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There are no approved diagnostic biomarkers for at-risk non-alcoholic steatohepatitis (NASH), defined by the presence of NASH, high histological activity and fibrosis stage ≥2, which is associated with higher incidence of liver-related events and mortality. FNIH-NIMBLE is a multi-stakeholder project to support regulatory approval of NASH-related biomarkers. The diagnostic performance of five blood-based panels was evaluated in an observational (NASH CRN DB2) cohort (n= 1,073) with full spectrum of non-alcoholic fatty liver disease (NAFLD). The panels were intended to diagnose at-risk NASH (NIS4), presence of NASH (OWLiver) or fibrosis stages >2, >3 or 4 (enhanced liver fibrosis (ELF) test, PROC3 and FibroMeter VCTE). The prespecified performance metric was an area under the receiver operating characteristic curve (AUROC) ≥0.7 and superiority over alanine aminotransferase for disease activity and the FIB-4 test for fibrosis severity. Multiple biomarkers met these metrics. NIS4 had an AUROC of 0.81 (95% confidence interval: 0.78–0.84) for at-risk NASH. The AUROCs of the ELF test, PROC3 and FibroMeterVCTE for clinically significant fibrosis (≥stage 2), advanced fibrosis (≥stage 3) or cirrhosis (stage 4), respectively, were all ≥0.8. ELF and FibroMeter VCTE outperformed FIB-4 for all fibrosis endpoints. These data represent a milestone toward qualification of several biomarker panels for at-risk NASH and also fibrosis severity in individuals with NAFLD.

Introduction: This post hoc analysis of phase 2 trial data assessed the efficacy of tofacitinib on magnetic resonance imaging (MRI) outcomes with the detailed anatomy-based Canada–Denmark (CANDEN) MRI scoring system and evaluated tofacitinib suppression of spinal inflammation in patients with active ankylosing spondylitis (AS). Methods: Patients with active AS (per modified New York criteria) were randomized 1:1:1:1 to receive tofacitinib 2, 5, or 10 mg twice daily (BID), or placebo, in a 16-week, phase 2, double-blind clinical trial. Spine MRI assessments were performed at baseline and week 12. For post hoc analysis, MRI images from patients receiving tofacitinib 5 or 10 mg BID, or placebo, were re-evaluated by two readers blinded to time point/treatment and assessed by the CANDEN MRI scoring system. Least squares mean changes from baseline to week 12 were reported for CANDEN-specific MRI outcomes, with analysis of covariance used for comparisons of pooled tofacitinib and tofacitinib 5 or 10 mg BID versus placebo. pvalues without multiplicity adjustment were reported. Results: MRI data from 137 patients were analyzed. At week 12, CANDEN spine inflammation score and vertebral body, posterior elements, corner, non-corner, facet joint, and posterolateral inflammation subscores were significantly reduced with pooled tofacitinib versus placebo (p< 0.0001; except non-corner subscore, p< 0.05). Total spine fat score was numerically increased with pooled tofacitinib versus placebo. Conclusions: In patients with AS, tofacitinib treatment was associated with significant reductions in MRI scores of spinal inflammation versus placebo, as assessed by the CANDEN MRI scoring system. Tofacitinib reduced inflammation in posterolateral elements of the spine and facet joints, which has not been described previously. Trial Registration: ClinicalTrials.gov registry (NCT01786668).

This prospective study defines expected US elastography measurement variability to guide clinical interpretation, enable diagnostic enrichment in clinical trials, and support U.S. Food and Drug Administration biomarker validation for nonalcoholic fatty liver disease.

When you next drink a cup of Ethiopian coffee remember the person who grew the beans, for you are now more likely to know precisely where it comes from. Up [...]

40Ar–39Ar dating of glass shards from silicic tuffs of the Ellensburg Formation (NW, USA) interbedding basaltic lavas yielded accurate, precise, reproducible plateau and isochron ages that are within error at the 2σ level. The age-spectra have flat plateaus and the inverse isochrons have atmospheric 40Ar/36Ar at the 2σ level. Ages of 12.00 ± 0.24, 11.37 ± 0.15, 10.67 ± 0.21 and 10.70 ± 0.18 Ma are consistent with the stratigraphy of four of the dated layers; the age of 10.77 ± 0.18 Ma for a fifth layer is at odds with the stratigraphy. This discrepancy arises due to the effect of glass alteration that induced K- and Ar-loss. There is no evidence of excess 40Ar or 39Ar recoil. The new ages indirectly constrain the timing of eruption of the lavas above and below the ash beds. This demonstrates that volcanic glass from interbeds can be used as an additional tool for indirectly dating basaltic lava sequences, which is independent of the lavas and complementary to other materials. Considering the numerous studies in which volcanic glass failed to provide reliable 40Ar–39Ar ages, additional and supportive constraints are still needed to assess the validity of the ages from glass shards. Supplementary material: A1 – sample location, stratigraphic position and depositional environments; A2 – electron microprobe information with calibration and sample data; A3 – Ar isotopic data of blanks and samples, data reduction software, J values, criteria for age calculation and images of age spectra and inverse isochrons are available at https://doi.org/10.6084/m9.figshare.c.5077705 [ABSTRACT FROM AUTHOR]

The late Cretaceous accretionary complex along the İzmir–Ankara–Erzincan suture zone, northern Turkey, includes various types of metamorphic rock together with radiolarite, sandstone, mudstone, serpentinite, basalt and limestone. Meta-plagiogranite blocks (up to 5 m in diameter) and a meta-gabbro slice (800 × 500 m) cross-cut by meta-plagiogranite are observed in a matrix of serpentinite, mudstone and radiolarian chert. These meta-gabbros and meta-plagiogranites show subduction-related geochemical characteristics. Laser ablation inductively coupled plasma mass spectrometry U–Pb dating of zircons from two meta-plagiogranites yielded 222.3 ± 1.5 and 227.2 ± 1.6 Ma crystallization ages. This study shows that the meta-gabbro and meta-plagiogranite from the accretionary complex are remnants of the metamorphosed equivalents of the late Triassic lower crustal rocks of the subducted Tethyan oceanic crust. They are the oldest lower crustal rocks observed in the İzmir–Ankara–Erzincan suture zone. Both the meta-gabbros and meta-plagiogranites have Na–Ca amphiboles, indicating blueschist facies metamorphism. However, phengites from a blueschist facies rock yielded an 40Ar/39Ar age of 104.3 ± 0.7 Ma, indicating that blueschist metamorphism occurred during the Albian. All these data suggest that the oceanic crust formed during the Norian, metamorphosed during the Jurassic to early Cretaceous and then dismembered during accretionary complex formation in the late Cretaceous. Supplementary material: A complete description of the analytical methods (electron microprobe, LA-ICP-MS zircon U–Pb and 40Ar/39Ar age analyses, pseudo-section modelling and THERMOCALC) are available at https://doi.org/10.6084/m9.figshare.6509984 Thematic collection: This article is part of the 'Tethyan ophiolites and Tethyan seaways collection' available at: https://www.lyellcollection.org/cc/tethyan-ophiolites-and-tethyan-seaways [ABSTRACT FROM AUTHOR]

The Kalkarindji flood basalt province of northern Australia erupted in the mid-Cambrian. Today, the province consists of scattered volcanic and intrusive suites, the largest being the Antrim Plateau Volcanics (APV) in Northern Territory. Accurate dating of the Kalkarindji flood basalt province has proved challenging, with previous studies focused on minor volcanic rocks and intrusive dykes in Northern Territory and Western Australia. These previously published data, corrected to the same decay constants, range from 512.8 to 509.6 ± 2.5 Ma [2s], placing the Kalkarindji flood basalt province in apparent synchronicity with the Cambrian Stage 4-5 biotic crisis at 510 ± 1 Ma. This study utilizes 40Ar/39Ar dating of basalts from the APV to accurately date the major volcanic eruptions in this province. The results yield an age of 508.0-498.3 ± 5.5 Ma [2s], indicating that the APV is younger than the intrusive rocks. These dates allude to a relative timing discrepancy, where intrusive activity in the North Australian Craton preceded the eruption of the APV as the last magmatic activity in the region. The determination of these largest eruptions to be later than 510 Ma effectively disassociates the Kalkarindji lavas from being a major cause of the 510 Ma biotic crisis, but cannot definitively discount any deleterious effects on the fragile Cambrian ecosystem. [ABSTRACT FROM AUTHOR]

NIMBLE 1.2 was a prospective study that evaluated repeatability of MRI biomarkers of liver fat, fibrosis, and body composition in participants with nonalcoholic fatty liver disease to inform their longitudinal use.

Safety, tolerability, anabolic effects, pharmacokinetics, and pharmacodynamics of single ascending and multiple doses of domagrozumab, an antimyostatin monoclonal antibody, were assessed following intravenous (IV) and subcutaneous (SC) administration in healthy subjects. A range of single ascending dose levels between 1 and 40 mg/kg IV and multiple doses (3 doses) of 10 mg/kg IV were tested (n = 8 per cohort). Additionally, a 3 mg/kg SC (n = 8) cohort also received domagrozumab. Magnetic resonance imaging and whole‐body dual‐energy x‐ray absorptiometry imaging were conducted to investigate the anabolic effects of domagrozumab. Domagrozumab was well tolerated with no severe and 1 non–treatment‐related serious adverse event. The most commonly reported adverse events were headache (21 subjects) and fatigue, upper respiratory tract infections, and muscle spasms (10 subjects each). Domagrozumab demonstrated typical IgG1 pharmacokinetics, with slow SC absorption and slow clearance, low volume of distribution, and a long half‐life. Target engagement was observed with an increase in extent of myostatin modulation, plateauing at the 20 mg/kg IV dose. Downstream pharmacology following myostatin binding by domagrozumab was only observed in the 10 mg/kg single IV cohort (increase in whole‐body lean mass of 5.38% using dual‐energy x‐ray absorptiometry) and the 10 mg/kg repeat‐dose cohort (muscle volume increase of 4.49% using magnetic resonance imaging).

Describe the radiograph-based screening program and frequencies of ineligibility in 3 large, international, randomized, double-blind, phase 3 studies of subcutaneous tanezumab in patients with osteoarthritis (OA).

New data from a gem-quality feldspar from Itrongay, Madagascar, record naturally occurring 40Ar/39Ar age profiles which can be numerically modelled by invoking a single diffusion mechanism and show that microtexturally simple crystals are capable of recording complex thermal histories. We present the longest directly measured, naturally produced 40Ar*-closure profiles from a single, homogeneous orthoclase feldspar. These data appear to confirm the assumption that laboratory derived diffusion parameters are valid in nature and over geological timescales. Diffusion domains are defined by crystal faces and ancient cracks, thus in gem-quality feldspars the diffusion domain size equates to the physical grain size. The data also illustrate the potential of large, gem-quality feldspars to record detailed thermal histories over tens of millions of years and such samples should be considered for future studies on the slow cooling of continental crust.Supplementary material:Ar-isotope data, standards and constants used in calculations and irradiation parameters are available at http://www.geolsoc.org.uk/SUP18720.

Graphite-coated, highly magnetic FeCo core–shell nanoparticles were synthesized by a chemical vapor deposition method and solubilized in aqueous solution through a unique polymer mixture modification, which significantly improved the biocompatibility and stability of the magnetic nanoparticles (MNPs). Such functionalized MNPs were proven to be very stable in different conditions which would be significant for biological applications. Cell staining, manipulation, enrichment, and detection were developed with these MNPs. Under external magnetic manipulation, the MNP-stained cells exhibited directed motions. Moreover, MNPs were printed on substrates to modulate the magnetic field distribution on the surface. Capture and detection of sparse populations of cancer cells spiked into whole blood has been explored in a microarray fashion. Cancer cells from hundreds down to only two were able to be simply and efficiently detected from 1 mL of whole blood on the MNP microarray chips. Interestingly, the cells captured through the MNP microarray still showed viability and adhered to the MNP spots after incubation, which could be utilized for cancer cell detection, localized growth, and proliferation.

FeCo/graphitic carbon shell (FeCo/GC) nanocrystals (∼4−5 nm in diameter) with ultrahigh magnetization are synthesized, functionalized, and developed into multifunctional biocompatible materials. We demonstrate the ability of this material to serve as an integrated system for combined drug delivery, near-infrared (NIR) photothermal therapy, and magnetic resonance imaging (MRI) in vitro. We show highly efficient loading of doxorubicin (DOX) by π-stacking on the graphitic shell to afford FeCo/GC−DOX complexes and pH sensitive DOX release from the particles. We observe enhanced intracellular drug delivery by FeCo/GC−DOX under 20 min of NIR laser (808 nm) induced hyperthermia to 43 °C, resulting in a significant increase of FeCo/GC−DOX toxicity toward breast cancer cells. The synergistic cancer cell killing by FeCo/GC−DOX drug delivery under photothermal heating is due to a ∼two-fold enhancement of cancer cell uptake of FeCo/GC−DOX complex and the increased DOX toxicity under the 43 °C hyperthermic condition. The combination of synergistic NIR photothermally enhanced drug delivery and MRI with the FeCo/GC nanocrystals could lead to a powerful multimodal system for biomedical detection and therapy.

Pseudotachylites within the Neoarchaean to Palaeoproterozoic basement of the Lewisian Gneiss Complex have been analysed using the high spatial resolution 40Ar/39Ar UV laserprobe technique. It has been possible to measure 40Ar/39Ar age and 'apparent' age variations that would be beyond resolution by lower spatial resolution or bulk 40Ar/39Ar dating methods. We report a range of complexities including significantly younger narrow (<1 mm) margins on much older pseudotachylite veins, and heterogeneous excess argon contamination. We also report pseudotachylite veins of varying magnitudes that have been subject to later thermal reheating, whereby there is a relationship between vein thickness and extent of argon loss. In spite of these it is still possible to determine geologically meaningful 40Ar/39Ar ages for pseudotachylite-forming events. In Lewis the c. 1900 Ma event may relate to early stages of Laxfordian reworking. In Barra and South Uist a 1300-1200 Ma event is recorded, whereas in Barra, South and North Uist a second event is recorded at c. 700 Ma, which is likely to be associated with NW- and west-directed thrusting, and could represent far-field effects of tectonic events recorded at this time east of the Moine Thrust in NW Scotland. [ABSTRACT FROM AUTHOR]

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Abstract—A new locality of in situ massive impact‐melt rock was discovered on the south‐southwestern rim of the Roter Kamm impact structure. While the sub‐samples from this new locality are relatively homogeneous at the hand specimen scale, and despite being from a nearby location, they do not have the same composition of the only previously analyzed impact‐melt rock sample from Roter Kamm. Both Roter Kamm impact‐melt rock samples analyzed to date, as well as several suevite samples, exhibit a granitic‐granodioritic precursor composition. Micro‐chemical analyses of glassy matrix and Al‐rich orthopyroxene microphenocrysts demonstrate rapid cooling and chemical disequilibrium at small scales. Platinum‐group element abundances and ratios indicate an ordinary chondritic composition for the Roter Kamm impactor. Laser argon dating of two sub‐samples did not reproduce the previously obtained age of 3.7 ± 0.3 (1s̀) for this impact event, based on 40Ar/39Ar dating of a single vesicular impact‐melt rock. Instead, we obtained ages between 3.9 and 6.3 Ma, with an inverse isochron age of 4.7 ± 0.3 Ma for one analyzed sub‐sample and 5.1 ± 0.4 Ma for the other. Clearly a post‐5 Ma impact at Roter Kamm remains indicated, but further analytical work is required to better constrain the currently best estimate of 4–5 Ma. Both impactor and age constraints are clearly obstructed by the inherent microscopic heterogeneity and disequilibrium melting and cooling processes demonstrated in the present study.

Abstract—We have re‐evaluated the published age information for the Haughton impact structure, which was believed to have formed ˜23 Ma ago during the Miocene age, and report new Ar/Ar laser probe data from shocked basement clasts. This reveals an Eocene age, which is at odds with the published Miocene stratigraphic, apatite fission track and Ar/Ar data; we discuss our new data within this context. We have found that the age of the Haughton impact structure is ˜39 Ma, which has implications for both crater recolonization models and post‐impact hydrothermal activity. Future work on the relationship between flora and fauna within the crater, and others at high latitude, may resolve this paradox.

Abstract—In earlier studies, the 65‐75 km diameter Siljan impact structure in Sweden has been linked to the Late Devonian mass extinction event. The Siljan impact event has previously been dated by K‐Ar and Ar‐Ar chronology at 342‐368 Ma, with the commonly quoted age being 362.7 ± 2.2 Ma (2 s̀, recalculated using currently accepted decay constants). Until recently, the accepted age for the Frasnian/Famennian boundary and associated extinction event was 364 Ma, which is within error limits of this earlier Siljan age. Here we report new Ar‐Ar ages extracted by laser spot and laser step heating techniques for several melt breccia samples from Siljan (interpreted to be impact melt breccia). The analytical results show some scatter, which is greater in samples with more extensive alteration; these samples generally yield younger ages. The two samples with the least alteration yield the most reproducible weighted mean ages: one yielded a laser spot age of 377.2 ± 2.5 Ma (95% confidence limits) and the other yielded both a laser spot age of 376.1 ± 2.8 Ma (95% confidence limits) and a laser stepped heating plateau age over 70.6% 39Ar release of 377.5 ± 2.4 Ma (2 s̀). Our conservative estimate for the age of Siljan is 377 ± 2 Ma (95% confidence limits), which is significantly different from both the previously accepted age for the Frasnian/Famennian (F/F) boundary and the previously quoted age of Siljan. However, the age of the F/F boundary has recently been revised to 374.5 ± 2.6 Ma by the International Commission for Stratigraphy, which is, within error, the same as our new age. However, the currently available age data are not proof that there was a connection between the Siljan impact event and the F/F boundary extinction. This new result highlights the dual problems of dating meteorite impacts where fine‐grained melt rocks are often all that can be isotopically dated, and constraining the absolute age of biostratigraphic boundaries, which can only be constrained by age extrapolation. Further work is required to develop and improve the terrestrial impact age record and test whether or not the terrestrial impact flux increased significantly at certain times, perhaps resulting in major extinction events in Earth's biostratigraphic record.

Focuses on the relationship between Caledonian tectonism, source block supply and sedimentation in the Arctic margin, from the viewpoint of [sup40]Argon/[sup39]Argon laserprobe data from detrital white micas from the Norwegian Sea. Regional setting; Laserprobe test results; Source region and sedimentary system characteristics deduced from the test data; Model for Caledonian uplift and sediment supply in a restricted region.

Mechanisms driving the tectonic evolution of the southeast (SE) margin of Tibet include the Paleogene extrusion of the coherent Indochina lithospheric block and the continuous deformation caused by lower crustal flow since the middle Miocene. The timing and style of regional deformations are keys to determining the role of each mechanism. Fault‐bounded and fault‐controlled Cenozoic basins within the SE margin of Tibet record regional deformation, surface uplift, and variations in paleoclimate but often are poorly dated. New magnetostratigraphy and 40Ar/39Ar dating of volcanic ashes constrain precisely the timing of sedimentation within the Lühe Basin to between ~35 and 26.5 Ma. The basin is located in the Chuandian terrane along the Chuxiong fault, which lies ~70 km north of, and parallel to, the Ailao Shan‐Red River fault. The asymmetric syncline of the Lühe Basin suggests syncontractional sedimentation, and the basal age of the basin represents the initiation of the Chuxiong fault and crustal shortening at ~35 Ma. This is coincident with the onset of the Ailao Shan‐Red River fault and supports a kinematic link between them. Our study suggests that, like the Ailao Shan‐Red River fault, the Chuxiong fault is a Paleogene transpressional structure that developed during the extrusion and clockwise rotation of Indochina around the Eastern Himalayan Syntaxis, which caused the late Paleogene deformation and surface uplift of the Chuandian terrane and Indochina. Our revised chronostratigraphy of the Lühe Basin provides further evidence that many of the “Neogene” sedimentary basins in the SE margin of Tibet may be much older than previously thought. We revised the Lühe Basin sedimentation from late Miocene to 35–26.5 Ma by magnetostratigraphy and 40Ar/39Ar chronologyOligocene uplift of the SE Tibet margin is related to the extrusion and clockwise rotation of IndochinaA reassessment on the age of other late Cenozoic basins in SE Tibet margin is required

The İzmir‐Ankara suture represents part of the boundary between Laurasia and Gondwana along which a wide Tethyan ocean was subducted. In northwest Turkey, it is associated with distinct oceanic subduction‐accretion complexes of Late Triassic, Jurassic, and Late Cretaceous ages. The Late Triassic and Jurassic accretion complexes consist predominantly of basalt with lesser amounts of shale, limestone, chert, Permian (274 Ma zircon U‐Pb age) metagabbro, and serpentinite, which have undergone greenschist facies metamorphism. Ar‐Ar muscovite ages from the phyllites range from 210 Ma down to 145 Ma with a broad southward younging. The Late Cretaceous subduction‐accretion complex, the ophiolitic mélange, consists of basalt, radiolarian chert, shale, and minor amounts of recrystallized limestone, serpentinite, and greywacke, showing various degrees of blueschist facies metamorphism and penetrative deformation. Ar‐Ar phengite ages from two blueschist metabasites are ca. 80 Ma (Campanian). The ophiolitic mélange includes large Jurassic peridotite‐gabbro bodies with plagiogranites with ca. 180 Ma U‐Pb zircon ages. Geochronological and geological data show that Permian to Cretaceous oceanic lithosphere was subducted north under the Pontides from the Late Triassic to the Late Cretaceous. This period was characterized generally by subduction‐accretion, except in the Early Cretaceous, when subduction‐erosion took place. In the Sakarya segment all the subduction‐accretion complexes, as well as the adjacent continental sequences, are unconformably overlain by Lower Eocene red beds. This, along with the stratigraphy of the Sakarya Zone, indicates that the hard collision between the Sakarya Zone and the Anatolide‐Tauride Block took place in Paleocene. Eurasia and the northern mountain ranges of Turkey, the Pontides, were separated by an ocean or oceans from the central and southern Anatolia, the Anatolide‐Tauride Block. The number of the intervening oceans, their age, and their mode of closure are controversial. We provide geological and geochronological data to show that a single İzmir‐Ankara ocean separated Eurasia‐Pontides from the Anatolide‐Block from at least the Permian (ca. 274 Ma) until the Late Cretaceous (ca. 80 Ma) with the İzmir‐Ankara ocean subducting north under the Pontides from the Late Triassic (ca. 210 Ma) to the Late Cretaceous (ca. 80 Ma). The Black Sea opened as a back‐arc basin in the Late Cretaceous separating the Pontides from the mainland Eurasia. The final closure of the İzmir‐Ankara ocean started in the Late Cretaceous (ca. 80 Ma) and finished in the Paleocene (ca. 60 Ma), when the zone of collision became a land area. Late Triassic, Jurassic, and Late Cretaceous oceanic subduction‐accretion complexes exist along the Izmir‐Ankara sutureThe İzmir‐Ankara ocean has affinity to the wide eastern Tethyan oceans rather than to the narrow and young Balkan and Alpine oceansLower Eocene red beds and regional stratigraphy indicate that the hard continental collision took place in the Paleocene

The relationships between meteorite impact craters, flood basalt volcanism and sudden environmental perturbation on Earth have been debated extensively. We present only the second example of contemporaneous meteorite impact and flood basalt volcanism: the 17 km diameter Logoisk impact structure (Belarus) and Afro-Arabian flood volcanism. The new precise 40Ar/39Ar age of 29.71 ± 0.48 Ma for Logoisk is coincident with the acme of flood volcanism. We argue that at least one crater the size of Logoisk is likely to form during the emplacement of a flood volcanic province, and that contemporaneity of impacts and flood volcanism was the norm. The absence of a biotic effect from the combined Logoisk-Afro-Arabian volcanism we attribute to the magnitude of these combined events, which are both significantly smaller than the other known example of the Chicxulub impact event and the Deccan Traps flood volcanism. [ABSTRACT FROM AUTHOR]

Infrared laserprobe 40Ar/39Ar dating has been used to date pseudotachylite and host-rock minerals from a crush belt in the Lewisian basement of Scotland. It has revealed complexity in the pseudotachylite data that is attributable to the presence of refractory host-rock clasts and mineral fragments in the pseudotachylite. In conjunction with the host-rock mineral laserprobe 40Ar/39Ar data it has been possible to simplify the pseudotachylite data for the samples, and the preferred ages for these are: 980 ± 39 Ma, 999 ± 31 Ma and 1024 ± 30 Ma (2 σ). These ages are the first record of Grenville-aged brittle deformation in the Lewisian. Further, this study serves to illustrate the complexity of dating pseudotachylites, and the advantages and limitations of the IR laserprobe applied to such materials. [ABSTRACT FROM AUTHOR]