Low-dimensional network formation in molten sodium carbonate

Molten carbonates are highly inviscid liquids characterized by low melting points and high solubility of rare earth elements and volatile molecules. An understanding of the structure and related properties of these intriguing liquids has been limited to date. We report the results of a study of molten sodium carbonate (Na2CO3) which combines high energy X-ray diffraction, containerless techniques and computer simulation to provide insight into the liquid structure. Total structure factors (Fx(Q)) are collected on the laser-heated carbonate spheres suspended in flowing gases of varying composition in an aerodynamic levitation furnace. The respective partial structure factor contributions to Fx(Q) are obtained by performing molecular dynamics simulations treating the carbonate anions as flexible entities. The carbonate liquid structure is found to be heavily temperature-dependent. At low temperatures a low-dimensional carbonate chain network forms, at T = 1100 K for example ~55% of the C atoms form part of a chain. The mean chain lengths decrease as temperature is increased and as the chains become shorter the rotation of the carbonate anions becomes more rapid enhancing the diffusion of Na+ ions

The ALSFRS-R Summit: a global call to action on the use of the ALSFRS-R in ALS clinical trials

The Amyotrophic Lateral Sclerosis Functional Rating Scale (ALSFRS) was developed more than 25 years ago as an instrument to monitor functional change over time in patients with ALS. It has since been revised and extended to meet the needs of high data quality in ALS trials (ALSFRS-R), however a full re-validation of the scale was not completed. Despite this, the scale has remained a primary outcome measure in clinical trials. We convened a group of clinical trialists to discuss and explore opportunities to improve the scale and propose alternative measures. In this meeting report, we present a call to action on the use of the ALSFRS-Revised scale in clinical trials, focusing on the need for (1) harmonization of the ALSFRS-R administration globally, (2) alignment on a set of recommendations for clinical trial design and statistical analysis plans (SAPs), and (3) use of additional outcome measures

Characterization of Granulations of Calcium and Apatite in Serum as Pleomorphic Mineralo-Protein Complexes and as Precursors of Putative Nanobacteria

Calcium and apatite granulations are demonstrated here to form in both human and fetal bovine serum in response to the simple addition of either calcium or phosphate, or a combination of both. These granulations are shown to represent precipitating complexes of protein and hydroxyapatite (HAP) that display marked pleomorphism, appearing as round, laminated particles, spindles, and films. These same complexes can be found in normal untreated serum, albeit at much lower amounts, and appear to result from the progressive binding of serum proteins with apatite until reaching saturation, upon which the mineralo-protein complexes precipitate. Chemically and morphologically, these complexes are virtually identical to the so-called nanobacteria (NB) implicated in numerous diseases and considered unusual for their small size, pleomorphism, and the presence of HAP. Like NB, serum granulations can seed particles upon transfer to serum-free medium, and their main protein constituents include albumin, complement components 3 and 4A, fetuin-A, and apolipoproteins A1 and B100, as well as other calcium and apatite binding proteins found in the serum. However, these serum mineralo-protein complexes are formed from the direct chemical binding of inorganic and organic phases, bypassing the need for any biological processes, including the long cultivation in cell culture conditions deemed necessary for the demonstration of NB. Thus, these serum granulations may result from physiologically inherent processes that become amplified with calcium phosphate loading or when subjected to culturing in medium. They may be viewed as simple mineralo-protein complexes formed from the deployment of calcification-inhibitory pathways used by the body to cope with excess calcium phosphate so as to prevent unwarranted calcification. Rather than representing novel pathophysiological mechanisms or exotic lifeforms, these results indicate that the entities described earlier as NB most likely originate from calcium and apatite binding factors in the serum, presumably calcification inhibitors, that upon saturation, form seeds for HAP deposition and growth. These calcium granulations are similar to those found in organisms throughout nature and may represent the products of more general calcium regulation pathways involved in the control of calcium storage, retrieval, tissue deposition, and disposal

Courage-als: a randomized, double-blind phase 3 study designed to improve participant experience and increase the probability of success

Objective: To determine the target population and optimize the study design of the phase 3 clinical trial evaluating reldesemtiv in participants with amyotrophic lateral sclerosis (ALS). Methods: We evaluated the phase 2 study of reldesemtiv, FORTITUDE-ALS, to inform eligibility criteria and design features that would increase trial efficiency and reduce participant burden of the phase 3 trial. Results: In FORTITUDE-ALS, the effect of reldesemtiv was particularly evident among participants in the intermediate- and fast-progressing tertiles for pre-study disease progression. These participants most often had symptom onset ≤24 months and an ALS Functional Rating Scale-Revised (ALSFRS-R) total score ≤44 at baseline. Compared with the overall FORTITUDE-ALS population, the subgroup meeting these criteria declined by fewer ALSFRS-R points at 12 weeks (difference of least-squares mean [SE] versus placebo 1.84 [0.49] and 0.87 [0.35] for the overall population). These inclusion criteria will be used for the phase 3 clinical trial, COURAGE-ALS, in which the primary outcome is the change in ALSFRS-R total score at week 24. We also measure durable medical equipment use and evaluate strength in muscles expected to change rapidly. To reduce participant burden, study visits are often remote, and strength evaluation is simplified to reduce time and effort. Conclusions: In COURAGE-ALS, the phase 3 clinical trial to evaluate reldesemtiv, the sensitivity of detecting a potential treatment effect may be increased by defining eligibility criteria that limit the proportion of participants who have slower disease progression. Implementing remote visits and simplifying strength measurements will reduce both site and participant burden.ClinicalTrials.gov identifiers: NCT03160898 (FORTITUDE-ALS) and NCT04944784 (COURAGE-ALS)

Fiamme degassing structures and their implications for the post-emplacement temperatures and H2O contents of high-grade ignimbrites

A new process in post-emplacement ignimbrite degassing is proposed from observations of unusual structures in a high-grade ignimbrite in Sardinia. The structures consist of fiamme decorated above and below by vesicles, termed here Fiamme Degassing Structures (FDS). The relative volumes of vesicles and fiamme have a positive, linear correlation, and the ratio between the volume of vesicles above and below fiamme (asymmetry ratio) is  1 wt% at <860 °C), explaining the rare occurrence of FDS. The H2O contents required to form these structures post-emplacement are relatively high for pyroclasts, suggesting they are indicators of unusually large supersaturation in water resulting from rapid excavation rate. These structures also illustrate that interaction of volatiles with fiamme occurs during post-emplacement degassing; FDS may act as baffles that channel volatiles into fumarole columns, slowing volatile loss

The importance of offering early genetic testing in everyone with amyotrophic lateral sclerosis

Several genetically-targeted therapies are being developed for ALS. Research is increasingly supportive of a greater incidence of clinically actionable variants in sporadic ALS than previously reported. Salmon et al. outline the need to improve access, and offer genetic testing to all people diagnosed with ALS

Safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis (the REFALS study): a randomised, double-blind, placebo-controlled phase 3 trial.

Background: There is an urgent unmet need for new therapies in amyotrophic lateral sclerosis. In a clinical study with healthy volunteers, levosimendan, a calcium sensitiser, was shown to improve neuromechanical efficiency and contractile function of the human diaphragm. We aimed to evaluate the safety and efficacy of oral levosimendan in people with amyotrophic lateral sclerosis, with a focus on respiratory function. Methods: The REFALS study is a randomised, double-blind, placebo-controlled phase 3 trial at 99 amyotrophic lateral sclerosis specialist centres in 14 countries worldwide. People with amyotrophic lateral sclerosis were eligible for participation if they were at least 18 years of age and had a sitting slow vital capacity (SVC) of 60-90% predicted. Participants were randomly assigned (2:1) by interactive web-response system to receive either levosimendan or placebo. The capsules for oral administration were identical in appearance to maintain blinding of participants and investigators. The primary endpoint was the change from baseline in supine SVC at 12 weeks, assessed as the percentage of predicted normal sitting SVC. The key secondary endpoint was the combined assessment of function and survival (CAFS) up to 48 weeks. Analyses were done in the intention-to-treat population, comprising all participants who were randomly assigned. This trial is registered at ClinicalTrials.gov (NCT03505021) and has been completed. An extension study (REFALS-ES; NCT03948178) has also been completed, but will be reported separately. Findings: Between June 21, 2018, and June 28, 2019, 871 people were screened for the study, of whom 496 were randomly assigned either levosimendan (n=329) or placebo (n=167). Participants were followed up between June 27, 2018 and June 26, 2020, for a median duration of 50·1 (IQR 37·5-51·1) weeks. The median duration of treatment was 47·9 (IQR 26·4-48·1) weeks. Change from baseline in supine SVC at 12 weeks was -6·73% with levosimendan and -6·99% with placebo, with no significant difference between the treatments (estimated treatment difference 0·26%, 95% CI -2·03 to 2·55, p=0·83). Similarly, at week 48, CAFS did not differ between treatment groups (least squares mean change from baseline 10·69, 95% CI -15·74 to 37·12; nominal p value=0·43). The most frequent adverse events were increased heart rate (106 [33%] of 326 receiving levosimendan vs 12 [7%] of 166 receiving placebo), fall (85 [26%] vs 48 [29%]), headache (93 [29%] vs 36 [22%]), and dyspnoea (59 [18%] vs 32 [19%]). 33 (10%) participants allocated levosimendan and 20 (12%) assigned placebo died during the trial, mainly due to respiratory failure or progression of amyotrophic lateral sclerosis. Interpretation: Levosimendan was not superior to placebo in maintaining respiratory function in a broad population with amyotrophic lateral sclerosis. Although levosimendan was generally well tolerated, increased heart rate and headache occurred more frequently with levosimendan than with placebo. The possibility of a clinically relevant subgroup of responsive individuals requires further evaluation

Laboratory experiments on the weathering of iron meteorites and carbonaceous chondrites by iron-oxidizing bacteria

Batch culture experiments were performed to investigate the weathering of meteoritic material by iron-oxidizing bacteria. The aerobic, acidophilic iron oxidizer (A. ferrooxidans) was capable of oxidizing iron from both carbonaceous chondrites (Murchison and Cold Bokkeveld) and iron meteorites (York and Casas Grandes). Preliminary iron isotope results clearly show contrasted iron pathways during oxidation with and without bacteria suggesting that a biological role in meteorite weathering could be distinguished isotopically. Anaerobic iron-oxidizers growing under pH-neutral conditions oxidized iron from iron meteorites. These results show that rapid biologically mediated alteration of extraterrestrial materials can occur in both aerobic and anaerobic environments. These results also demonstrate that iron can act as a source of energy for microorganisms from both iron and carbonaceous chondrites in aerobic and anaerobic conditions with implications for life on the early Earth and the possible use of microorganisms to extract minerals from asteroidal material