Academic attainment and special educational needs in extremely preterm children at 11 years of age : the EPICure Study

Aim: To assess academic attainment and special educational needs (SEN) in extremely preterm (EP) children in middle childhood. Methods: Of 307 EP (=25 weeks) survivors born in the UK and Ireland in 1995, 219 (71%) were re-assessed at 11 years, with a comparison group of 153 classmates born at term, using standardised tests of cognitive ability and academic attainment and teacher reports of school performance and special educational needs (SEN). Multiple imputation was used to correct for selective dropout. Results: EP children had significantly lower scores than classmates for cognitive ability (-20 points; 95%CI: -23,-17), reading (-18 points; -22,-15) and mathematics (-27 points; -31,-23). Twenty-nine (13%) EP children attended special school. In mainstream schools, 105 (57%) EP children had SEN (OR: 10; 6, 18) and 103 (55%) required SEN resource provision (OR: 10; 5, 18). Teachers rated 50% of EP children with attainment below the average range compared with 5% of classmates (OR: 18; CI: 8, 41). EP children who are entered for mainstream education an academic year early due to preterm birth had similar academic attainment but required more SEN support (OR: 2; 1.1,3.8). Conclusions: EP survivors remain at high risk for learning impairments and poor academic attainment in middle childhood. A significant proportion require full-time specialist education and over half of those attending mainstream schools require additional health or educational resources in order to access the national curriculum. The prevalence and impact of SEN is likely to increase as these children approach the transition to secondary school. -------------------------------------------------------------------------------

Breast cancer: are long-term and intermittent endocrine therapies equally effective?

PURPOSE In breast cancer (BC), the duration of endocrine adjuvant therapies (AT) has been extended continuously up to 10~years. We present an alternative explanation for the effect, which could enable shorter treatments. METHOD The relevant literature on chemoprevention and (neo-)adjuvant therapy was reviewed. Data for initiation and growth of primary and contralateral BCs and their metastases (MET) were considered. Also, population-based data from the Munich Cancer Registry for MET-free survival, time trends of MET patterns, and survival achieved by improved ATs are used to estimate all events in the long-term follow-up. RESULTS Extended ATs (EAT) that continue after 1, 2, or 5~years reduce mortality only slightly. The effect is delayed, occurring more than 5~years after extension. EATs does not affect the prognosis of 1stBCs, they preventively eradicate contralateral 2ndBCs and thus their future life-threatening METs. Because chemoprevention can eradicate BCs from the smallest clusters to almost detectable BCs, ATs can be temporarily suspended without imposing harm. Results equal to EATs can be achieved by short-term ATs of the 1stBC and by repeated neo-ATs targeted at the indefinitely developing 2ndBCs. Considering this potential in de-escalation, a 70-80% reduction of overtreatment seems possible. CONCLUSION Knowledge of initiation and growth of tumors with known effects of neo-ATs suggest that intermittent endocrine ATs may achieve the same results as EATs but with improved quality of life and survival because of fewer side effects and better compliance. The challenge for developments of repeated ATs becomes: how short is short enough

Geochemical heterogeneity of sand deposits and its implications for the provenance determination of Roman glass

During the production of natron glass most features of the raw materials are lost and only some bulk geochemical characteristics have potential as provenance indicators. To determine the primary origin of archaeological glass artefacts, suitable sand raw materials have to be accurately characterised. In this respect, information about the possible variation in geochemical properties within a silica source is also vital to account for potential (partial) overlap of different sources. In this study, it is shown that the variation in major and minor elemental composition of beach sand on a local scale is smaller than the variation in Roman natron glass. Therefore, a single sand deposit can be seen as a relatively homogeneous source of silica for glass production. Nd isotopic signatures are identical for all samples analysed. The isotopic composition of Sr however varies considerably due to local variations in the relative proportions of carbonates and silicates (mostly feldspar).status: publishe

Continuous production of amines directly from alkenes via cyclodextrin-mediated hydroaminomethylation using only water as the solvent

Aqueous hydroaminomethylation (HAM) is an atom economical route for the efficient production of amines in one reaction step, starting from basic chemicals like alkenes. Herein we present the first successful establishment of a continuous process for HAM in an aqueous multiphase system. The green mass transfer agents randomly methylated-β-cyclodextrins (CD) enabled the catalytic system consisting of rhodium/sulfoXantphos to achieve high yields of up to 70% with selectivities of up to 80% in several continuous experiments with a total run time of more than 220 h. The key here is that water and products have large polarity differences, but the reaction still proceeds effectively due to the addition of cyclodextrin, which made the application of solvents obsolete. The main achievements in this way were the investigation of the influence of the randomly methylated-β-cyclodextrin concentration on the reaction rate and the selectivity in batch studies and finding promising operating points in the first continuous experiments. In a final experiment, the separation temperature was investigated. It was shown that the catalyst loss in the product phase is enormously small at 0.003% h−1 of the initial mass (0.24% in total), which is the lowest ever reported value for the HAM on this scale. Within a run time of 78 hours, 2.87 kg of tertiary amine were produced using only 0.2 g (>14[thin space (1/6-em)]000[thin space (1/6-em)]:[thin space (1/6-em)]1) of transition metal, while the loss of rhodium per kg of product produced was mostly around 0.15 mg kg−1, suggesting possible economical applicability

Visual setup of logical models of signaling and regulatory networks with ProMoT

BACKGROUND: The analysis of biochemical networks using a logical (Boolean) description is an important approach in Systems Biology. Recently, new methods have been proposed to analyze large signaling and regulatory networks using this formalism. Even though there is a large number of tools to set up models describing biological networks using a biochemical (kinetic) formalism, however, they do not support logical models. RESULTS: Herein we present a flexible framework for setting up large logical models in a visual manner with the software tool ProMoT. An easily extendible library, ProMoT's inherent modularity and object-oriented concept as well as adaptive visualization techniques provide a versatile environment. Both the graphical and the textual description of the logical model can be exported to different formats. CONCLUSION: New features of ProMoT facilitate an efficient set-up of large Boolean models of biochemical interaction networks. The modeling environment is flexible; it can easily be adapted to specific requirements, and new extensions can be introduced. ProMoT is freely available from

Combinatorial Diversity of Fission Yeast SCF Ubiquitin Ligases by Homo- and Heterooligomeric Assemblies of the F-Box Proteins Pop1p and Pop2p

Background: SCF ubiquitin ligases share the core subunits cullin 1, SKP1, and HRT1/RBX1/ROC1, which associate with different F-box proteins. F-box proteins bind substrates following their phosphorylation upon stimulation of various signaling pathways. Ubiquitin-mediated destruction of the fission yeast cyclin-dependent kinase inhibitor Rum1p depends on two heterooligomerizing F-box proteins, Pop1p and Pop2p. Both proteins interact with the cullin Pcu1p when overexpressed, but it is unknown whether this reflects their co-assembly into bona fide SCF complexes. Results: We have identified Psh1p and Pip1p, the fission yeast homologues of human SKP1 and HRT1/RBX1/ROC1, and show that both associate with Pop1p, Pop2p, and Pcu1p into a ~500 kDa SCFPop1p-Pop2p complex, which supports polyubiquitylation of Rum1p. Only the F-box of Pop1p is required for SCFPop1p-Pop2p function, while Pop2p seems to be attracted into the complex through binding to Pop1p. Since all SCFPop1p-Pop2p subunits, except for Pop1p, which is exclusively nuclear, localize to both the nucleus and the cytoplasm, the F-box of Pop2p may be critical for the assembly of cytoplasmic SCFPop2p complexes. In support of this notion, we demonstrate individual SCFPop1p and SCFPop2p complexes bearing ubiquitin ligase activity. Conclusion: Our data suggest that distinct homo- and heterooligomeric assemblies of Pop1p and Pop2p generate combinatorial diversity of SCFPop function in fission yeast. Whereas a heterooligomeric SCFPop1p-Pop2p complex mediates polyubiquitylation of Rum1p, homooligomeric SCFPop1p and SCFPop2p complexes may target unknown nuclear and cytoplasmic substrates

Analysis of the DNA adducts of phenyl glycidyl ether in a calf thymus DNA hydrolysate by capillary zone electrophoresis-electrospray mass spectrometry: evidence for phosphate alkylation

Calf thymus DNA was reacted irt vitro with phenyl glycidyl ether (PGE) and was hydrolysed enzymatically, to the 5'-monophosphate nucleotides using deoxyribonuclease I (DNA-ase I) and nuclease P1, The adducts were concentrated using solid phase extraction (SPE), on a polystyrene divinylbenzene copolymer in order to remove the unmodified nucleotides. The adducts could be identified using capillary zone electrophoresis-electrospray tandem mass spectrometry (CZE ES-MS/MS), using sample stacking. In addition to the base alkylated 2'-deoxynucleotides present in the DNA-hydrolysate, also phosphate alkylated 2'-deoxynucleotide adducts were identified for TMP and dAMP, An additional adduct, dUMP alkylated on the uridine moiety was found originating from the hydrolytic deamination of dCMP alkylated on N-3 Of the cytosine moiety, Enzymatic hydrolysis using nuclease P1 was incomplete as shown by the presence of dinucleotides alkylated on the base moiety, They were successfully hydrolysed to the corresponding 2'-deoxynucleotides by snake venom phosphodiesterase (SVP), Data are shown indicating that alkylations on the pyrimidine bases were more resistant to enzymatic hydrolysis with nuclease P1 than the purine alkylated products

Could a Kilonova Kill: a Threat Assessment

Binary neutron star mergers (BNS) produce high-energy emissions from several physically different sources, including a gamma-ray burst (GRB) and its afterglow, a kilonova, and, at late times, a remnant many parsecs in size. Ionizing radiation from these sources can be dangerous for life on Earth-like planets when located too close. Work to date has explored the substantial danger posed by the GRB to on-axis observers: here we focus instead on the potential threats posed to nearby off-axis observers. Our analysis is based largely on observations of the GW 170817/GRB 170817A multi-messenger event, as well as theoretical predictions. For baseline kilonova parameters, we find that the X-ray emission from the afterglow may be lethal out to $\sim 5$ pc and the off-axis gamma-ray emission may threaten a range out to $\sim 4$ pc, whereas the greatest threat comes years after the explosion, from the cosmic rays accelerated by the kilonova blast, which can be lethal out to distances up to $\sim 11$ pc. The distances quoted here are typical, but the values have significant uncertainties and depend on the viewing angle, ejected mass, and explosion energy in ways we quantify. Assessing the overall threat to Earth-like planets, have a similar kill distance to supernovae, but are far less common. However, our results rely on the scant available kilonova data, and multi-messenger observations will clarify the danger posed by such events.Comment: 21 pages, 5 figures. Comments welcom