The effects of the natural vertebrate steroid 17β-oestradiol and the xeno-biotic vertebrate oestrogen receptor agonist bisphenol-A on reproduction in selected temperate freshwater gastropods : the potential for (neuro-) endocrine disruption

Evidence of feminising effects, including additional or enlarged female organs, have been reported in the (sub)-tropical freshwater prosobranch Marisa cornuarietis exposed to vertebrate estrogen receptor agonists. The primary symptom is an increase in the number of eggs laid, but this is only observed when exposure occurs at relatively low temperatures. This research project exposed temperate freshwater prosobranchs and a pulmonate to 17β-oestradiol (10-200 ngL-l, nominal) in an outdoor mesocosm subject to natural seasons to determine whether similar effects occur in European native temperate freshwater gastropods. Laboratory exposures to 17β-oestradiol (1-100 ngL-l, nominal) and Bisphenol-A (0.2-20 ngL-l, nominal) were also carried out over a range of different temperatures and photoperiods to simulate natural seasons. In the mesocosm exposures, significant increases in reproduction were measured in Viviparus viviparus, Bithynia tentaculata and, if the mortality rate was not significantly increased, Planorbarius corneus. It was observed that increases only occurred after the onset of autumn. In the laboratory, the oviposition rate in P. corneus was constant at 20oC with a 16h photoperiod, but declined significantly at 15oC with a 12h photoperiod, except at 100 ngL-l 17β-oestradiol, when the rate remained constant. There were no similar effects from Bisphenol-A exposure. Small increases in reproduction were observed in all the prosobranch exposures to both compounds, but the interpretation of the data was confounded by several factors (test chemical degradation, high mortality rates and parasitized organisms) and there were no significant differences. In conclusion, there were indications that all of the assessed species were capable of increased reproduction, and in P. corneus this appears to be a perpetuation of summer oviposition rates in autumnal conditions. The consequences of this effect in annual semelparous pulmonates may not be detrimental at the population level, but the long-term fitness of iteroparous prosobranchs that practice ‘restrained reproduction’ in early breeding seasons may be adversely affected.EThOS - Electronic Theses Online ServiceEnvironment AgencyGBUnited Kingdo

Chemically Controllable Magnetic Transition Temperature and Magneto-Elastic Coupling in MnZnSb Compounds

International audienceMagneto-caloric materials offer the possibility to design environmentally friendlier thermal management devices compared to the widely used gas-based systems. The challenges to develop this solid-state based technology lie in the difficulty of finding materials presenting a large magneto-caloric effect over a broad temperature span together with suitable secondary appli-cation parameters such as low heat capacity and high thermal conductivity. A series of compounds derived from the PbFCl structure is investigated using a combination of computational and experimental methods focusing on the change of cell volume in magnetic and non-magnetic ground states. Scaling analysis of the magnetic properties determines that they are second order phase transition ferromagnets and that the magnetic entropy change is driven by the coupling of magneto-elastic strain in the square-net through the magnetic transition determined from neutron and synchrotron X-ray diffraction. The primary and secondary application related properties are measured experimentally, and the c/a parameter is identified as an accurate proxy to control the magnetic transition. Chemical substitution on the square-net affords tuning of the Curie temperature over a broad temperature span between 252 and 322 K. A predictive machine learning model for the c/aparameter is developed to guide future exploratory synthesis

Meta-analysis of epigenome-wide association studies in neonates reveals widespread differential DNA methylation associated with birthweight

Birthweight is associated with health outcomes across the life course, DNA methylation may be an underlying mechanism. In this meta-analysis of epigenome-wide association studies of 8,825 neonates from 24 birth cohorts in the Pregnancy And Childhood Epigenetics Consortium, we find that DNA methylation in neonatal blood is associated with birthweight at 914 sites, with a difference in birthweight ranging from -183 to 178 grams per 10% increase in methylation (P-Bonferroni <1.06 x 10(-7)). In additional analyses in 7,278 participants,Peer reviewe

Percutaneous revascularization for ischemic left ventricular dysfunction: Cost-effectiveness analysis of the REVIVED-BCIS2 trial

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently undertaken in patients with ischemic left ventricular systolic dysfunction. The REVIVED (Revascularization for Ischemic Ventricular Dysfunction)-BCIS2 (British Cardiovascular Society-2) trial concluded that PCI did not reduce the incidence of all-cause death or heart failure hospitalization; however, patients assigned to PCI reported better initial health-related quality of life than those assigned to optimal medical therapy (OMT) alone. The aim of this study was to assess the cost-effectiveness of PCI+OMT compared with OMT alone. METHODS: REVIVED-BCIS2 was a prospective, multicenter UK trial, which randomized patients with severe ischemic left ventricular systolic dysfunction to either PCI+OMT or OMT alone. Health care resource use (including planned and unplanned revascularizations, medication, device implantation, and heart failure hospitalizations) and health outcomes data (EuroQol 5-dimension 5-level questionnaire) on each patient were collected at baseline and up to 8 years post-randomization. Resource use was costed using publicly available national unit costs. Within the trial, mean total costs and quality-adjusted life-years (QALYs) were estimated from the perspective of the UK health system. Cost-effectiveness was evaluated using estimated mean costs and QALYs in both groups. Regression analysis was used to adjust for clinically relevant predictors. RESULTS: Between 2013 and 2020, 700 patients were recruited (mean age: PCI+OMT=70 years, OMT=68 years; male (%): PCI+OMT=87, OMT=88); median follow-up was 3.4 years. Over all follow-ups, patients undergoing PCI yielded similar health benefits at higher costs compared with OMT alone (PCI+OMT: 4.14 QALYs, £22 352; OMT alone: 4.16 QALYs, £15 569; difference: −0.015, £6782). For both groups, most health resource consumption occurred in the first 2 years post-randomization. Probabilistic results showed that the probability of PCI being cost-effective was 0. CONCLUSIONS: A minimal difference in total QALYs was identified between arms, and PCI+OMT was not cost-effective compared with OMT, given its additional cost. A strategy of routine PCI to treat ischemic left ventricular systolic dysfunction does not seem to be a justifiable use of health care resources in the United Kingdom

Arrhythmia and death following percutaneous revascularization in ischemic left ventricular dysfunction: Prespecified analyses from the REVIVED-BCIS2 trial

BACKGROUND: Ventricular arrhythmia is an important cause of mortality in patients with ischemic left ventricular dysfunction. Revascularization with coronary artery bypass graft or percutaneous coronary intervention is often recommended for these patients before implantation of a cardiac defibrillator because it is assumed that this may reduce the incidence of fatal and potentially fatal ventricular arrhythmias, although this premise has not been evaluated in a randomized trial to date. METHODS: Patients with severe left ventricular dysfunction, extensive coronary disease, and viable myocardium were randomly assigned to receive either percutaneous coronary intervention (PCI) plus optimal medical and device therapy (OMT) or OMT alone. The composite primary outcome was all-cause death or aborted sudden death (defined as an appropriate implantable cardioverter defibrillator therapy or a resuscitated cardiac arrest) at a minimum of 24 months, analyzed as time to first event on an intention-to-treat basis. Secondary outcomes included cardiovascular death or aborted sudden death, appropriate implantable cardioverter defibrillator (ICD) therapy or sustained ventricular arrhythmia, and number of appropriate ICD therapies. RESULTS: Between August 28, 2013, and March 19, 2020, 700 patients were enrolled across 40 centers in the United Kingdom. A total of 347 patients were assigned to the PCI+OMT group and 353 to the OMT alone group. The mean age of participants was 69 years; 88% were male; 56% had hypertension; 41% had diabetes; and 53% had a clinical history of myocardial infarction. The median left ventricular ejection fraction was 28%; 53.1% had an implantable defibrillator inserted before randomization or during follow-up. All-cause death or aborted sudden death occurred in 144 patients (41.6%) in the PCI group and 142 patients (40.2%) in the OMT group (hazard ratio, 1.03 [95% CI, 0.82–1.30]; P =0.80). There was no between-group difference in the occurrence of any of the secondary outcomes. CONCLUSIONS: PCI was not associated with a reduction in all-cause mortality or aborted sudden death. In patients with ischemic cardiomyopathy, PCI is not beneficial solely for the purpose of reducing potentially fatal ventricular arrhythmias. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT01920048

Chemically Controllable Magnetic Transition Temperature and Magneto‐Elastic Coupling in MnZnSb Compounds

International audienceMagneto-caloric materials offer the possibility to design environmentally friendlier thermal management devices compared to the widely used gas-based systems. The challenges to develop this solid-state based technology lie in the difficulty of finding materials presenting a large magneto-caloric effect over a broad temperature span together with suitable secondary appli-cation parameters such as low heat capacity and high thermal conductivity. A series of compounds derived from the PbFCl structure is investigated using a combination of computational and experimental methods focusing on the change of cell volume in magnetic and non-magnetic ground states. Scaling analysis of the magnetic properties determines that they are second order phase transition ferromagnets and that the magnetic entropy change is driven by the coupling of magneto-elastic strain in the square-net through the magnetic transition determined from neutron and synchrotron X-ray diffraction. The primary and secondary application related properties are measured experimentally, and the c/a parameter is identified as an accurate proxy to control the magnetic transition. Chemical substitution on the square-net affords tuning of the Curie temperature over a broad temperature span between 252 and 322 K. A predictive machine learning model for the c/aparameter is developed to guide future exploratory synthesis

In vivo selection of genetically modified erythroblastic progenitors leads to long-term correction of β-thalassemia

Gene therapy for β-thalassemia requires stable transfer of a β-globin gene into hematopoietic stem cells (HSCs) and high and regulated hemoglobin expression in the erythroblastic progeny. We developed an erythroid-specific lentiviral vector driving the expression of the human β-globin gene from a minimal promoter/enhancer element containing two hypersensitive sites from the β-globin locus control region. Transplantation of transduced HSCs into thalassemic mice leads to stable and long-term correction of anemia with all red blood cells expressing the transgene. A frequency of 30–50% of transduced HSCs, harboring an average vector copy number per cell of 1, was sufficient to fully correct the thalassemic phenotype. In the mouse model of Cooley's anemia transplantation of transduced cells rescues lethality, leading to either a normal or a thalassemia intermedia phenotype. We show that genetically corrected erythroblasts undergo in vivo selection with preferential survival of progenitors harboring proviral integrations in genome sites more favorable to high levels of vector-derived expression. These data provide a rationale for a gene therapy approach to β-thalassemia based on partially myeloablative transplantation protocols