Composition and evolution of the Ancestral South Sandwich Arc: implications for the flow of deep ocean water and mantle through the Drake Passage gateway

The Ancestral South Sandwich Arc (ASSA) has a short life-span of c.20 m.y. (Early Oligocene to Middle-Upper Miocene) before slab retreat and subsequent ‘resurrection’ as the active South Sandwich Island Arc (SSIA). The ASSA is, however, significant because it straddled the eastern margin of the Drake Passage Gateway where it formed a potential barrier to deep ocean water and mantle flow from the Pacific to Atlantic. The ASSA may be divided into three parts, from north to south: the Central Scotia Sea (CSS), the Discovery segment, and the Jane segment. Published age data coupled with new geochemical data (major elements, trace elements, Hf-Nd-Sr-Pb isotopes) from the three ASSA segments place constraints on models for the evolution of the arc and hence gateway development. The CSS segment has two known periods of activity. The older, Oligocene, period produced basic-acid, mostly calc-alkaline rocks, best explained in terms of subduction initiation volcanism of Andean-type (no slab rollback). The younger, Middle-Late Miocene period produced basic-acid, high-K calc-alkaline rocks (lavas and pyroclastic rocks with abundant volcanigenic sediments) which, despite being erupted on oceanic crust, have continental arc characteristics best explained in terms of a large, hot subduction flux most typical of a syn- or post-collision arc setting. Early-Middle Miocene volcanism in the Discovery and Jane arc segments is geochemically quite different, being typically tholeiitic and compositionally similar to many lavas from the active South Sandwich island arc front. There is indirect evidence for Western Pacific-type (slab rollback) subduction initiation in the southern part of the ASSA and for the back-arc basins (the Jane and Scan Basins) to have been active at the time of arc volcanism. Models for the death of the ASSA in the south following a series of ridge-trench collisions, are not positively supported by any geochemical evidence of hot subduction, but cessation of subduction by approach of progressively more buoyant oceanic lithosphere is consistent with both geochemistry and geodynamics. In terms of deep ocean water flow the early stages of spreading at the East Scotia Ridge (starting at 17-15 Ma) may have been important in breaking up the ASSA barrier while the subsequent establishment of a STEP (Subduction-Transform Edge Propagator) fault east of the South Georgia microcontinent (< 11 Ma) led to formation of the South Georgia Passage used by the Antarctic Circumpolar Current today. In terms of mantle flow, the subduction zone and arc root likely acted as a barrier to mantle flow in the CSS arc segment such that the ASSA itself became the Pacific-South Atlantic mantle domain boundary. This was not the case in the Discovery and Jane arc segments, however, because northwards flow of South Atlantic mantle behind the southern part of the ASSA gave an Atlantic provenance to the whole southern ASSA

Fine-mapping of prostate cancer susceptibility loci in a large meta-analysis identifies candidate causal variants

Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Prostate cancer is a polygenic disease with a large heritable component. A number of common, low-penetrance prostate cancer risk loci have been identified through GWAS. Here we apply the Bayesian multivariate variable selection algorithm JAM to fine-map 84 prostate cancer susceptibility loci, using summary data from a large European ancestry meta-analysis. We observe evidence for multiple independent signals at 12 regions and 99 risk signals overall. Only 15 original GWAS tag SNPs remain among the catalogue of candidate variants identified; the remainder are replaced by more likely candidates. Biological annotation of our credible set of variants indicates significant enrichment within promoter and enhancer elements, and transcription factor-binding sites, including AR, ERG and FOXA1. In 40 regions at least one variant is colocalised with an eQTL in prostate cancer tissue. The refined set of candidate variants substantially increase the proportion of familial relative risk explained by these known susceptibility regions, which highlights the importance of fine-mapping studies and has implications for clinical risk profiling. © 2018 The Author(s).Peer reviewe

The Influence of Age and Sex on Genetic Associations with Adult Body Size and Shape : A Large-Scale Genome-Wide Interaction Study

Genome-wide association studies (GWAS) have identified more than 100 genetic variants contributing to BMI, a measure of body size, or waist-to-hip ratio (adjusted for BMI, WHRadjBMI), a measure of body shape. Body size and shape change as people grow older and these changes differ substantially between men and women. To systematically screen for age-and/or sex-specific effects of genetic variants on BMI and WHRadjBMI, we performed meta-analyses of 114 studies (up to 320,485 individuals of European descent) with genome-wide chip and/or Metabochip data by the Genetic Investigation of Anthropometric Traits (GIANT) Consortium. Each study tested the association of up to similar to 2.8M SNPs with BMI and WHRadjBMI in four strata (men 50y, women 50y) and summary statistics were combined in stratum-specific meta-analyses. We then screened for variants that showed age-specific effects (G x AGE), sex-specific effects (G x SEX) or age-specific effects that differed between men and women (G x AGE x SEX). For BMI, we identified 15 loci (11 previously established for main effects, four novel) that showed significant (FDR= 50y). No sex-dependent effects were identified for BMI. For WHRadjBMI, we identified 44 loci (27 previously established for main effects, 17 novel) with sex-specific effects, of which 28 showed larger effects in women than in men, five showed larger effects in men than in women, and 11 showed opposite effects between sexes. No age-dependent effects were identified for WHRadjBMI. This is the first genome-wide interaction meta-analysis to report convincing evidence of age-dependent genetic effects on BMI. In addition, we confirm the sex-specificity of genetic effects on WHRadjBMI. These results may providefurther insights into the biology that underlies weight change with age or the sexually dimorphism of body shape.Peer reviewe

Novel Loci for Adiponectin Levels and Their Influence on Type 2 Diabetes and Metabolic Traits : A Multi-Ethnic Meta-Analysis of 45,891 Individuals

J. Kaprio, S. Ripatti ja M.-L. Lokki työryhmien jäseniä.Peer reviewe

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p&lt;0·0001) and independently associated with COVID-19 status (odds ratio [OR] 2·9 [95% CI 1·5–5·8]; padjusted=0·0023) after adjusting for relevant confounders. Compared with controls, patients were more likely to have MRI evidence of lung abnormalities (p=0·0001; parenchymal abnormalities), brain abnormalities (p&lt;0·0001; more white matter hyperintensities and regional brain volume reduction), and kidney abnormalities (p=0·014; lower medullary T1 and loss of corticomedullary differentiation), whereas cardiac and liver MRI abnormalities were similar between patients and controls. Patients with multiorgan abnormalities were older (difference in mean age 7 years [95% CI 4–10]; mean age of 59·8 years [SD 11·7] with multiorgan abnormalities vs mean age of 52·8 years [11·9] without multiorgan abnormalities; p&lt;0·0001), more likely to have three or more comorbidities (OR 2·47 [1·32–4·82]; padjusted=0·0059), and more likely to have a more severe acute infection (acute CRP &gt;5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification

Multiorgan MRI findings after hospitalisation with COVID-19 in the UK (C-MORE): a prospective, multicentre, observational cohort study

Introduction: The multiorgan impact of moderate to severe coronavirus infections in the post-acute phase is still poorly understood. We aimed to evaluate the excess burden of multiorgan abnormalities after hospitalisation with COVID-19, evaluate their determinants, and explore associations with patient-related outcome measures. Methods: In a prospective, UK-wide, multicentre MRI follow-up study (C-MORE), adults (aged ≥18 years) discharged from hospital following COVID-19 who were included in Tier 2 of the Post-hospitalisation COVID-19 study (PHOSP-COVID) and contemporary controls with no evidence of previous COVID-19 (SARS-CoV-2 nucleocapsid antibody negative) underwent multiorgan MRI (lungs, heart, brain, liver, and kidneys) with quantitative and qualitative assessment of images and clinical adjudication when relevant. Individuals with end-stage renal failure or contraindications to MRI were excluded. Participants also underwent detailed recording of symptoms, and physiological and biochemical tests. The primary outcome was the excess burden of multiorgan abnormalities (two or more organs) relative to controls, with further adjustments for potential confounders. The C-MORE study is ongoing and is registered with ClinicalTrials.gov, NCT04510025. Findings: Of 2710 participants in Tier 2 of PHOSP-COVID, 531 were recruited across 13 UK-wide C-MORE sites. After exclusions, 259 C-MORE patients (mean age 57 years [SD 12]; 158 [61%] male and 101 [39%] female) who were discharged from hospital with PCR-confirmed or clinically diagnosed COVID-19 between March 1, 2020, and Nov 1, 2021, and 52 non-COVID-19 controls from the community (mean age 49 years [SD 14]; 30 [58%] male and 22 [42%] female) were included in the analysis. Patients were assessed at a median of 5·0 months (IQR 4·2–6·3) after hospital discharge. Compared with non-COVID-19 controls, patients were older, living with more obesity, and had more comorbidities. Multiorgan abnormalities on MRI were more frequent in patients than in controls (157 [61%] of 259 vs 14 [27%] of 52; p5mg/L, OR 3·55 [1·23–11·88]; padjusted=0·025) than those without multiorgan abnormalities. Presence of lung MRI abnormalities was associated with a two-fold higher risk of chest tightness, and multiorgan MRI abnormalities were associated with severe and very severe persistent physical and mental health impairment (PHOSP-COVID symptom clusters) after hospitalisation. Interpretation: After hospitalisation for COVID-19, people are at risk of multiorgan abnormalities in the medium term. Our findings emphasise the need for proactive multidisciplinary care pathways, with the potential for imaging to guide surveillance frequency and therapeutic stratification. Funding: UK Research and Innovation and National Institute for Health Research

Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease

One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood1. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials

Geochemistry and petrogenesis of Cretaceous oceanic plateau lavas in eastern Jamaica

Basaltic lavas of Turonian to Coniacian age belonging to the Bath–Dunrobin Formation occur with intercalated island arc tuffs in the south of the Blue Mountain inlier, have been interpreted as being derived from the Caribbean oceanic plateau. This study presents new major and trace element and Sr–Pb–Nd–Hf isotopic data for these igneous rocks. The Jamaican rocks are altered by tropical weathering, hydrothermal and metamorphic processes, which have mobilised many of their elements (e.g. K and Ba). Consequently, the basalts and dacitic tuffs have been classified by using immobile trace elements. The trace element and Hf(i)–Nd(i) geochemistry suggests that the basaltic lavas are derived from a chemically similar source region by variable degrees of partial melting. The Caribbean plateau basalts lie on a mixing line between a depleted plume component and HIMU in Nd–Hf isotopic space. The Pb isotope data also demonstrate that the Jamaican plateau lavas are composed of a larger HIMU component than the other plateau lavas within the Caribbean region. The intercalated island arc tuffs are the first to be found in any oceanic plateau succession in the Caribbean and imply that the Caribbean oceanic plateau at 90 Ma was relatively close to the subduction zone along South America and the Great Arc of the Antilles

Geochemistry of compositionally distinct Late Cretaceous back-arc basin lavas: implications for the tectonomagmatic evolution of the Caribbean plate

The Cretaceous Blue Mountain Inlier of eastern Jamaica contains the Bellevue lavas, which represent a Mid- to Late Campanian back-arc basin succession of tholeiitic volcanic rocks. The lavas are composed of basic/intermediate and intermediate/acidic subgroups that can be related by intraformation fractional crystallization. Trace element and Hf radiogenic isotope data reveal that the mantle component of the Bellevue magmas is consistent with derivation from a mantle plume (oceanic plateau) source region. Modeling indicates that the magmas formed by 10%–20% partial melting of an oceanic plateau mantle source comprising spinel peridotite that had previously undergone approximately 5%–7.5% prior melt extraction in the garnet stability field. Trace element and radiogenic isotope systematics suggest that the Bellevue mantle source region was contaminated with a slab-derived component from both the altered basaltic slab and its pelagic sedimentary veneer. The data from the Bellevue lavas support the plateau reversal model of Caribbean tectonic evolution, whereby subduction on the Great Arc of the Caribbean was to the northeast until the Caribbean oceanic plateau collided with the southern portion of the Great Arc in the Santonian (85.8–83.5 Ma), resulting in subduction polarity reversal and thus southwest-dipping subduction. This polarity reversal allowed oceanic plateau source regions to be melted beneath a new back-arc basin to the southwest of the Great Arc