Magnetic resonance imaging plaque hemorrhage for risk stratification in carotid artery disease with moderate risk under current medical therapy

Background and Purpose—Magnetic resonance imaging (MRI)–defined carotid plaque hemorrhage (MRIPH) can predict recurrent cerebrovascular ischemic events in severe symptomatic carotid stenosis. It is less clear whether MRIPH can improve risk stratification despite optimized medical secondary prevention in those with moderate risk. Methods—One-hundred fifty-one symptomatic patients with 30% to 99% carotid artery stenosis (median age: 77, 60.5% men) clinically deemed to not benefit from endarterectomy were prospectively recruited to undergo MRI and clinical follow-up (mean, 22 months). The clinical carotid artery risk score could be evaluated in 88 patients. MRIPH+ve was defined as plaque intensity >150% that of adjacent muscle. Survival analyses were performed with recurrent infarction (stroke or diffusion-positive cerebral ischemia) as the main end point. Results—Fifty-five participants showed MRIPH+ve; 47 had low, 36 intermediate, and 5 high carotid artery risk scores. Cox regression showed MRIPH as a strong predictor of future infarction (hazard ratio, 5.2; 95% confidence interval, 1.64–16.34; P=0.005, corrected for degree of stenosis), also in the subgroup with 50% to 69% stenosis (hazard ratio, 4.1; 95% confidence interval, 1–16.8; P=0.049). The absolute risk of future infarction was 31.7% at 3 years in MRIPH+ve versus 1.8% in patients without (P<0.002). MRIPH increased cumulative risk difference of future infarction by 47.1% at 3 years in those with intermediate carotid artery risk score (P=0.004). Conclusions—The study confirms MRIPH to be a powerful risk marker in symptomatic carotid stenosis with added value over current risk scores. For patients undergoing current secondary prevention medication with clinically uncertain benefit from recanalization, that is, those with moderate degree stenosis and intermediate carotid artery risk scores, MRIPH offers additional risk stratification

Refined histopathological predictors of BRCA1 and BRCA2 mutation status: A large-scale analysis of breast cancer characteristics from the BCAC, CIMBA, and ENIGMA consortia

Introduction: The distribution of histopathological features of invasive breast tumors in BRCA1 or BRCA2 germline mutation carriers differs from that of individuals with no known mutation. Histopathological features thus have utility for mutation prediction, including statistical modeling to assess pathogenicity of BRCA1 or BRCA2 variants of uncertain clinical significance. We analyzed large pathology datasets accrued by the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA) and the Breast Cancer Association Consortium (BCAC) to reassess histopathological predictors of BRCA1 and BRCA2 mutation status, and provide robust likelihood ratio (LR) estimates for statistical modeling. Methods: Selection criteria for study/center inclusion were estrogen receptor (ER) status or grade data available for invasive breast cancer diagnosed younger than 70 years. The dataset included 4,477 BRCA1 mutation carriers, 2,565 BRCA2 mutation carriers, and 47,565 BCAC breast cancer cases. Country-stratified estimates of the

Genome-wide association and Mendelian randomisation analysis provide insights into the pathogenesis of heart failure

Heart failure (HF) is a leading cause of morbidity and mortality worldwide. A small proportion of HF cases are attributable to monogenic cardiomyopathies and existing genome-wide association studies (GWAS) have yielded only limited insights, leaving the observed heritability of HF largely unexplained. We report results from a GWAS meta-analysis of HF comprising 47,309 cases and 930,014 controls. Twelve independent variants at 11 genomic loci are associated with HF, all of which demonstrate one or more associations with coronary artery disease (CAD), atrial fibrillation, or reduced left ventricular function, suggesting shared genetic aetiology. Functional analysis of non-CAD-associated loci implicate genes involved in cardiac development (MYOZ1, SYNPO2L), protein homoeostasis (BAG3), and cellular senescence (CDKN1A). Mendelian randomisation analysis supports causal roles for several HF risk factors, and demonstrates CAD-independent effects for atrial fibrillation, body mass index, and hypertension. These findings extend our knowledge of the pathways underlying HF and may inform new therapeutic strategies

Genome-wide association meta-analysis identifies five novel loci for age-related hearing impairment

Previous research has shown that genes play a substantial role in determining a person's susceptibility to age-related hearing impairment. The existing studies on this subject have different results, which may be caused by difficulties in determining the phenotype or the limited number of participants involved. Here, we have gathered the largest sample to date (discovery n = 9,675; replication n = 10,963; validation n = 356,141), and examined phenotypes that represented low/mid and high frequency hearing loss on the pure tone audiogram. We identified 7 loci that were either replicated and/or validated, of which 5 loci are novel in hearing. Especially the ILDR1 gene is a high profile candidate, as it contains our top SNP, is a known hearing loss gene, has been linked to age-related hearing impairment before, and in addition is preferentially expressed within hair cells of the inner ear. By verifying all previously published SNPs, we can present a paper that combines all new and existing findings to date, giving a complete overview of the genetic architecture of age-related hearing impairment. This is of importance as age-related hearing impairment is highly prevalent in our ageing society and represents a large socio-economic burden

Role of root clusters in phosphorus acquisition and increasing biological diversity in agriculture

Soils in the south-west of Western Australia and South Africa are among the most phosphorusimpoverished in the world, and at the same time both of these regions are Global Biodiversity Hotspots. This unique combination offers an excellent opportunity to study root adaptations that are significant in phosphorus (P) acquisition. A large proportion of species from these P-poor environments cannot produce an association with mycorrhizal fungi, but, instead, produce ‘root clusters’. In Western Australia, rootcluster- bearing Proteaceae occur on the most P-impoverished soils, whereas the mycorrhizal Myrtaceae tend to inhabit the less P-impoverished soils in this region. Root clusters are an adaptation both in structure and in functioning; characterized by high densities of short lateral roots that release large amounts of exudates, in particular carboxylates (anions of di- and tri-carboxylic acids). The functioning of root clusters in Proteaceae (’proteoid’ roots) and Fabaceae (‘cluster’ roots) has received considerable attention, but that of ‘dauciform’ root clusters developed by species in Cyperaceae has barely been explored. Research on the physiology of ‘capillaroid’ root clusters formed by species in Restionaceae has yet to be published. Root-cluster initiation and growth in species of the Cyperaceae, Fabaceae and Proteaceae are systemically stimulated when plants are grown at a very low P supply, and are suppressed as leaf P concentrations increase. Root clusters in Proteaceae, Fabaceae and Cyperaceae are short-lived structures, which release large amounts of carboxylates, briefly, at a particular stage of root development. The rates of carboxylate release are considerably faster than reported for non-specialized roots of a wide range of species. Root clusters play a pivotal role in mobilization of P from P-sorbing soil. Because the world P reserves are being depleted whilst vast amounts of P are stored in fertilized soils, there is a growing need for crops with a high efficiency of P acquisition. Some Australian and African native species as well as some existing crops have traits that would be highly desirable for future crops. The possibilities of introducing P-acquisition-efficient species in new cropping and pasture systems are explored. In addition, possible strategies to introduce traits associated with a high P-acquisition efficiency into future crop species are discusse

No evidence of regulation in root-mediated iron reduction in two Strategy I cluster-rooted Banksia species (Proteaceae)

Aims: Non-mycorrhizal species such as Banksia (Proteaceae) that depend on root exudates to acquire phosphorus (P) are prominent in south-western Australia, a biodiversity hotspot on severely P-impoverished soils. We investigated the consequences of an exudate-releasing P-mobilising strategy related to control of iron (Fe) acquisition in two Banksia species, B. attenuata R.Br. and B. laricina C. Gardner, that differ greatly in their geographical distribution and rarity. Methods: We undertook solution culture experiments to measure root-mediated Fe reduction (FeR) in non-cluster and cluster roots at four stages of cluster-root development, and whole root systems for plants grown at 2 to 300 μM Fe (as Fe-EDTA). As a positive control, we used Pisum sativum (cv. Dunn) to validate the FeR assay. Results: Unlike typical Strategy I species, both Banksia species showed no significant variation in FeR, for either cluster or non-cluster roots, when grown at a wide range of Fe supply. For roots of different developmental stages, we measured a range for B. attenuata cluster roots of 0.13 ± 0.03 to 1.29 ± 0.14 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹ and 0.56 ± 0.11 to 1.10 ± 0.24 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹ in non-cluster roots. Similarly, for B. laricina cluster-roots, FeR ranged from 0.22 ± 0.07 to 1.21 ± 0.37 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹, and in non-cluster roots from 0.56 ± 0.11 to 0.71 ± 0.08 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹. We also observed only minor differences for whole-root system FeR, and even though B. attenuata showed signs of leaf Fe deficiency in the 2 μM Fe treatment, its FeR was the lowest of both species across all treatments at 0.079 ± 0.009 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹, compared with the fastest rate of 0.20 ± 0.014 μmol Fe³⁺ reduced g⁻¹ FW h⁻¹ for B. laricina in the 28 μM Fe treatment. Taking plants through a pulse from low to high Fe, then back to low Fe supply did not elucidate any significant response in FeR.: Conclusions: Although Fe acquisition is tightly controlled in the investigated Banksia species, such control is not based on regulation of FeR, which challenges the model that is commonly accepted for Strategy I species.Gregory R. Cawthray, Matthew D. Denton, Michael A. Grusak, Michael W. Shane, Erik J. Veneklaas, Hans Lamber

Opportunities for improving phosphorus-use efficiency in crop plants

Limitation of grain crop productivity by phosphorus (P) is widespread and will probably increase in the future. Enhanced P efficiency can be achieved by improved uptake of phosphate from soil (P-acquisition efficiency) and by improved productivity per unit P taken up (P-use efficiency). This review focuses on improved P-use efficiency, which can be achieved by plants that have overall lower P concentrations, and by optimal distribution and redistribution of P in the plant allowing maximum growth and biomass allocation to harvestable plant parts. Significant decreases in plant P pools may be possible, for example, through reductions of superfluous ribosomal RNA and replacement of phospholipids by sulfolipids and galactolipids. Improvements in P distribution within the plant may be possible by increased remobilization from tissues that no longer need it (e.g. senescing leaves) and reduced partitioning of P to developing grains. Such changes would prolong and enhance the productive use of P in photosynthesis and have nutritional and environmental benefits. Research considering physiological, metabolic, molecular biological, genetic and phylogenetic aspects of P-use efficiency is urgently needed to allow significant progress to be made in our understanding of this complex trait