The Kaapvaal Craton, South Africa: no evidence for a supercontinental affinity prior to 2.0 Ga?

We briefly examine the possible antiquity of the supercontinental cycle while noting the likely unreliability of palaeomagnetic data >ca.1.8 Ga, assuming a gradual change from a magmatically dominated Hadean Earth to a plate tectonically dominated Neoarchaean system. A brief review of one of Earth’s oldest cratons, Kaapvaal, where accent is placed on the lithostratigraphic and geodynamic-chronological history of its cover rocks from ca. 3.1 to 2.05 Ga, forms the factual basis for this article. The ca. 3.1–2.8 Ga Witwatersrand–Pongola (Supergroups) complex retroarc flexural foreland basin developed while growth and stabilization of the craton were still underway. Accretion of relatively small composite granite-gneiss-greenstone terranes (island arc complexes) from both north and west does not support the formation of a Neoarchaean supercontinent, but may well have been related to a mantle plume which enhanced primary gold sources in the accreted terranes and possibly controlled the timing and rate of craton growth through plate convergent processes. Subsequent deformation of the Witwatersrand Basin fill with concomitant loss of ≤1.5 km of stratigraphy must have been due to far-field tectonic effects, but no known mobile belt or even greenstone belts can be related to this contractional event. At ca. 2714–2709 Ma, a large mantle plume impinged beneath the thinned crust underlying theWitwatersrand Basin forming thick, locally komatiitic flood basalts at the base of the Ventersdorp Supergroup, with subsequent thermal doming leading to graben basins within which medial bimodal volcanics and immature sediments accumulated. Finally (possibly at ca. 2.66–2.68 Ga), thermal subsidence enabled the deposition of uppermost Ventersdorp sheet-like lavas and sediments, with minor komatiites still present. Ongoing plume-related influences are thus inferred, and an analogous cause is ascribed to a ca. 2.66–2.68 Ga dike swarm to the north of the Ventersdorp, where associated rifting allowed formation of discrete ‘protobasinal’ depositories of the Transvaal (ca. 2.6–2.05 Ga Supergroup, preserved in three basins). Thin fluvial sheet sandstones (Black Reef Formation, undated) above these lowermost rift fills show an association with localized compressive deformation along the palaeo-Rand anticline, north of Johannesburg, but again with no evidence of any major terrane amalgamations with the Kaapvaal. From ca. 2642 to 2432 Ma, the craton was drowned with a long-lived epeiric marine carbonate-banded iron formation platform covering much of it and preserved in all three Transvaal Basins (TB). During this general period, at ca. 2691–2610 Ma, the Kaapvaal Craton collided with a small exotic terrane [the Central Zone (CZ), Limpopo Belt] in the north. Although farfield tectonic effects are likely implicit in TB geodynamics, again there is no case to be made for supercontinent formation. Following an 80–200 million years (?) hiatus, with localized deformation and removal of large thicknesses of chemically precipitated sediments along the palaeo-Rand anticline, the uppermost Pretoria Group of the Transvaal Supergroup was deposited. This reflects two episodes of rifting associated with volcanism, and subsequent thermal subsidence within a sag basin setting; an association of the second such event with flood basalts supports a plume affinity. At ca. 2050 Ma the Bushveld Complex intruded the northern Kaapvaal Craton and reflects a major plume, following which Kaapvaal–CZ collided with the Zimbabwe Craton, when for the first time, strong evidence exists for a small supercontinent assembly, at ca. 2.0 Ga. We postulate that the long-lived evidence in favour of active mantle (cf. plume) influences with subordinate and localized tectonic shortening, implicit within the review of ca. 3.1–2.05 Ga geological history of the Kaapvaal Craton, might reflect the influence of earlier Precambrian mantle-dominated thermal systems, at least for this craton.University of Pretoria and the National Research Foundation of South Africa.http://www.tandfonline.com/loi/tigr20nf201

Efficacy and safety of elexacaftor plus tezacaftor plus ivacaftor versus tezacaftor plus ivacaftor in people with cystic fibrosis homozygous for F508del-CFTR: a 24-week, multicentre, randomised, double-blind, active-controlled, phase 3b trial

Background Elexacaftor plus tezacaftor plus ivacaftor is a triple-combination cystic fibrosis transmembrane conductance regulator (CFTR) modulator regimen shown to be generally safe and efficacious in people with cystic fibrosis aged 12 years or older with at least one F508del-CFTR allele. We aimed to assess the magnitude and durability of the clinical effects of this triple combination regimen in people with cystic fibrosis homozygous for the F508del-CFTR mutation. Methods We conducted a multicentre, randomised, double-blind, active-controlled, phase 3b trial of elexacaftor plus tezacaftor plus ivacaftor at 35 medical centres in Australia, Belgium, Germany, and the UK. Eligible participants were those with cystic fibrosis homozygous for the F508del-CFTR mutation, aged 12 years or older with stable disease, and with a percent predicted FEV1 of 40–90% inclusive. After a 4-week run-in period, in which participants received tezacaftor 100 mg orally once daily and ivacaftor 150 mg orally every 12 h, participants were randomly assigned (1:1) to receive 24 weeks of either elexacaftor 200 mg orally once daily plus tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (elexacaftor plus tezacaftor plus ivacaftor group) or tezacaftor 100 mg orally once daily plus ivacaftor 150 mg orally every 12 h (tezacaftor plus ivacaftor group). Randomisation was stratified by percent predicted FEV1, age at screening visit, and whether the participant was receiving CFTR modulators at the time of the screening visit. Patients, investigators, and sponsor's study execution team were masked to treatment assignment. The primary endpoint was the absolute change in Cystic Fibrosis Questionnaire-Revised (CFQ-R) respiratory domain score from baseline (ie, at the end of the tezacaftor plus ivacaftor run-in period) up to and including week 24. The key secondary endpoint was the absolute change from baseline in percent predicted FEV1 up to and including week 24; other secondary endpoints were the absolute change from baseline in sweat chloride concentrations up to and including week 24, and safety and tolerability. All endpoints were assessed in all randomised patients who had received at least one dose of their assigned regimen. This study is registered with ClinicalTrials.gov, NCT04105972. Findings Between Oct 3, 2019, and July 24, 2020, 176 participants were enrolled. Following the 4-week tezacaftor plus ivacaftor run-in period, 175 participants were randomly assigned (87 to the elexacaftor plus tezacaftor plus ivacaftor group and 88 to the tezacaftor plus ivacaftor group) and dosed in the treatment period. From baseline up to and including week 24, the mean CFQ-R respiratory domain score increased by 17·1 points (95% CI 14·1 to 20·1) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·2 points (−1·7 to 4·2) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 15·9 points [95% CI 11·7 to 20·1], p<0·0001), the mean percent predicted FEV1 increased by 11·2 percentage points (95% CI 9·8 to 12·6) in the elexacaftor plus tezacaftor plus ivacaftor group and by 1·0 percentage points (−0·4 to 2·4) in the tezacaftor plus ivacaftor group (least squares mean treatment difference 10·2 percentage points [8·2 to 12·1], p<0·0001), and the mean sweat chloride concentration decreased by 46·2 mmol/L (95% CI 43·7 to 48·7) in the elexacaftor plus tezacaftor plus ivacaftor group and by 3·4 mmol/L (1·0 to 5·8) in the tezacaftor plus ivacaftor group (least squares mean treatment difference −42·8 mmol/L [–46·2 to −39·3], nominal p<0·0001). Most participants (70 [80%] in the elexacaftor plus tezacaftor plus ivacaftor group and 74 [84%] in the tezacaftor plus ivacaftor group) had adverse events that were mild or moderate in severity; serious adverse events occurred in five (6%) of 87 participants in the elexacaftor plus tezacaftor plus ivacaftor group and 14 (16%) of 88 participants in the tezacaftor plus ivacaftor group. One (1%) participant in the elexacaftor plus tezacaftor plus ivacaftor group discontinued treatment due to an adverse event of anxiety and depression. Two (2%) participants in the tezacaftor plus ivacaftor group discontinued treatment due to adverse events of psychotic disorder (n=1) and obsessive-compulsive disorder (n=1). Interpretation The elexacaftor plus tezacaftor plus ivacaftor regimen was safe and well tolerated, and led to significant and clinically meaningful improvements in respiratory-related quality of life and lung function, as well as improved CFTR function, changes that were durable over 24 weeks and superior to those seen with tezacaftor plus ivacaftor in this patient population. Funding Vertex Pharmaceuticals

Using ancestry-informative markers to identify fine structure across 15 populations of European origin

The Wellcome Trust Case Control Consortium 3 anorexia nervosa genome-wide association scan includes 2907 cases from 15 different populations of European origin genotyped on the Illumina 670K chip. We compared methods for identifying population stratification, and suggest list of markers that may help to counter this problem. It is usual to identify population structure in such studies using only common variants with minor allele frequency (MAF) &gt;5%; we find that this may result in highly informative SNPs being discarded, and suggest that instead all SNPs with MAF &gt;1% may be used. We established informative axes of variation identified via principal component analysis and highlight important features of the genetic structure of diverse European-descent populations, some studied for the first time at this scale. Finally, we investigated the substructure within each of these 15 populations and identified SNPs that help capture hidden stratification. This work can provide information regarding the designing and interpretation of association results in the International Consortia. © 2014 Macmillan Publishers Limited All rights reserved