Constraints from mantle xenoliths on the geodynamic evolution of Earth’s upper mantle

Geophysical studies identify a region of slow seismic velocity mantle beneath the central Rio Grande rift that potentially represents a region of hot asthenospheric mantle that has replaced destabilized lithosphere. We determine that the majority of mantle xenoliths from Elephant Butte on the central Rio Grande rift axis are, based on their geochemical affinity to depleted mantle, derived from asthenospheric mantle that has accreted to the base of the Proterozoic lithosphere. Using mantle heat flow models, we estimate the boundary between residual lithosphere and accreted asthenosphere to be at ~45km depth. The amount of lithosphere thinning that has occurred cannot be accounted for by rift-related extension and we therefore suggest that convective removal of a large portion of Proterozoic lithosphere has occurred. Convecting upper mantle-derived peridotites display extreme isotopic depletions that are not observed in mid-ocean ridge basalts (MORB). Previous studies suggest that these isotopically ultradepleted domains represent rare refractory mantle domains that do not participate in MORB petrogenesis. We demonstrate the isotopically ultradepleted domains are not only a ubiquitous feature of convecting upper mantle, but are also capable of melting if advected beneath mid-ocean ridges. To explain the lack of MORB with ultradepleted isotopes, we suggest that MORB compositions are biased towards fertile enriched source components. Estimates of upper mantle composition based on MORB therefore overestimate the fertility of the upper mantle. The Lu-Hf system is commonly used to estimate the timing of melt depletion events in the lithospheric mantle. This is typically done with pseudoisochrons from genetically related mantle xenoliths. Most studies, however, misinterpret Lu/Hf – Hf isotopes correlations by using Cpx Lu/Hf ratios when whole rock Lu/Hf ratios are appropriate due to equilibration above the Lu-Hf closure temperature. Hafnium isotopes do not typically correlate with indicators of melt depletion, which suggests that Hf isotopes do not record ancient melting events. This is likely due to overprinting of Hf isotopes by later metasomatic events.Geological Science

Safety and efficacy of rozanolixizumab in patients with generalised myasthenia gravis (MycarinG): a randomised, double-blind, placebo-controlled, adaptive phase 3 study

Background: Generalised myasthenia gravis is a chronic, unpredictable, and debilitating autoimmune disease. New treatments for this disease are needed because conventional therapies have limitations, such as side-effects (eg, increased infection risk) or inadequate control of symptoms. Rozanolixizumab is a neonatal Fc receptor blocker that might provide a novel therapeutic option for myasthenia gravis. We aimed to assess the safety and efficacy of rozanolixizumab for generalised myasthenia gravis. Methods: MycarinG is a randomised, double-blind, placebo-controlled, adaptive phase 3 study done at 81 outpatient centres and hospitals in Asia, Europe, and North America. We enrolled patients (aged ≥18 years) with acetylcholine receptor (AChR) or muscle-specific kinase (MuSK) autoantibody-positive generalised myasthenia gravis (Myasthenia Gravis Foundation of America class II-IVa), a Myasthenia Gravis Activities of Daily Living (MG-ADL) score of at least 3 (non-ocular symptoms), and a quantitative myasthenia gravis score of at least 11. Patients were randomly assigned (1:1:1) to receive subcutaneous infusions once a week for 6 weeks of either rozanolixizumab 7 mg/kg, rozanolixizumab 10 mg/kg, or placebo. Randomisation was stratified by AChR and MuSK autoantibody status. Investigators, patients, and people assessing outcomes were masked to random assignments. The primary efficacy endpoint was change from baseline to day 43 in MG-ADL score, assessed in the intention-to-treat population. Treatment-emergent adverse events (TEAEs) were assessed in all randomly assigned patients who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT03971422) and EudraCT (2019-000968-18); an open-label extension study has been completed (NCT04124965; EudraCT 2019-000969-21) and another is underway (NCT04650854; EudraCT 2020-003230-20). Findings: Between June 3, 2019, and June 30, 2021, 300 patients were assessed for eligibility, of whom 200 were enrolled. 66 (33%) were randomly assigned to rozanolixizumab 7 mg/kg, 67 (34%) to rozanolixizumab 10 mg/kg, and 67 (34%) to placebo. Reductions in MG-ADL score from baseline to day 43 were greater in the rozanolixizumab 7 mg/kg group (least-squares mean change -3·37 [SE 0·49]) and in the rozanolixizumab 10 mg/kg group (-3·40 [0·49]) than with placebo (-0·78 [0·49]; for 7 mg/kg, least-squares mean difference -2·59 [95% CI -4·09 to -1·25], p<0·0001; for 10 mg/kg, -2·62 [-3·99 to -1·16], p<0·0001). TEAEs were experienced by 52 (81%) of 64 patients treated with rozanolixizumab 7 mg/kg, 57 (83%) of 69 treated with rozanolixizumab 10 mg/kg, and 45 (67%) of 67 treated with placebo. The most frequent TEAEs were headache (29 [45%] patients in the rozanolixizumab 7 mg/kg group, 26 [38%] in the rozanolixizumab 10 mg/kg group, and 13 [19%] in the placebo group), diarrhoea (16 [25%], 11 [16%], and nine [13%]), and pyrexia (eight [13%], 14 [20%], and one [1%]). Five (8%) patients in the rozanolixizumab 7 mg/kg group, seven (10%) in the rozanolixizumab 10 mg/kg group, and six (9%) in the placebo group had a serious TEAE. No deaths occurred. Interpretation: Rozanolixizumab showed clinically meaningful improvements in patient-reported and investigator-assessed outcomes in patients with generalised myasthenia gravis, for both 7 mg/kg and 10 mg/kg doses. Both doses were generally well tolerated. These findings support the mechanism of action of neonatal Fc receptor inhibition in generalised myasthenia gravis. Rozanolixizumab represents a potential additional treatment option for patients with generalised myasthenia gravis. Funding: UCB Pharma

Firefly: The Case for a Holistic Understanding of the Global Structure and Dynamics of the Sun and the Heliosphere

This white paper is on the HMCS Firefly mission concept study. Firefly focuses on the global structure and dynamics of the Sun's interior, the generation of solar magnetic fields, the deciphering of the solar cycle, the conditions leading to the explosive activity, and the structure and dynamics of the corona as it drives the heliosphere