SummaryBackgroundMutations in the gene encoding the bone morphogenetic protein receptor type II (BMPR2) are the commonest genetic cause of pulmonary arterial hypertension (PAH). However, the effect of BMPR2 mutations on clinical phenotype and outcomes remains uncertain.MethodsWe analysed individual participant data of 1550 patients with idiopathic, heritable, and anorexigen-associated PAH from eight cohorts that had been systematically tested for BMPR2 mutations. The primary outcome was the composite of death or lung transplantation. All-cause mortality was the secondary outcome. Hazard ratios (HRs) for death or transplantation and all-cause mortality associated with the presence of BMPR2 mutation were calculated using Cox proportional hazards models stratified by cohort.FindingsOverall, 448 (29%) of 1550 patients had a BMPR2 mutation. Mutation carriers were younger at diagnosis (mean age 35·4 [SD 14·8] vs 42·0 [17·8] years), had a higher mean pulmonary artery pressure (60·5 [13·8] vs 56·4 [15·3] mm Hg) and pulmonary vascular resistance (16·6 [8·3] vs 12·9 [8·3] Wood units), and lower cardiac index (2·11 [0·69] vs 2·51 [0·92] L/min per m2; all p<0·0001). Patients with BMPR2 mutations were less likely to respond to acute vasodilator testing (3% [10 of 380] vs 16% [147 of 907]; p<0·0001). Among the 1164 individuals with available survival data, age-adjusted and sex-adjusted HRs comparing BMPR2 mutation carriers with non-carriers were 1·42 (95% CI 1·15–1·75; p=0·0011) for the composite of death or lung transplantation and 1·27 (1·00–1·60; p=0·046) for all-cause mortality. These HRs were attenuated after adjustment for potential mediators including pulmonary vascular resistance, cardiac index, and vasoreactivity. HRs for death or transplantation and all-cause mortality associated with BMPR2 mutation were similar in men and women, but higher in patients with a younger age at diagnosis (p=0·0030 for death or transplantation, p=0·011 for all-cause mortality).InterpretationPatients with PAH and BMPR2 mutations present at a younger age with more severe disease, and are at increased risk of death, and death or transplantation, compared with those without BMPR2 mutations.FundingCambridge NIHR Biomedical Research Centre, Medical Research Council, British Heart Foundation, Assistance Publique-Hôpitaux de Paris, INSERM, Université Paris-Sud, Intermountain Research and Medical Foundation, Vanderbilt University, National Center for Advancing Translational Sciences, National Institutes of Health, National Natural Science Foundation of China, and Beijing Natural Science Foundation.

BackgroundHigh-sensitivity assays can quantify cardiac troponins I and T (hs-cTnI, hs-cTnT) in individuals with no clinically manifest myocardial injury.ObjectivesThe goal of this study was to assess associations of cardiac troponin concentration with cardiovascular disease (CVD) outcomes in primary prevention studies.MethodsA search was conducted of PubMed, Web of Science, and EMBASE for prospective studies published up to September 2016, reporting on associations of cardiac troponin concentration with first-ever CVD outcomes (i.e., coronary heart disease [CHD], stroke, or the combination of both). Study-specific estimates, adjusted for conventional risk factors, were extracted by 2 independent reviewers, supplemented with de novo data from PROSPER (Pravastatin in Elderly Individuals at Risk of Vascular Disease Study), then pooled by using random effects meta-analysis.ResultsA total of 28 relevant studies were identified involving 154,052 participants. Cardiac troponin was detectable in 80.0% (hs-cTnI: 82.6%; hs-cTnT: 69.7%). In PROSPER, positive associations of log-linear shape were observed between hs-cTnT and CVD outcomes. In the meta-analysis, the relative risks comparing the top versus the bottom troponin third were 1.43 (95% confidence interval [CI]: 1.31 to 1.56) for CVD (11,763 events), 1.67 (95% CI: 1.50 to 1.86) for fatal CVD (7,775 events), 1.59 (95% CI: 1.38 to 1.83) for CHD (7,061 events), and 1.35 (95% CI: 1.23 to 1.48) for stroke (2,526 events). For fatal CVD, associations were stronger in North American studies (p = 0.010) and those measuring hs-cTnT rather than hs-cTnI (p = 0.027).ConclusionsIn the general population, high cardiac troponin concentration within the normal range is associated with increased CVD risk. This association is independent of conventional risk factors, strongest for fatal CVD, and applies to both CHD and stroke.

In this paper we compute the homotopy groups of the symplectomorphism groups of the 3-, 4-and 5-point blow-ups of the projective plane (considered as monotone symplectic Del Pezzo surfaces). Along the way, we need to compute the homotopy groups of the compactly supported symplectomorphism groups of the cotangent bundle of RP 2 and of C * × C. We also make progress in the case of the An-Milnor fibres: here we can show that the (compactly supported) Hamiltonian group is contractible and that the symplectic mapping class group embeds in the braid group on n-strands.Contents 1 1.2. New results. The aim of this paper is to add to the list of symplectic 4manifolds whose symplectomorphism group we understand (up to weak homotopy equivalence). In particular, we prove the following theorems:Theorem 3. Let D n denote the blow-up of CP 2 at n ≤ 5 points in general position and let ω denote its anticanonical Kähler form. In each case let Symp 0 (D n ) denote the group of symplectomorphisms of (D n , ω) which act trivially on H * (D n , Z).• Symp 0 (D 3 ) is weakly homotopy equivalent to T 2 , • Symp 0 (D 4 ) is weakly contractible, • Symp 0 (D 5 ) is weakly homotopy equivalent to Diff + (S 2 , 5), the group of orientation-preserving diffeomorphisms of S 2 preserving five points.The author has since learned that these results on monotone symplectic Del Pezzo surfaces have also been obtained independently by Martin Pinsonnault [Pin].Theorem 4. Let W be the A n -Milnor fibre, the affine variety given by the equationand let ω be the Kähler form on W induced from the ambient C 3 . Then the group of compactly supported symplectomorphisms of (W, ω) is weakly homotopy equivalent to its group of components. This group of components injects homomorphically into the braid group Br n of n-strands on the disc.En route to proving these theorems, we prove and use:Theorem 5. Let ω be the canonical symplectic form on the cotangent bundle of RP 2 . The group of compactly supported symplectomorphisms Symp c (T * RP 2 ) is weakly homotopy equivalent to Z.Theorem 6. Let ω be the product symplectic form on C * × C. The group of compactly supported symplectomorphisms Symp c (C * × C) is weakly contractible.1.3. Comments. Theorem 4 is not as strong as we would like: the injection is probably also a surjection. I have been unable to prove this for technical reasons. However, we can still deduce something more about the symplectic mapping class group π 0 (Symp c (W )) in the case n ≥ 4. Khovanov and Seidel demonstrated [KS01] using Fukaya categories that the braid group Br n always injects into π 0 (Symp c (W )). The composition of their injection with ours is therefore a homomorphic injection K : Br n → Br n . While the braid group is not co-Hopfian, it is known [BM06] that, when n ≥ 4, all such injections are of the formwhere σ i are the usual generators, h is a homeomorphism of the marked disc, z ∈ Z(Br n ) is a full-twist and ℓ ∈ Z. In particular, we know that the subgroup K(Br n ) is of finite index and that all intermediate subgroups between K(...

National Health Service Blood and Transplant and National Institute for Health Research. (PROSPERO: CRD42017072284).

A series of Cr complexes varying in oxidation state, ligand and geometry were studied with Cr K-edge XANES. The main absorption edge energy shift for an oxidation state change from Cr 0 to Cr 6+ is found to be similar to that for a series of Cr 3+ complexes with different ligands. Theoretical XANES and density of states calculations using FEFF8.0 provided detailed insights in the origin of the XANES features for the series of distorted octahedral CrCl 3 L complexes. The geometry of the CrCl 3 L complex governs the position of the main absorption edge. Hard versus soft donor effects are overruled by the chlorine ligand for complexes with a facial geometry, whereas the chlorine ligand does not play a significant role in meridional geometry. The combined results call for a redefinition of generally used concepts like oxidation state.

We study Lagrangian embeddings of a class of two-dimensional cell complexes Lp,q into the complex projective plane. These cell complexes, which we call pinwheels, arise naturally in algebraic geometry as vanishing cycles for quotient singularities of type 1 p 2 (pq − 1, 1) (Wahl singularities). We show that if a pinwheel admits a Lagrangian embedding into CP 2 then p is a Markov number and we completely characterise q. We also show that a collection of Lagrangian pinwheels Lp i ,q i , i = 1, . . . , N , cannot be made disjoint unless N ≤ 3 and the pi form part of a Markov triple. These results are the symplectic analogue of a theorem of Hacking and Prokhorov, which classifies complex surfaces with quotient singularities admitting a Q-Gorenstein smoothing whose general fibre is CP 2 . Theorem 1.2. Let N be a positive integer and B p i ,q i ⊂ CP 2 , i = 1, . . . , N , be a collection of symplectic embeddings having pairwise disjoint images. Equivalently, let L p i ,q i ⊂ CP 2 be a collection of pairwise disjoint Lagrangian pinwheels. Then N ≤ 3 (Corollary 4.19). Moreover:A. (Theorem 4.15) If N = 1 then p 1 belongs to a Markov triple (p 1 , b, c). Moreover, q 1 = ±3b/c mod p 1 .B. (Theorem 4.16) If N = 2 then p 1 and p 2 belong to a Markov triple (p 1 , p 2 , c). Moreover, q 1 = ±3p 2 /c mod p 1 and q 2 = ±3p 1 /c mod p 2 .C. (Theorem 4.18k is a permutation of 1, 2, 3. Corollary 1.3. We have the following consequences for Lagrangian embeddings. A. If p is not a Markov number, or if p is Markov but q = ±3b/c for any b, c < p with p 2 + b 2 + c 2 = 3pbc, then there is no Lagrangian embedding of L p,q into CP 2 . In particular, if q 2 = −9 mod p then there is no Lagrangian embedding of L p,q into CP 2 . B. If p and p ′ are Markov numbers but do not form part of a Markov triple, and L p,q and L p ′ ,q ′ are Lagrangian pinwheels in CP 2 then they cannot be disjoined from one another by a Hamiltonian isotopy.Proof. This is immediate from Theorem 1.2 A and B. The only nontrivial observation is that if q = ±3b/c for some Markov triple (p, b, c) then q 2 = −9 mod p [4, Chapter I.3, Equation (6)].Remark 1.6. The sign ambiguity in q i = ±3p j /p k mod p i is not really an ambiguity at all, as B p,q and B p,p−q are symplectomorphic; see Remark 2.8.Remark 1.7. The equivalence of the statements about Lagrangian pinwheels and symplectic rational homology balls follows from a neighbourhood theorem due to Khodorovskiy, see Section 2.1 below.Remark 1.8. The exotic monotone Lagrangian tori discovered by Vianna [23,24] are also in bijection with Markov triples; they are constructed by taking the barycentric torus in a toric weighted projective plane CP(p 2 1 , p 2 2 , p 2 3 ) and transporting it to a nearby smooth fibre in the Q-Gorenstein degeneration (as such, they are disjoint from the pinwheel vanishing cycles). Indeed, the neck-stretching arguments used to constrain the superpotential in Vianna's paper [24] were important inspiration for the current paper.Remark 1.9. It would be interesting to investigate this relationship furth...

The Tonian-Cryogenian System boundary is to be defined at a GSSP (Global Boundary Stratigraphic Section and Point) beneath the first evidence of widespread glaciation. A candidate lies within the Dalradian Supergroup of Scotland and Ireland, which is least deformed and metamorphosed in Argyll, western Scotland. We present new stratigraphic profiles and interpretations from the Isle of Islay and the Garvellach Islands, update the chemostratigraphy of the Appin Group Tonian carbonates underlying the thick (ca. 1 km) glacigenic Port Askaig Formation (PAF) and demonstrate an environmental transition at the contact.The Appin Group forms a regionally extensive, >4 km-thick, succession of limestones, shales and sandstones deposited on a marine shelf. On Islay, the upper part of the lithostratigraphy has been clarified by measuring and correlating two sections containing distinctive stratigraphic levels including molar tooth structure, oolite, stromatolitic dolomite and intraclastic microbial mounds. Significantly deeper erosion at the unconformity at the base of the overlying PAF is demonstrated in the southern section. Carbonate facies show a gradual decline in δ 13 C VPDB from +5 to +2‰ upwards.In NE Garbh Eileach (Garvellach Islands), a continuously exposed section of Appin Group carbonates, 70 m thick, here designated the Garbh Eileach Formation (GEF), lies conformably beneath the PAF. The GEF and the GEF-PAF boundary relationships are re-described with new sedimentological logs, petrological and stable isotope data. Interstratified limestone and dolomicrosparite with δ 13 C of -4 to -7 ‰ (a feature named the Garvellach anomaly, replacing the term Islay anomaly) are overlain by dolomite in which the isotope signature becomes weakly positive (up to +1 ‰) upwards. Shallow subtidal conditions become peritidal upwards, with evidence of wave and storm activity. Gypsum pseudomorphs and subaerial exposure surfaces are common near the top of the GEF. The basal diamictite (D1) of the PAF is rich in carbonate clasts similar to slightly deeper-water parts of the underlying succession. D1 is typically several metres thick with interstratified sandstone and conglomerate, but dies out laterally. Scattered siliciclastic coarse sandstone to pebble conglomerate with dropstones associated with soft-sediment deformation is interbedded with carbonate below and above D1. Dolomite beds with derived intraclasts and gypsum pseudomorphs are found above D1 (or equivalent position, where D1 is absent).Published and new Sr isotope studies, including successive leach data, demonstrate primary Tonian 87 Sr/ 86 Sr values of 0.7066-0.7069 on Islay, decreasing to 0.7064-0.7066 in the younger GEF limestones on the Garvellachs, with 1700-2700 ppm Sr. Other typically Tonian characteristics of the carbonates are the Sr-rich nature of limestones, molar tooth structure, and dolomitized peritidal facies with evidence of aridity. Seabed surveys suggesting uniformly-dipping strata and shallow borehole core material illustrate the potential for extending the...

We study holomorphic discs with boundary on a Lagrangian submanifold L in a Kähler manifold admitting a Hamiltonian action of a group K which has L as an orbit. We prove various transversality and classification results for such discs which we then apply to the case of a particular Lagrangian in CP 3 first noticed by Chiang [13]. We prove that this Lagrangian has non-vanishing Floer cohomology if and only if the coefficient ring has characteristic 5, in which case it generates the split-closed derived Fukaya category as a triangulated category.Mathematics Subject Classification (2010). 53D12, 53D37, 53D40.The results above imply immediately that: Corollary B. The Chiang Lagrangian is not displaceable from itself or from the Clifford torus via Hamiltonian isotopies. Remark 1.2.5. Note that L ∆ and RP 3 intersect along a pair of circles in their standard positions and it is an interesting open question if they can be displaced from one another. Standard techniques in Floer theory cannot answer this question because HF (L ∆ , RP 3 ) is not well-defined: Floer cohomology can only be defined for Lagrangians with the same m 0 -value and m 0 (RP 3 ) = 0 as RP 3 has minimal Maslov 4.