Deeply subducted continental fragments - Part 2: Insight from petrochronology in the central Sesia Zone (western Italian Alps)

Subducted continental terranes commonly comprise an assembly of subunits that reflect the different tectono-metamorphic histories they experienced in the subduction zone. Our challenge is to unravel how, when, and in which part of the subduction zone these subunits were juxtaposed. Petrochronology offers powerful tools to decipher pressure–temperature–time (P–T–t) histories of metamorphic rocks that preserve a record of several stages of transformation. A major issue is that the driving forces for re-equilibration at high pressure are not well understood. For example, continental granulite terrains subducted to mantle depths frequently show only partial and localized eclogitization. The Sesia Zone (NW Italy) is exceptional because it comprises several continental subunits in which eclogitic rocks predominate and high-pressure (HP) assemblages almost completely replaced the Permian granulite protoliths. This field-based study comprises both main complexes of the Sesia terrane, covering some of the recently recognized tectonic subunits involved in its assembly; hence our data constrain the HP tectonics that formed the Sesia Zone. We used a petrochronological approach consisting of petrographic and microstructural analysis linked with thermodynamic modelling and U–Th–Pb age dating to reconstruct the P–T–t trajectories of these tectonic subunits. Our study documents when and under what conditions re-equilibration took place. Results constrain the main stages of mineral growth and deformation, associated with fluid influx that occurred in the subduction channel. In the Internal Complex (IC), pulses of fluid percolated at eclogite facies conditions between 77 and 55 Ma with the HP conditions reaching  ∼  2 GPa and 600–670 °C. By contrast, the External Complex (EC) records a lower pressure peak of  ∼  0.8 GPa for 500 °C at  ∼  63 Ma. The juxtaposition of the two complexes occurred during exhumation, probably at  ∼  0.8 GPa and 350 °C; the timing is constrained between 46 and 38 Ma. Mean vertical exhumation velocities are constrained between 0.9 and 5.1 mm year−1 for the IC, up to its juxtaposition with the EC. Exhumation to the surface occurred before 32 Ma, as constrained by the overlying Biella Volcanic Suite, at a mean vertical velocity between 1.6 and 4 mm year−1. These findings constrain the processes responsible for the assembly and exhumation of HP continental subunits, thus adding to our understanding of how continental terranes behave during subduction

Towards a population synthesis of discs and planets. II. Confronting disc models and observations at the population level

Aims. We want to find the distribution of initial conditions that best reproduces disc observations at the population level. Methods. We first ran a parameter study using a 1D model that includes the viscous evolution of a gas disc, dust, and pebbles, coupled with an emission model to compute the millimetre flux observable with ALMA. This was used to train a machine learning surrogate model that can compute the relevant quantity for comparison with observations in seconds. This surrogate model was used to perform parameter studies and synthetic disc populations. Results. Performing a parameter study, we find that internal photoevaporation leads to a lower dependency of disc lifetime on stellar mass than external photoevaporation. This dependence should be investigated in the future. Performing population synthesis, we find that under the combined losses of internal and external photoevaporation, discs are too short lived. Conclusions. To match observational constraints, future models of disc evolution need to include one or a combination of the following processes: infall of material to replenish the discs, shielding of the disc from internal photoevaporation due to magnetically driven disc winds, and extinction of external high-energy radiation. Nevertheless, disc properties in low-external-photoevaporation regions can be reproduced by having more massive and compact discs. Here, the optimum values of the $\alpha$ viscosity parameter lie between $3\times10^{-4}$ and $10^{-3}$ and with internal photoevaporation being the main mode of disc dispersal.Comment: Accepted for publication in A&A; minor changes in the reference lis

Pervasive Eclogitization Due to Brittle Deformation and Rehydration of Subducted Basement: Effects on Continental Recycling?

The buoyancy of continental crust opposes its subduction to mantle depths, except where mineral reactions substantially increase rock density. Sluggish kinetics limit such densification, especially in dry rocks, unless deformation and hydrous fluids intervene. Here we document how hydrous fluids in the subduction channel invaded lower crustal granulites at 50–60 km depth through a dense network of probably seismically induced fractures. We combine analyses of textures and mineral composition with thermodynamic modeling to reconstruct repeated stages of interaction, with pulses of high‐pressure (HP) fluid at 650–670°C, rehydrating the initially dry rocks to micaschists. SIMS oxygen isotopic data of quartz indicate fluids of crustal composition. HP growth rims in allanite and zircon show uniform U‐Th‐Pb ages of ∼65 Ma and indicate that hydration occurred during subduction, at eclogite facies conditions. Based on this case study in the Sesia Zone (Western Italian Alps), we conclude that continental crust, and in particular deep basement fragments, during subduction can behave as substantial fluid sinks, not sources. Density modeling indicates a bifurcation in continental recycling: Chiefly mafic crust, once it is eclogitized to >60%, are prone to end up in a subduction graveyard, such as is tomographically evident beneath the Alps at ∼550 km depth. By contrast, dominantly felsic HP fragments and mafic granulites remain positively buoyant and tend be incorporated into an orogen and be exhumed with it. Felsic and intermediate lithotypes remain positively buoyant even where deformation and fluid percolation allowed them to equilibrate at HP

Conceptual Art

Providing a re-examination of what Osborne identifies as a major turning point in contemporary art, this monograph takes a chronological and stylistic look at conceptual art from its “pre-history” (1950-1960) to contemporary practices that use conceptual strategies. Osborne surveys the development of the movement in relation to the social, cultural and political contexts within which it evolved. With extended captions, key works are compiled according to ten themes that also serve to present a collection of critical texts, artists’ statements, interviews and commentaries. Includes biographical notes on artists (6 p.) and authors (2 p.), a bibliography (2 p.) and an onomastic index (4 p.) Circa 150 bibl. ref

Biallelic loss-of-function variants in PLD1 cause congenital right-sided cardiac valve defects and neonatal cardiomyopathy

Congenital heart disease is the most common type of birth defect, accounting for one-third of all congenital anomalies. Using whole-exome sequencing of 2718 patients with congenital heart disease and a search in GeneMatcher, we identified 30 patients from 21 unrelated families of different ancestries with biallelic phospholipase D1 (PLD1) variants who presented predominantly with congenital cardiac valve defects. We also associated recessive PLD1 variants with isolated neonatal cardiomyopathy. Furthermore, we established that p.I668F is a founder variant among Ashkenazi Jews (allele frequency of ~2%) and describe the phenotypic spectrum of PLD1-associated congenital heart defects. PLD1 missense variants were overrepresented in regions of the protein critical for catalytic activity, and, correspondingly, we observed a strong reduction in enzymatic activity for most of the mutant proteins in an enzymatic assay. Finally, we demonstrate that PLD1 inhibition decreased endothelial-mesenchymal transition, an established pivotal early step in valvulogenesis. In conclusion, our study provides a more detailed understanding of disease mechanisms and phenotypic expression associated with PLD1 loss of function

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2):a multicentre observational cohort study

Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation: In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding: The Stroke Association and the British Heart Foundation

Genetic mechanisms of critical illness in COVID-19.

Host-mediated lung inflammation is present1, and drives mortality2, in the critical illness caused by coronavirus disease 2019 (COVID-19). Host genetic variants associated with critical illness may identify mechanistic targets for therapeutic development3. Here we report the results of the GenOMICC (Genetics Of Mortality In Critical Care) genome-wide association study in 2,244 critically ill patients with COVID-19 from 208 UK intensive care units. We have identified and replicated the following new genome-wide significant associations: on chromosome 12q24.13 (rs10735079, P = 1.65 × 10-8) in a gene cluster that encodes antiviral restriction enzyme activators (OAS1, OAS2 and OAS3); on chromosome 19p13.2 (rs74956615, P = 2.3 × 10-8) near the gene that encodes tyrosine kinase 2 (TYK2); on chromosome 19p13.3 (rs2109069, P = 3.98 ×  10-12) within the gene that encodes dipeptidyl peptidase 9 (DPP9); and on chromosome 21q22.1 (rs2236757, P = 4.99 × 10-8) in the interferon receptor gene IFNAR2. We identified potential targets for repurposing of licensed medications: using Mendelian randomization, we found evidence that low expression of IFNAR2, or high expression of TYK2, are associated with life-threatening disease; and transcriptome-wide association in lung tissue revealed that high expression of the monocyte-macrophage chemotactic receptor CCR2 is associated with severe COVID-19. Our results identify robust genetic signals relating to key host antiviral defence mechanisms and mediators of inflammatory organ damage in COVID-19. Both mechanisms may be amenable to targeted treatment with existing drugs. However, large-scale randomized clinical trials will be essential before any change to clinical practice

Neurofilament light levels predict clinical progression and death in multiple system atrophy

Disease-modifying treatments are currently being trialed in multiple system atrophy (MSA). Approaches based solely on clinical measures are challenged by heterogeneity of phenotype and pathogenic complexity. Neurofilament light chain protein has been explored as a reliable biomarker in several neurodegenerative disorders but data in multiple system atrophy have been limited. Therefore, neurofilament light chain is not yet routinely used as an outcome measure in MSA. We aimed to comprehensively investigate the role and dynamics of neurofilament light chain in multiple system atrophy combined with cross-sectional and longitudinal clinical and imaging scales and for subject trial selection. In this cohort study we recruited cross-sectional and longitudinal cases in multicentre European set-up. Plasma and cerebrospinal fluid neurofilament light chain concentrations were measured at baseline from 212 multiple system atrophy cases, annually for a mean period of 2 years in 44 multiple system atrophy patients in conjunction with clinical, neuropsychological and MRI brain assessments. Baseline neurofilament light chain characteristics were compared between groups. Cox regression was used to assess survival; ROC analysis to assess the ability of neurofilament light chain to distinguish between multiple system atrophy patients and healthy controls. Multivariate linear mixed effects models were used to analyse longitudinal neurofilament light chain changes and correlated with clinical and imaging parameters. Polynomial models were used to determine the differential trajectories of neurofilament light chain in multiple system atrophy. We estimated sample sizes for trials aiming to decrease NfL levels. We show that in multiple system atrophy, baseline plasma neurofilament light chain levels were better predictors of clinical progression, survival, and degree of brain atrophy than the NfL rate of change. Comparative analysis of multiple system atrophy progression over the course of disease, using plasma neurofilament light chain and clinical rating scales, indicated that neurofilament light chain levels rise as the motor symptoms progress, followed by deceleration in advanced stages. Sample size prediction suggested that significantly lower trial participant numbers would be needed to demonstrate treatment effects when incorporating plasma neurofilament light chain values into multiple system atrophy clinical trials in comparison to clinical measures alone. In conclusion, neurofilament light chain correlates with clinical disease severity, progression, and prognosis in multiple system atrophy. Combined with clinical and imaging analysis, neurofilament light chain can inform patient stratification and serve as a reliable biomarker of treatment response in future multiple system atrophy trials of putative disease-modifying agents.European Union’s Horizon 2020 research and innovation programm

Cerebral microbleeds and intracranial haemorrhage risk in patients anticoagulated for atrial fibrillation after acute ischaemic stroke or transient ischaemic attack (CROMIS-2): a multicentre observational cohort study

Summary Background: Cerebral microbleeds are a potential neuroimaging biomarker of cerebral small vessel diseases that are prone to intracranial bleeding. We aimed to determine whether presence of cerebral microbleeds can identify patients at high risk of symptomatic intracranial haemorrhage when anticoagulated for atrial fibrillation after recent ischaemic stroke or transient ischaemic attack. Methods: Our observational, multicentre, prospective inception cohort study recruited adults aged 18 years or older from 79 hospitals in the UK and one in the Netherlands with atrial fibrillation and recent acute ischaemic stroke or transient ischaemic attack, treated with a vitamin K antagonist or direct oral anticoagulant, and followed up for 24 months using general practitioner and patient postal questionnaires, telephone interviews, hospital visits, and National Health Service digital data on hospital admissions or death. We excluded patients if they could not undergo MRI, had a definite contraindication to anticoagulation, or had previously received therapeutic anticoagulation. The primary outcome was symptomatic intracranial haemorrhage occurring at any time before the final follow-up at 24 months. The log-rank test was used to compare rates of intracranial haemorrhage between those with and without cerebral microbleeds. We developed two prediction models using Cox regression: first, including all predictors associated with intracranial haemorrhage at the 20% level in univariable analysis; and second, including cerebral microbleed presence and HAS-BLED score. We then compared these with the HAS-BLED score alone. This study is registered with ClinicalTrials.gov, number NCT02513316. Findings: Between Aug 4, 2011, and July 31, 2015, we recruited 1490 participants of whom follow-up data were available for 1447 (97%), over a mean period of 850 days (SD 373; 3366 patient-years). The symptomatic intracranial haemorrhage rate in patients with cerebral microbleeds was 9·8 per 1000 patient-years (95% CI 4·0–20·3) compared with 2·6 per 1000 patient-years (95% CI 1·1–5·4) in those without cerebral microbleeds (adjusted hazard ratio 3·67, 95% CI 1·27–10·60). Compared with the HAS-BLED score alone (C-index 0·41, 95% CI 0·29–0·53), models including cerebral microbleeds and HAS-BLED (0·66, 0·53–0·80) and cerebral microbleeds, diabetes, anticoagulant type, and HAS-BLED (0·74, 0·60–0·88) predicted symptomatic intracranial haemorrhage significantly better (difference in C-index 0·25, 95% CI 0·07–0·43, p=0·0065; and 0·33, 0·14–0·51, p=0·00059, respectively). Interpretation In patients with atrial fibrillation anticoagulated after recent ischaemic stroke or transient ischaemic attack, cerebral microbleed presence is independently associated with symptomatic intracranial haemorrhage risk and could be used to inform anticoagulation decisions. Large-scale collaborative observational cohort analyses are needed to refine and validate intracranial haemorrhage risk scores incorporating cerebral microbleeds to identify patients at risk of net harm from oral anticoagulation. Funding The Stroke Association and the British Heart Foundation