Screen-printed electrochemical sensing platforms, due to their scales of economy and high reproducibility, can provide a useful approach to translate laboratory-based electrochemistry into the field. ...An important factor when utilising screen-printed electrodes (SPEs) is the determination of their real electrochemical surface area, which allows for the benchmarking of these SPEs and is an important parameter in quality control. In this paper, we consider the use of cyclic voltammetry and chronocoulometry to allow for the determination of the real electrochemical area of screen-printed electrochemical sensing platforms, highlighting to experimentalists the various parameters that need to be diligently considered and controlled in order to obtain useful measurements of the real electroactive area.
Arc lavas display elevated Fe3+/ΣFe ratios relative to MORB. One mechanism to explain this is the mobilization and transfer of oxidized or oxidizing components from the subducting slab to the mantle ...wedge. Here we use iron and zinc isotopes, which are fractionated upon complexation by sulfide, chloride, and carbonate ligands, to remark on the chemistry and oxidation state of fluids released during prograde metamorphism of subducted oceanic crust. We present data for metagabbros and metabasalts from the Chenaillet massif, Queyras complex, and the Zermatt‐Saas ophiolite (Western European Alps), which have been metamorphosed at typical subduction zone P‐T conditions and preserve their prograde metamorphic history. There is no systematic, detectable fractionation of either Fe or Zn isotopes across metamorphic facies, rather the isotope composition of the eclogites overlaps with published data for MORB. The lack of resolvable Fe isotope fractionation with increasing prograde metamorphism likely reflects the mass balance of the system, and in this scenario Fe mobility is not traceable with Fe isotopes. Given that Zn isotopes are fractionated by S‐bearing and C‐bearing fluids, this suggests that relatively small amounts of Zn are mobilized from the mafic lithologies in within these types of dehydration fluids. Conversely, metagabbros from the Queyras that are in proximity to metasediments display a significant Fe isotope fractionation. The covariation of δ56Fe of these samples with selected fluid mobile elements suggests the infiltration of sediment derived fluids with an isotopically light signature during subduction.
Key Points
Iron and zinc stable isotope and elemental data are presented for a prograde suite of metabasalts and metagabbros from Western Alpine ophiolite complexes
Bulk rock δ56Fe and δ66Zn do not vary across metamorphic facies and the eclogitic samples show a MORB‐like isotope composition
Blueschist facies metagabbros preserve evidence for infiltration of sediment derived fluids that impart a light δ56Fe isotope composition to the gabbro
Tenosynovial giant cell tumour (TGCT), a rare, locally aggressive neoplasm, overexpresses colony-stimulating factor 1 (CSF1). Surgery is standard with no approved systemic therapy. We aimed to ...evaluate pexidartinib, a CSF1 receptor inhibitor, in patients with TGCT to provide them with a viable systemic treatment option, especially in cases that are not amenable to surgical resection.
This phase 3 randomised trial had two parts. Part one was a double-blind study in which patients with symptomatic, advanced TGCT for whom surgery was not recommended were randomly assigned via an integrated web response system (1:1) to the pexidartinib or placebo group. Individuals in the pexidartinib group received a loading dose of 1000 mg pexidartinib per day orally (400 mg morning; 600 mg evening) for the first 2 weeks, followed by 800 mg per day (400 mg twice a day) for 22 weeks. Part two was an open-label study of pexidartinib for all patients. The primary endpoint, assessed in all intention-to-treat patients, was overall response at week 25, and was centrally reviewed by RECIST, version 1.1. Safety was analysed in all patients who received at least one dose of the study drug. This study is registered with ClinicalTrials.gov, number NCT02371369.
Between May 11, 2015, and Sept 30, 2016, of 174 patients assessed for eligibility, 120 patients were randomly assigned to, and received, pexidartinib (n=61) or placebo (n=59). There were 11 dropouts in the placebo group and nine in the pexidartinib group. Emergence of mixed or cholestatic hepatotoxicity caused the data monitoring committee to stop enrolment six patients short of target. The proportion of patients who achieved overall response was higher for pexidartinib than placebo at week 25 by RECIST (24 39% of 61 vs none of 59; absolute difference 39% 95% CI 27-53; p<0·0001). Serious adverse events occurred in eight (13%) of 61 patients in the pexidartinib group and one (2%) of 59 patients in the placebo group. Hair colour changes (67%), fatigue (54%), aspartate aminotransferase increase (39%), nausea (38%), alanine aminotransferase increase (28%), and dysgeusia (25%) were the most frequent pexidartinib-associated adverse events. Three patients given pexidartinib had aminotransferase elevations three or more times the upper limit of normal with total bilirubin and alkaline phosphatase two or more times the upper limit of normal indicative of mixed or cholestatic hepatotoxicity, one lasting 7 months and confirmed by biopsy.
Pexidartinib is the first systemic therapy to show a robust tumour response in TGCT with improved patient symptoms and functional outcomes; mixed or cholestatic hepatotoxicity is an identified risk. Pexidartinib could be considered as a potential treatment for TGCT associated with severe morbidity or functional limitations in cases not amenable to improvement with surgery.
Daiichi Sankyo.
Late accretion of primitive chondritic material to Earth, the Moon, and Mars, after core formation had ceased, can account for the absolute and relative abundances of highly siderophile elements ...(HSEs) in their silicate mantles. Here we show that smaller planetesimals also possess elevated HSE abundances in chondritic proportions. This demonstrates that late addition of chondritic material was a common feature of all differentiated planets and planetesimals, irrespective of when they accreted; occurring < 5 to > 150 million years after the formation of the solar system. Parent-body size played a role in producing variations in absolute HSE abundances among these bodies; however, the oxidation state of the body exerted the major control by influencing the extent to which late-accreted material was mixed into the silicate mantle rather than removed to the core.
Preventing, treating, and promoting recovery from critical illness due to pulmonary disease are foundational goals of the critical care community and the NHLBI. Decades of clinical research in acute ...respiratory distress syndrome, acute respiratory failure, pneumonia, and sepsis have yielded improvements in supportive care, which have translated into improved patient outcomes. Novel therapeutics have largely failed to translate from promising preclinical findings into improved patient outcomes in late-phase clinical trials. Recent advances in personalized medicine, "big data," causal inference using observational data, novel clinical trial designs, preclinical disease modeling, and understanding of recovery from acute illness promise to transform the methods of pulmonary and critical care clinical research. To assess the current state of, research priorities for, and future directions in adult pulmonary and critical care research, the NHLBI assembled a multidisciplinary working group of investigators. This working group identified recommendations for future research, including
) focusing on understanding the clinical, physiological, and biological underpinnings of heterogeneity in syndromes, diseases, and treatment response with the goal of developing targeted, personalized interventions;
) optimizing preclinical models by incorporating comorbidities, cointerventions, and organ support;
) developing and applying novel clinical trial designs; and
) advancing mechanistic understanding of injury and recovery to develop and test interventions targeted at achieving long-term improvements in the lives of patients and families. Specific areas of research are highlighted as especially promising for making advances in pneumonia, acute hypoxemic respiratory failure, and acute respiratory distress syndrome.
The Pseudomonas genus contains a metabolically versatile group of organisms that are known to occupy numerous ecological niches, including the rhizosphere and endosphere of many plants. Their ...diversity influences the phylogenetic diversity and heterogeneity of these communities. On the basis of average amino acid identity, comparative genome analysis of >1,000 Pseudomonas genomes, including 21 Pseudomonas strains isolated from the roots of native Populus deltoides (eastern cottonwood) trees resulted in consistent and robust genomic clusters with phylogenetic homogeneity. All Pseudomonas aeruginosa genomes clustered together, and these were clearly distinct from other Pseudomonas species groups on the basis of pangenome and core genome analyses. In contrast, the genomes of Pseudomonas fluorescens were organized into 20 distinct genomic clusters, representing enormous diversity and heterogeneity. Most of our 21 Populus-associated isolates formed three distinct subgroups within the major P. fluorescens group, supported by pathway profile analysis, while two isolates were more closely related to Pseudomonas chlororaphis and Pseudomonas putida. Genes specific to Populus-associated subgroups were identified. Genes specific to subgroup 1 include several sensory systems that act in two-component signal transduction, a TonB-dependent receptor, and a phosphorelay sensor. Genes specific to subgroup 2 contain hypothetical genes, and genes specific to subgroup 3 were annotated with hydrolase activity. This study justifies the need to sequence multiple isolates, especially from P. fluorescens, which displays the most genetic variation, in order to study functional capabilities from a pangenomic perspective. This information will prove useful when choosing Pseudomonas strains for use to promote growth and increase disease resistance in plants.
Community differentiation is a fundamental topic of the social sciences, and its prehistoric origins in Europe are typically assumed to lie among the complex, densely populated societies that ...developed millennia after their Neolithic predecessors. Here we present the earliest, statistically significant evidence for such differentiation among the first farmers of Neolithic Europe. By using strontium isotopic data from more than 300 early Neolithic human skeletons, we find significantly less variance in geographic signatures among males than we find among females, and less variance among burials with ground stone adzes than burials without such adzes. From this, in context with other available evidence, we infer differential land use in early Neolithic central Europe within a patrilocal kinship system.
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