cel pretreated patients (33%/1.8 months). Nonetheless, the duration of response in ide-cel pretreated patients was comparable to that of anti-BCMA naive patients. Infections and grade ≥3 cytopenias were the most frequent adverse events. In summary, we found that teclistamab exhibited a comparable efficacy and safety profile in the real-world setting as in the pivotal trial.

Soft-Phonon and Charge-Density-Wave Formation in Nematic BaNi_{2}As_{2}.

We use diffuse and inelastic x-ray scattering to study the formation of an incommensurate charge-density-wave (I-CDW) in BaNi_{2}As_{2}, a candidate system for charge-driven electronic nematicity. Intense diffuse scattering is observed around the modulation vector of the I-CDW, Q_{I-CDW}. It is already visible at room temperature and collapses into superstructure reflections in the long-range ordered state where a small orthorhombic distortion occurs. A clear dip in the dispersion of a low-energy transverse optical phonon mode is observed around Q_{I-CDW}. The phonon continuously softens upon cooling, ultimately driving the transition to the I-CDW state. The transverse character of the soft-phonon branch elucidates the complex pattern of the I-CDW satellites observed in the current and earlier studies and settles the debated unidirectional nature of the I-CDW. The phonon instability and its reciprocal space position are well captured by our ab initio calculations. These, however, indicate that neither Fermi surface nesting, nor enhanced momentum-dependent electron-phonon coupling can account for the I-CDW formation, demonstrating its unconventional nature.

Dominant In-Plane Symmetric Elastoresistance in CsFe_{2}As_{2}.

We study the elastoresistance of the highly correlated material CsFe_{2}As_{2} in all symmetry channels. Neutralizing its thermal expansion by means of a piezoelectric-based strain cell is demonstrated to be essential. The elastoresistance response in the in-plane symmetric channel is found to be large, while the response in the symmetry-breaking channels is weaker and provides no evidence for a divergent nematic susceptibility. Rather, our results can be interpreted naturally within the framework of a coherence-incoherence crossover, where the low-temperature coherent state is sensitively tuned by the in-plane atomic distances.

Randomised clinical trial: alisporivir combined with peginterferon and ribavirin in treatment-naïve patients with chronic HCV genotype 1 infection (ESSENTIAL II).

BACKGROUND: Alisporivir (ALV) is an oral, host-targeting agent with pangenotypic anti-hepatitis C virus (HCV) activity and a high barrier to resistance. AIM: To evaluate efficacy and safety of ALV plus peginterferon-α2a and ribavirin (PR) in treatment-naïve patients with chronic HCV genotype 1 infection. METHODS: Double-blind, randomised, placebo-controlled, Phase 3 study evaluating ALV 600 mg once daily [response-guided therapy (RGT) for 24 or 48 weeks or 48 weeks fixed duration] or ALV 400 mg twice daily RGT with PR, compared to PR alone. Following a Food and Drug Administration partial clinical hold, ALV/placebo was discontinued and patients completed treatment with PR only. At that time, 87% of patients had received ≥12 weeks and 20% had received ≥24 weeks of ALV/PR triple therapy. RESULTS: A total of 1081 patients were randomised (12% cirrhosis, 55% CT/TT IL28B). Addition of ALV to PR improved virological response in a dose-dependent fashion. Overall, sustained virological response (SVR12; primary endpoint) was 69% in all ALV groups vs. 53% in PR control. Highest SVR12 (90%) was achieved in patients treated with ALV 400 mg twice daily and PR for >24 weeks. Seven cases of pancreatitis were reported, with similar frequency between ALV/PR and PR control groups (0.6% vs. 0.8% respectively). Adverse events seen more frequently with ALV/PR than with PR alone were anaemia, thrombocytopenia, hyperbilirubinaemia and hypertension. CONCLUSIONS: Alisporivir, especially the 400 mg twice daily regimen, increased efficacy of PR therapy in treatment-naïve patients with HCV genotype 1 infection. The mechanism of action and pangenotypic activity suggest that alisporivir could be useful in interferon-free combination regimens.

Phase III trial of bortezomib, cyclophosphamide and dexamethasone (VCD) versus bortezomib, doxorubicin and dexamethasone (PAd) in newly diagnosed myeloma.

We aimed at demonstrating non-inferiority of bortezomib/cyclophosphamide/dexamethasone (VCD) compared to bortezomib/doxorubicin/dexamethasone (PAd) induction therapy with respect to very good partial response rates or better (⩾VGPR) in 504 newly diagnosed, transplant-eligible multiple myeloma patients. VCD was found to be non-inferior to PAd with respect to ⩾VGPR rates (37.0 versus 34.3%, P=0.001). The rates of progressive disease (PD) were 0.4% (VCD) versus 4.8% (PAd; P=0.003). In the PAd arm, 11 of 12 patients with PD had either renal impairment (creatinine ⩾2 mg/dl) at diagnosis or the cytogenetic abnormality gain 1q21, whereas no PD was observed in these subgroups in the VCD arm. Leukocytopenia/neutropenia (⩾3°) occurred more frequently in the VCD arm (35.2% versus 11.3%, P<0.001). Neuropathy rates (⩾2°) were higher in the PAd group (14.9 versus 8.4%, P=0.03). Serious adverse events, both overall and those related to thromboembolic events, were higher in the PAd group (32.7 versus 24.0%, P=0.04 and 2.8 versus 0.4%, P=0.04). Stem cell collection was not impeded by VCD. VCD is as effective as PAd in terms of achieving ⩾VGPR rates with fewer PD and has a favorable toxicity profile. Therefore, VCD is preferable to PAd as induction therapy.

A comparison of bleeding patterns and cycle control using two transdermal contraceptive systems: a multicenter, open-label, randomized study.

OBJECTIVE(S): To investigate the bleeding pattern and cycle control parameters of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a patch containing 0.6 mg EE and 6 mg norelgestromin (NGMN). STUDY DESIGN: In this phase III, open-label, randomized, parallel-group trial, healthy women aged 18-35 years (smokers aged 18-30 years) received either the EE/GSD patch (n=200) or the EE/NGMN patch (n=198). Treatment consisted of one patch per week for 3 weeks followed by a 7-day, patch-free interval for seven cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: In reference period 1, mean number of bleeding/spotting days was comparable across treatment groups (p>0.05). However, in reference period 2, there were fewer bleeding/spotting days in the EE/GSD patch group (15.7 versus 18.4; p<0.0001). Mean number of bleeding/spotting episodes was comparable across groups for both reference periods, but bleeding/spotting episodes were shorter for the EE/GSD patch than the EE/NGMN patch during reference period 1 (5.13 days versus 5.53 days, respectively; p<0.05) and reference period 2 (5.07 versus 5.66; p=0.0001). Both treatment groups showed a similar frequency of withdrawal bleeding episodes; however, across all seven cycles, the length of these episodes was consistently shorter with the EE/GSD patch (p<0.01). There were no notable treatment differences in intracyclic bleeding. CONCLUSION(S): Bleeding pattern and cycle control achieved with the EE/GSD patch was similar to that of the EE/NGMN patch. IMPLICATIONS STATEMENT: The paper presents data on the bleeding pattern and cycle control parameters of an investigational transdermal contraceptive patch containing EE and GSD compared with an approved contraceptive patch containing EE and NGMN. This descriptive study found that bleeding patterns associated with the EE/GSD patch were similar to those of an EE/NGMN patch providing higher EE exposure.

Bleeding pattern and cycle control of a low-dose transdermal contraceptive patch compared with a combined oral contraceptive: a randomized study.

OBJECTIVE(S): The aim of this study was to investigate the bleeding pattern and cycle control of a contraceptive patch containing 0.55 mg ethinyl estradiol (EE) and 2.1 mg gestodene (GSD) compared with a combined oral contraceptive (COC) containing 0.02 mg EE and 0.1 mg levonorgestrel (LNG). STUDY DESIGN: In this phase III, randomized, controlled, double-blind, double-dummy, multicenter trial, healthy women aged 18-45 years (smokers aged 18-35 years) received either the EE/GSD patch and a placebo tablet (n=171), or a placebo patch and the COC (n=175) for seven 28-day cycles. Bleeding control was assessed in two 90-day reference periods. RESULTS: Mean number of bleeding/spotting days was comparable across treatment groups in both reference periods (p>.05). Mean number of bleeding/spotting episodes was also comparable in reference period 1; however, there were fewer bleeding/spotting episodes for COC in reference period 2 (3.4 versus 3.1; p=.01). Mean length of bleeding/spotting episodes was comparable across treatment groups for both reference periods (p>.05). Withdrawal bleeding occurred consistently in both groups over the entire treatment period, but its absence was more common in the COC group in cycles 4 and 6 of reference period 2 (p<.01). Intracyclic bleeding was comparable between groups. CONCLUSION(S): Bleeding pattern and cycle control with the EE/GSD patch was comparable to an EE/LNG-containing COC. IMPLICATIONS STATEMENT: The findings suggest that bleeding patterns with the EE/GSD patch are similar to an EE/LNG-containing COC, except for absence of withdrawal bleeding, which was less common in patch users. The EE/GSD patch may constitute an additional contraceptive option for women.

Predictive value of longitudinal whole-body magnetic resonance imaging in patients with smoldering multiple myeloma.

Previous studies demonstrated the relevance of focal lesions (FL) in whole-body magnetic resonance imaging (wb-MRI) at the initial workup of patients with smoldering multiple myeloma (SMM). The aim of this study was to assess the effects of longitudinal wb-MRIs on progression into multiple myeloma (MM). Sixty-three patients with SMM were analyzed who received at least two wb-MRIs for follow-up before progression into MM. Radiological progressive disease (MRI-PD) was defined as detection of new FL or increase in diameter of existing FL and a novel or progressive diffuse infiltration. Radiological stable disease (MRI-SD) was defined by no change compared with the prior MRI. Patients were followed-up every 3-6 months, including a serological and clinical evaluation. One Hundred and eighty-two wb-MRIs were analyzed. MRI-PD occurred in 31 patients (49%), and 25 (40%) patients developed MM. MRI-PD was highly significantly associated with progression into MM, regardless of findings at the initial MRI. In multivariate analysis, MRI-PD remained a risk factor, independent of relevant baseline parameters like serum monoclonal protein or ⩾95% aberrant plasma cells in the bone marrow. Patients with MRI-SD had no higher risk of progression, even when FL were present at the initial MRI. Therefore, MRI is suitable for the follow-up of patients with SMM.

Autologous stem cell transplantation for elderly patients with newly diagnosed multiple myeloma in the era of novel agents.

BACKGROUND: High-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is considered the standard of care for multiple myeloma (MM) patients <65 years. Safety and outcome of ASCT for patients >65 years is currently uncertain, especially since the introduction of novel agents for induction and maintenance therapy. Furthermore, there are no conclusive data available on risk assessment in elderly patients treated with HDT. PATIENTS AND METHODS: We retrospectively analyzed 202 patients ≥60 years with newly diagnosed MM who underwent ASCT at our institution. Patients were stratified by age into three groups (60-64, 65-69 and 70-75 years). For safety assessment, we compared data about hospitalization, hematopoetic reconstitution and early mortality. Remission before and after ASCT was analyzed according to age and application of novel agents. Event-free (EFS) and overall survival (OS) were analyzed to identify impact of age, remission before/after ASCT and maintenance therapy as well as ISS score and cytogenetic aberrations on outcome in elderly patients. RESULTS: The assessment of safety, remission before/after ASCT as well as EFS and OS showed no significant differences between the three groups (median EFS: 60-64 years: 27 months; 65-69 years: 23 months; 70-75 years: 23 months; median OS: not reached). Patients receiving novel agents as part of induction therapy achieved significantly higher nCR + CR rates than patients treated without novel agents. In Cox regression analysis, ISS and cytogenetics as well as remission after ASCT had the highest prognostic impact on EFS and OS. Maintenance therapy was associated with longer EFS in uni- and multivariate analyses. CONCLUSION: ASCT is feasible for selected patients >65 and >70 years without increased mortality. Age at transplantation has no prognostic significance on outcome after ASCT. Novel agents during induction therapy and maintenance therapy improves outcome of older patients eligible for ASCT. ISS and cytogenetic analysis should be carried out routinely for risk assessment.

Beyond the Heisenberg model: anisotropic exchange interaction between a Cu-tetraazaporphyrin monolayer and Fe3O4(100).

The exchange coupling of a single spin localized at the central ion of Cu-tetraazaporphyrin on a magnetite(100) surface has been studied using x-ray magnetic circular dichroism (XMCD). Sum rule analysis of the XMCD spectra results in Cu spin and orbital magnetic moments as a function of the applied external field at low temperatures (20 K). The exchange coupling is positive for magnetization direction perpendicular to the surface (ferromagnetic) while it is negative for in-plane magnetization direction (antiferromagnetic). We attribute the anisotropy of the Heisenberg exchange coupling to an orbitally dependent exchange Hamiltonian.

Double exchange via t(2g) orbitals and the Jahn-Teller effect in ferromagnetic La0.7Sr0.3CoO3 probed by epitaxial strain.

The magnetic exchange in hole-doped ferromagnetic cobaltates is investigated by studying the magnetic and electronic properties of La0.7Sr0.3CoO3 films as a function of epitaxial strain. We found a strong-coupling double exchange mechanism between Co3+ (4t(2g)   2e(g)) and Co4+ (3t(2g)   2e(g)) high-spin states mediated by t(2g) electrons--in contrast to the moderate coupling provided by the e(g) exchange in manganites. The strong sensitivity of the Curie temperature TC to the bulk compression can be explained by the small bandwidth of the t(2g)-derived states. A strain-induced Jahn-Teller effect is likewise observed. The experimental results clarify the magnetic exchange mechanism in the cobaltates.

Magnetic proximity effect in YBa2Cu3O7/La(2/3)Ca(1/3)MnO3 and YBa2Cu3O7/LaMnO(3+δ) superlattices.

Using neutron reflectometry and resonant x-ray techniques we studied the magnetic proximity effect (MPE) in superlattices composed of superconducting YBa2Cu3O7 and ferromagnetic-metallic La0.67Ca0.33MnO3 or ferromagnetic-insulating LaMnO(3+δ). We find that the MPE strongly depends on the electronic state of the manganite layers, being pronounced for the ferromagnetic-metallic La0.67Ca0.33MnO3 and almost absent for ferromagnetic-insulating LaMnO(3+δ). We also detail the change of the magnetic depth profile due to the MPE and provide evidence for its intrinsic nature.

Serum microRNA biomarkers for drug-induced liver injury.

New biomarkers of drug-induced liver injury (DILI) are required in the clinic and in preclinical pharmaceutical evaluation. Liver-enriched microRNAs are promising serum biomarkers of acetaminophen-induced acute liver injury in mice. The utility of circulating microRNAs as biomarkers of human acute DILI is discussed in the context of correlation with existing biomarkers of liver injury and patient outcomes in acetaminophen toxicity, mechanisms of cellular microRNA release, and their potential advantages over current clinical biomarkers of DILI.

Clinical multicenter evaluation of a new FXa-based Antithrombin assay.

INTRODUCTION: The determination of functional Antithrombin is a central part of thrombophilia screening. In this multicenter study, a new FXa-based method (INNOVANCE® Antithrombin) was evaluated on four different analyzers. METHODS: The INNOVANCE Antithrombin method was evaluated by precision and reference interval studies and by comparing the new method with established methods through parallel measurement of samples from 249 patients and 151 apparently healthy individuals. RESULTS: The INNOVANCE Antithrombin assay demonstrated on all analyzers repeatability coefficients of variation (CVs) ≤ 3.2% and within-device and between-run CVs ≤ 6.9%. The reference intervals of all analyzers are comparable with 2.5th percentiles between 80% and 85% of normal. The INNOVANCE Antithrombin and the FIIa-based Berichrom® AT III (A) methods demonstrated good concordance with correlation coefficients of r = 0.908 or higher. The INNOVANCE Antithrombin method demonstrated furthermore an excellent comparability with the STA® Antithrombin III assay and an acceptable comparability with the Coamatic® LR Antithrombin assay. The patients with congenital deficiency (n = 31) were identified with all assays except for the patients carrying the P41L heparin-binding site mutation, which was only identified with the INNOVANCE Antithrombin and the STA Antithrombin III methods. CONCLUSION: The INNOVANCE Antithrombin assay has high sensitivity for Antithrombin deficiencies and is reliable, precise and suitable for routine clinical use.

Bioequivalence of oxcarbazepine oral suspension vs. film-coated tablet in healthy Chinese male subjects.

OBJECTIVE: Oxcarbazepine (Trileptal) is an antiepileptic drug used as monotherapy or adjunctive therapy in the treatment of partial seizures in adults and children. The primary objective of this study was to assess the bioequivalence of Trileptal oral suspension formulation vs. the film-coated tablet after single and multiple twice-daily administrations in fasted, healthy Chinese male subjects. METHODS: This was an open-label, randomized, two-period crossover study in 19 healthy Chinese male subjects. Treatment periods consisted of a single dose of 300 mg oxcarbazepine (either oral suspension formulation or film-coated tablet) on Day 1, b.i.d. administrations of 300 mg from Day 4 to Day 8 inclusive, and a final dose of 300 mg on the morning of Day 9. A 1-week washout period was implemented between treatment periods. Plasma levels of 10-monohydroxy derivative (MHD), the main metabolite mediating the pharmacologic activity of oxcarbazepine, were measured by a validated liquid chromatography tandem mass spectrometry method. Bioequivalence was assessed by the MHD areas under the concentration time curve (AUCs) and maximum concentrations (Cmax) of the oral suspension vs. the film-coated tablet. Safety was evaluated throughout the study. RESULTS: Trileptal oral suspension formulation was bioequivalent to film-coated tablet after single dose and multiple b.i.d. administrations, as assessed by MHD AUCs and Cmax. The 90% confidence intervals (CI) of the geometric mean of the MHD individual ratios were within the bioequivalence CI limits (0.80 - 1.25). No safety concerns were raised. CONCLUSIONS: Trileptal oral suspension formulation and film-coated tablets are bioequivalent in healthy Chinese males.

Structural phase transition and hydrogen ordering of TlH2PO4 at low temperature.

The crystal structure of TlH(2)PO(4) (TDP) has been studied at low temperature. The lattice parameters were derived from high-resolution X-ray powder diffraction in the temperature range between 8 and 300 K. A detailed crystal structure analysis of the antiferroelectric low-temperature phase TDP-III has been performed based on neutron diffraction data measured at 210 K on a twinned crystal consisting of two domain states. The structure model in the triclinic space group P\bar 1 is characterized by a complete ordering of all the H atoms in the asymmetric O-H...O hydrogen bonds. The phase transition from the ferroelastic TDP-II to the antiferroelectric TDP-III phase at 229.5 +/- 0.5 K is only slightly of first order and shows no detectable hysteresis effects. Its mechanism is driven by the hydrogen ordering between the partially ordered TDP-II state and the completely ordered TDP-III state. The polymorphism of TDP and the fully deuterated TlD(2)PO(4) (DTDP) is presented in the form of group-subgroup relations between the different space groups.

[Association of a positive family history with histopathology and clinical course in early-onset prostate cancer]. / Assoziation von familiärem Status mit Histologie und klinischem Verlauf beim frühen Prostatakarzinom.

BACKGROUND: In a large number of studies a positive family history is documented as one of the main risk factors for the development of prostate cancer. In a US population an association between early-onset prostate cancer among familial patients and a more differentiated tumour was shown. The aim of this study was to compare clinical parameters between sporadic and familial or hereditary patients with an age at diagnosis < or =55 years. MATERIAL AND METHODS: The clinical data of prostate cancer patients with an age at diagnosis < or =55 years and who were recruited between July 1999 and the end of June 2004 to the database "familial prostate cancer in Germany" were analysed. The following data were documented for all patients: PSA at diagnosis, histopathological stage, grading, Gleason score and progression-free survival. RESULTS: The clinical data of 685 patients could be completed: 222 (32.4%) had one first-degree relative with prostate cancer, 48 of whom (7.0%) were hereditary; 463 (67.6%) were sporadic. The median age at diagnosis in the hereditary patients was 51.6 (41-55) years, in the familial patients 51.1 (35-55) years and in the sporadic patients 52.0 (38-55) years. The median follow-up was 24 months in hereditary, 36 months in familial and 35 months in sporadic patients. An initial curative therapy with radical prostatectomy or radiotherapy/brachytherapy was planned in 657/685 (95.9%) of the patients. There were no clear differences regarding PSA at diagnosis, the postoperative parameters (organ-confined disease, lymph node involvement, Gleason score, grading) and the progression-free survival in sporadic and familial or hereditary patients. CONCLUSIONS: Patients with an age at diagnosis < or =55 years have a positive family history more often than all prostate cancer patients in Germany. No association could be shown between pathohistological stage or clinical course and a positive family history in patients with an age at diagnosis < or =55 years.