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In non-magnetic materials the combination of inversion symmetry breaking (ISB) and spin-orbit coupling (SOC) determines the spin polarization of the band structure. However, a local spin polarization can also arise in centrosymmetric crystals containing ISB subunits. This is namely the case for the nodal-line semimetal ZrSiTe where, by combining spin- and angle-resolved photoelectron spectroscopy with ab initio band structure calculations, we reveal a complex spin polarization. In the bulk, the valence and conduction bands exhibit opposite spin orientations in two spatially separated two-dimensional ZrTe sectors within the unit cell, yielding no net polarization. We also observe spin-polarized surface states that are well separated in energy and momentum from the bulk bands. A layer-by-layer analysis of the spin polarization allows us to unveil the complex evolution of the signal in the bulk states near the surface, thus bringing the intertwined nature of surface and bulk effects to the fore. Local inversion symmetry breaking in centrosymmetric materials can lead to large spin polarization of the electronic band structure in separate sectors of the unit cell. Here, the authors reveal such hidden spin polarisation in ZrSiTe using spin and angle resolved photoemission spectroscopy in combination with ab initio band structure calculations and investigate the resultant spin polarised bulk and surface properties

Collective modes are responsible for the emergence of novel quantum phases in topological materials. In the quasi-one dimensional (1D) Weyl semimetal ( T a S e 4 ) 2 I , a charge density wave (CDW) opens band gaps at the Weyl points, thus turning the system into an axionic insulator. Melting the CDW would restore the Weyl phase, but 1D fluctuations extend the gapped regime far above the 3D transition temperature ( T C D W = 263 K), thus preventing the investigation of this topological phase transition with conventional spectroscopic methods. Here we use a non-equilibrium approach: we perturb the CDW phase by photoexcitation, and we monitor the dynamical evolution of the band structure by time- and angle-resolved photoelectron spectroscopy. We find that, upon optical excitation, electrons populate the linearly dispersing states at the Fermi level ( E F ), and fill the CDW gap. The dynamics of both the charge carrier population and the band gap renormalization (BGR) show a fast component with a characteristic time scale of a few hundreds femtoseconds. However, the BGR also exhibits a second slow component on the µ s time scale. The combination of an ultrafast response and of persistent changes in the spectral weight at E F , and the resulting sensitivity of the linearly dispersing states to optical excitations, may explain the high performances of ( T a S e 4 ) 2 I as a material for broadband infrared photodetectors.

Standard-of-care treatment for patients with newly diagnosed multiple myeloma includes combination therapies for patients who are not eligible for autologous stem-cell transplantation. At the primary analysis for progression-free survival of the phase 3 ALCYONE trial, progression-free survival was significantly longer with daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) alone in patients with transplant-ineligible, newly diagnosed multiple myeloma. Here we report updated efficacy and safety results from a prespecified, interim, overall survival analysis of ALCYONE with more than 36 months of follow-up. ALCYONE was a multicentre, randomised, open-label, active-controlled, phase 3 trial that enrolled patients between Feb 9, 2015, and July 14, 2016, at 162 sites in 25 countries across North America, South America, Europe, and the Asia-Pacific region. Patients were eligible for inclusion if they had newly diagnosed multiple myeloma and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or because of substantial comorbidities. Patients were randomly assigned in a 1:1 ratio and by permuted block randomisation to receive D-VMP or VMP. An interactive web-based randomisation system was used. Randomisation was stratified by International Staging System disease stage, geographical region, and age. There was no masking to treatment assignments. All patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area on days 1, 4, 8, 11, 22, 25, 29, and 32 of cycle one and on days 1, 8, 22, and 29 of cycles two through nine), oral melphalan (9 mg/m2 once daily on days 1 through 4 of each cycle), and oral prednisone (60 mg/m2 once daily on days 1 through 4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab (16 mg/kg of bodyweight, once weekly during cycle one, once every 3 weeks in cycles two through nine, and once every 4 weeks thereafter as maintenance therapy until disease progression or unacceptable toxicity). The primary endpoint was progression-free survival, which has been reported previously. Results presented are from a prespecified interim analysis for overall survival. The primary analysis population (including for overall survival) was the intention-to-treat population of all patients who were randomly assigned to treatment. The safety population included patients who received any dose of study treatment. This trial is registered with ClinicalTrials.gov, NCT02195479. 706 patients were randomly assigned to treatment groups (350 to the D-VMP group, 356 to the VMP group). At a median follow-up of 40·1 months (IQR 37·4–43·1), a significant benefit in overall survival was observed for the D-VMP group. The hazard ratio (HR) for death in the D-VMP group compared with the VMP group was 0·60 (95% CI 0·46–0·80; p=0·0003). The Kaplan-Meier estimate of the 36-month rate of overall survival was 78·0% (95% CI 73·2–82·0) in the D-VMP group and 67·9% (62·6–72·6) in the VMP group. Progression-free survival, the primary endpoint, remained significantly improved for the D-VMP group (HR 0·42 [0·34–0·51]; p<0·0001). The most frequent adverse events during maintenance daratumumab monotherapy in patients in the D-VMP group were respiratory infections (54 [19%] of 278 patients had upper respiratory tract infections; 42 [15%] had bronchitis, 34 [12%] had viral upper respiratory tract infections), cough (34 [12%]), and diarrhoea (28 [10%]). D-VMP prolonged overall survival in patients with newly diagnosed multiple myeloma who were ineligible for stem-cell transplantation. With more than 3 years of follow-up, the D-VMP group continued to show significant improvement in progression-free survival, with no new safety concerns. Janssen Research & Development.

In the phase 3 ALCYONE study, the addition of daratumumab to bortezomib, melphalan, and prednisone (D-VMP) significantly improved outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma. Here, we present results from the final analysis of ALCYONE. ALCYONE was an international, multicentre, randomised, open-label, active-controlled, phase 3 trial in adults aged 18 years or older with newly diagnosed multiple myeloma who were ineligible for high-dose chemotherapy with autologous stem-cell transplantation, because of their age (≥65 years) or presence of substantial comorbidities, and had an Eastern Cooperative Oncology Group performance status of 0–2. Patients were enrolled between Feb 9, 2015, and July 14, 2016, and were randomly assigned (1:1) by randomly permuted blocks using an interactive web-based randomisation system to receive bortezomib, melphalan, and prednisone (VMP) alone or D-VMP, with randomisation stratified by International Staging System disease stage, geographical region, and age. Patients received up to nine 6-week cycles of subcutaneous bortezomib (1·3 mg/m2 of body surface area, twice per week on weeks 1, 2, 4, and 5 of cycle 1 and once weekly on weeks 1, 2, 4, and 5 of cycles 2–9), oral melphalan (9 mg/m2, once daily on days 1–4 of each cycle), and oral prednisone (60 mg/m2, once daily on days 1–4 of each cycle). Patients in the D-VMP group also received intravenous daratumumab at a dose of 16 mg/kg once weekly during cycle 1, once every 3 weeks in cycles 2–9, and once every 4 weeks thereafter until disease progression, unacceptably toxicity, or the end of study. The primary endpoint, progression-free survival, has been previously reported. The ALCYONE study has completed; presented here are final analyses for selected secondary endpoints related to overall survival, depth of response, subsequent therapy, and safety. The intention-to-treat population was the primary analysis population (including for overall survival), defined as all patients who were randomly assigned to study treatment. The safety population, consisting of patients who received any dose of study treatment, was used in safety analyses. This trial is registered with ClinicalTrials.gov, NCT02195479. In total, 706 patients were enrolled and randomly assigned to receive D-VMP (n=350) or VMP (n=356). Baseline characteristics were balanced between the two treatment groups; most participants were female (379 [54%] of 706 patients) and White (601 [85%] of 706 patients). At a median follow-up of 86·7 months (IQR 28·5–85·2), median overall survival was 83·0 months (95% CI 72·5–not estimable) with D-VMP versus 53·6 months (46·3–60·9) with VMP (hazard ratio [HR] 0·65 [95% CI 0·53–0·80]; p<0·0001). The most common grade 3 or 4 treatment-emergent adverse events were neutropenia (140 [40%] of 346 patients in the D-VMP group vs 138 [39%] of 354 patients in the VMP group), thrombocytopenia (120 [35%] vs 134 [38%]), and anaemia (63 [18%] vs 70 [20%]). Serious treatment-related adverse events occurred in 74 (21%) of 346 patients in the D-VMP group and 56 (16%) of 354 patients in the VMP group. Deaths due to treatment-related adverse events occurred in five (1%) of 346 patients in the D-VMP group (pneumonia, acute myocardial infarction, neuroendocrine tumour, tumour lysis syndrome, and acute respiratory failure) and three (1%) of 354 patients in the VMP group (acute myeloid leukaemia, pulmonary embolism, and bacterial pneumonia). With more than 7 years of follow-up, D-VMP continued to elicit clinical benefits in transplant-ineligible patients with newly diagnosed multiple myeloma, supporting the efficacy and safety of frontline daratumumab-based therapy in this patient population. Janssen Research & Development.

Background In the phase III ALCYONE trial, daratumumab plus bortezomib/melphalan/prednisone (D-VMP) significantly improved overall response rate and progression-free status compared with VMP alone in transplant-ineligible patients with newly diagnosed multiple myeloma (NDMM). Here, we present patient-reported outcomes (PROs) from ALCYONE. Methods The European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaire were administered at baseline, every 3 months (year 1) and every 6 months (until progression). Treatment effects were assessed using a repeated-measures, mixed-effects model. Results Compliance with PRO assessments was comparable at baseline (> 90%) and throughout study (> 76%) for both treatment groups. Improvements from baseline were observed in both groups for EORTC QLQ-C30 Global Health Status (GHS), most functional scales, symptom scales and EQ-5D-5L visual analog scale (VAS). Between-group differences were significant for GHS ( p  = 0.0240) and VAS ( p  = 0.0160) at month 3. Improvements in pain were clinically meaningful in both groups at all assessment time points. Cognitive function declined in both groups, but the magnitude of the decline was not clinically meaningful. Conclusions Patients with transplant-ineligible NDMM demonstrated early and continuous improvements in health-related quality of life, including improvements in functioning and symptoms, following treatment with D-VMP or VMP. Trial registration ClinicalTrials.gov identifier NCT02195479 , registered September 21, 2014

The combination of chronic kidney disease (CKD) and peripheral artery disease (PAD) enhances the already present high cardiovascular risk, exposing the affected patients to unfavourable long-term clinical outcomes. Physical exercise is considered an effective treatment for reducing sedentary behaviour and improving quality of life, but several barriers limit patient participation. In this parallel-design, single-blinded, randomised controlled trial, we will enrol 130 patients with concomitant CKD at stages III and IV and PAD at the claudication stage to be randomised into a 6-month exercise (Ex) or control (Co) intervention. The Ex programme will consist of two daily 10 min interval walking sessions (1 min of walking followed by 1 min of resting), with gait speed controlled via a metronome and increased approximately weekly. The Co group will receive standard nephrological care. Outcomes will be assessed before and after treatment, as well as at the 12-month follow-up. The primary outcome will be the 6 min walking distance. The secondary outcomes will include quality of life, lower limb and handgrip strength, body composition and bone mineral density, as well as circulating indexes of kidney function and long-term clinical outcomes. Since no trials have been published that purposely enrol this high-risk population (CKD-PAD), the eventual positive results will validate a simple, pain-free exercise intervention that can be carried out at home to improve patients’ mobility and quality of life. Trial registration number: NCT06621264.

This observational study aimed to monitor the 5-year trends of kidney function in patients with peripheral artery disease (PAD) and concomitant chronic kidney disease (CKD) enrolled or not enrolled into a rehabilitative exercise program. Sixty-six patients (aged 72 ± 10, males n = 52) at KDOQI stages III-IV and PAD at Rutherford’s stage I-III were included in the study, with a group (Exercise, EX; n = 32) receiving a 6-month structured pain-free home-based walking program and a group (Control, CO; n = 34) receiving walking advice and optimal nephrological care. Outcomes included kidney function measured through serum creatinine (sCr) and clinical outcomes, including the rate of advance of CKD stages and admission to dialysis, revascularizations, and hospitalizations. At baseline, the two groups were comparable for age, nephropathy, medications, comorbidities, and PAD severity. Patients in the EX group safely completed the exercise program. SCr values were slightly increased in EX (baseline: 2.35 ± 0.32; 5-year: 2.71 ± 0.39 mg/dL) and progressively worsened in CO (baseline: 2.30 ± 0.31; 5-year 4.22 ± 0.42 mg/dL), with a significant between-group difference (p = 0.002). The control group also showed a higher number of dialysis admissions (5 vs. 0, p = 0.025) and advancing CKD stage as well a higher risks for lower limb revascularization (hazard ratio: 2.59; 95%CI: 1.11–6.02; p = 0.027) and for all-cause hospitalization (hazard ratio: 1.77; 95%CI: 1.05–2.97; p = 0.031). PAD-CKD patients enrolled in a low-moderate intensity home-exercise program showed more favorable long-term trends in kidney function and clinical outcomes than patients with usual care. These preliminary observations need to be confirmed in randomized trials.

This study aimed to determine cortical activation responses to two different rehabilitative programs, as measured through functional near-infrared spectroscopy (fNIRS). As a secondary analysis of the RAGTIME trial, we studied 24 patients with progressive multiple sclerosis (MS) and severe disability who were randomized to a regimen of robot-assisted gait training (RAGT) or overground walking (OW). Cortical activation during a treadmill walking task, assessed through fNIRS recordings from the motor and premotor cortexes (M1/PM), was calculated as the area under the curve (AUC) of oxyhemoglobin for each hemisphere and the total area (Tot-OxyAUC). Gait speed, endurance, and balance were also measured, along with five healthy control subjects. At baseline, Tot-OxyAUC during walking was significantly increased in MS patients compared to healthy people and was significantly higher for those with more severe disabilities; it was also inversely correlated with physical performance. After rehabilitation, significant opposite variations in Tot-OxyAUC were observed, with activity levels being increased after OW and decreased after RAGT (+242,080 ± 361,902 and −157,031 ± 172,496 arbitrary units, respectively; p = 0.002), particularly in patients who were trained at a lower speed. Greater reductions in the cortical activation of the more affected hemisphere were significantly related to improvements in gait speed (r = −0.42) and endurance (r = −0.44). Cortical activation, assessed through fNIRS, highlighted the brain activity in response to the type and intensity of rehabilitation.

Collective modes are responsible for the emergence of novel quantum phases in topological materials. In the quasi-one dimensional (1D) Weyl semimetal(\\mathrm{TaSe}{₄}{)}₂\\mathrm{I}{}{,} a charge density wave (CDW) opens band gaps at the Weyl points, thus turning the system into an axionic insulator. Melting the CDW would restore the Weyl phase, but 1D fluctuations extend the gapped regime far above the 3D transition temperature ( T_(\\mathrm{CDW}{}{=}) 263 K), thus preventing the investigation of this topological phase transition with conventional spectroscopic methods. Here we use a non-equilibrium approach: we perturb the CDW phase by photoexcitation, and we monitor the dynamical evolution of the band structure by time- and angle-resolved photoelectron spectroscopy. We find that, upon optical excitation, electrons populate the linearly dispersing states at the Fermi level ( E_(\\mathrm{F}{}{)}), and fill the CDW gap. The dynamics of both the charge carrier population and the band gap renormalization (BGR) show a fast component with a characteristic time scale of a few hundreds femtoseconds. However, the BGR also exhibits a second slow component on the µ s time scale. The combination of an ultrafast response and of persistent changes in the spectral weight at E_(\\mathrm{F}{}{,}) and the resulting sensitivity of the linearly dispersing states to optical excitations, may explain the high performances of(\\mathrm{TaSe}{₄}{)}₂\\mathrm{I}{}{a}s a material for broadband infrared photodetectors.

To analyze indications safety and potential complications of cosmetic therapeutic corneal keratopigmentation to treat disfiguring aspect of opaque corneas. Eight eyes of 8 consecutive patients were enrolled in therapeutic corneal keratopigmentation. Surgery was performed using manual technique, and a two-plane corneal dissection was performed. In the deeper pocket, brown pigment was injected to mimic iris color. In the more superficial and smaller pocket, black pigment was used to simulate pupillary opening. Seven out of 8 eyes had significant improvements in cosmesis after surgery. One patient did not have a major improvement due to significant superficial corneal neovascularization. In two eyes, there was pigment fading in the postoperative period, but no additional surgeries were performed. No complications were noted in any of the patients. Therapeutic corneal keratopigmentation can lead to a significant change in ocular appearance and may improve self-esteem and overall life quality. Pigment fading and corneal neovascularization can be a potential problem. Careful patient selection and counseling are important to avoid patients seeking unachievable results.