Safety of fluticasone propionate prescribed for asthma during pregnancy: A UK population-based cohort study

Background: Asthma is commonly treated during pregnancy, yet data on the safety of asthma medicines used during pregnancy are sparse. Objective: The objective of this study was to evaluate the safety of the inhaled corticosteroid (ICS) fluticasone propionate (FP), alone and in fixed-dose combination with salmeterol (FSC) in terms of the risk of all major congenital malformations (MCMs), compared with all other non-FP ICS. Methods: Women with asthma who had a pregnancy between January 1, 2000, and December 31, 2010, were identified in the United Kingdom's Clinical Practice Research Datalink. Exposure to asthma medicines during the first trimester of pregnancy was based on issued prescriptions. The mothers' and infants' medical records were linked where possible, and pregnancy outcomes with an MCM diagnosed by age 1 year were identified based on medical codes in the mother's and infant's medical records, including those MCMs prenatally diagnosed that ended in an induced pregnancy termination. The absolute and relative risks of an MCM after different ICS exposures, stratified by the asthma treatment intensity level, were calculated. Results: A total of 14,654 mother-infant pairs were identified, of which 6,174 received an ICS prescription during the first trimester, in addition to 13 first trimester ICS exposed pregnancies that ended in an induced termination after a prenatal MCM diagnosis. In total, 5,362 pregnancies were eligible for the primary analysis at age 1 year. The absolute risk of an MCM after any first trimester FP exposure was 2.4% (CI95 0.8-4.1) and2.7% (CI95 1.8-3.6) for the "moderate" and "considerable/severe" asthma treatment intensity levels, respectively. The adjusted odds ratios when compared with non-FP ICS were 1.1 (CI95 0.5-2.3) and 1.2 (CI95 0.7-2.0) for the "moderate" and "considerable/severe" intensity levels; risks for any FP and for FSC did not differ substantially. Conclusion: No increase in the overall risk of MCMs was identified after first trimester FP exposure compared with non-FP ICS. © 2015 American Academy of Allergy, Asthma & Immunology

Sensitivity of the UK clinical practice research datalink to detect neurodevelopmental effects of medicine exposure in utero:comparative analysis of an antiepileptic drug-exposed cohort

Introduction: Electronic healthcare data have several advantages over prospective observational studies, but the sensitivity of data on neurodevelopmental outcomes and its comparability with data generated through other methodologies is unknown. Objectives: The objectives of this study were to determine whether data from the UK Clinical Practice Research Datalink (CPRD) produces similar risk estimates to a prospective cohort study in relation to the risk of neurodevelopmental disorders (NDDs) following prenatal antiepileptic drug (AED) exposure. Methods: A cohort of mother–child pairs of women with epilepsy (WWE) was identified in the CPRD and matched to a cohort without epilepsy. The study period ran from 1 January 2000 to 31 March 2007 and children were required to be in the CPRD at age 6 years. AED exposure during pregnancy was determined from prescription data and children with an NDD diagnosis by 6 years were identified from Read clinical codes. The prevalence and risk of NDDs was calculated for mother–child pairs in WWE stratified by AED regimen and for those without epilepsy. Comparisons were made with the results of the prospective Liverpool and Manchester Neurodevelopment Group study which completed assessment on 201 WWE and 214 without epilepsy at age 6 years. Results: In the CPRD, 1018 mother–child pairs to WWE and 6048 to women without epilepsy were identified. The CPRD identified a lower prevalence of NDDs than the prospective study. In both studies, NDDs were more frequently reported in children of WWE than women without epilepsy, although the CPRD risk estimate was lower (2.16 vs. 0.96%, p < 0.001 and 7.46 vs. 1.87%, p = 0.0128). NDD prevalence differed across AED regimens but the CPRD data did not replicate the significantly higher risk of NDDs following in utero monotherapy valproate exposure (adjusted odds ratio [ORadj] 2.02, 95% confidence interval [CI] 0.52–7.86) observed in the prospective study (ORadj 6.05, 95% CI 1.65–24.53). Conclusion: It was possible to identify NDDs in the CPRD; however, the CPRD appears to under-record these outcomes. Larger studies are required to investigate further

In vivo CRISPRa decreases seizures and rescues cognitive deficits in a rodent model of epilepsy

Epilepsy is a major health burden, calling for new mechanistic insights and therapies. CRISPR-mediated gene editing shows promise to cure genetic pathologies, although hitherto it has mostly been applied ex vivo. Its translational potential for treating non-genetic pathologies is still unexplored. Furthermore, neurological diseases represent an important challenge for the application of CRISPR, because of the need in many cases to manipulate gene function of neurons in situ. A variant of CRISPR, CRISPRa, offers the possibility to modulate the expression of endogenous genes by directly targeting their promoters. We asked if this strategy can effectively treat acquired focal epilepsy, focusing on ion channels because their manipulation is known be effective in changing network hyperactivity and hypersynchronziation. We applied a doxycycline-inducible CRISPRa technology to increase the expression of the potassium channel gene Kcna1 (encoding Kv1.1) in mouse hippocampal excitatory neurons. CRISPRa-mediated Kv1.1 upregulation led to a substantial decrease in neuronal excitability. Continuous video-EEG telemetry showed that AAV9-mediated delivery of CRISPRa, upon doxycycline administration, decreased spontaneous generalized tonic-clonic seizures in a model of temporal lobe epilepsy, and rescued cognitive impairment and transcriptomic alterations associated with chronic epilepsy. The focal treatment minimizes concerns about off-target effects in other organs and brain areas. This study provides the proof-of-principle for a translational CRISPR-based approach to treat neurological diseases characterized by abnormal circuit excitability

Evolution of the solar irradiance during the Holocene

Aims. We present a physically consistent reconstruction of the total solar irradiance for the Holocene. Methods. We extend the SATIRE models to estimate the evolution of the total (and partly spectral) solar irradiance over the Holocene. The basic assumption is that the variations of the solar irradiance are due to the evolution of the dark and bright magnetic features on the solar surface. The evolution of the decadally averaged magnetic flux is computed from decadal values of cosmogenic isotope concentrations recorded in natural archives employing a series of physics-based models connecting the processes from the modulation of the cosmic ray flux in the heliosphere to their record in natural archives. We then compute the total solar irradiance (TSI) as a linear combination of the jth and jth + 1 decadal values of the open magnetic flux. Results. Reconstructions of the TSI over the Holocene, each valid for a di_erent paleomagnetic time series, are presented. Our analysis suggests that major sources of uncertainty in the TSI in this model are the heritage of the uncertainty of the TSI since 1610 reconstructed from sunspot data and the uncertainty of the evolution of the Earth's magnetic dipole moment. The analysis of the distribution functions of the reconstructed irradiance for the last 3000 years indicates that the estimates based on the virtual axial dipole moment are significantly lower at earlier times than the reconstructions based on the virtual dipole moment. Conclusions. We present the first physics-based reconstruction of the total solar irradiance over the Holocene, which will be of interest for studies of climate change over the last 11500 years. The reconstruction indicates that the decadally averaged total solar irradiance ranges over approximately 1.5 W/m2 from grand maxima to grand minima

Hypofractionated Stereotactic Ablative Radiotherapy for Recurrent or Oligometastatic Tumours in Children and Young Adults

AIMS Cancer remains a leading cause of death in children and adolescents in the developed world. Despite advances in oncological management, rates of primary treatment failure remain significant. Radiation of recurrent or metastatic disease improves survival in adults but there is little data to support clinical decision making in the paediatric/teenage and young adult population. Materials And Methods We present a retrospective case series of 14 patients treated with stereotactic ablative body radiotherapy or stereotactic radiosurgery at The Royal Marsden Hospital from September 2011 to December 2015. Eligible patients were aged <25 years, with Lansky/Karnofsky performance status ≥60 with confirmed relapsed or metastatic tumour in fewer than three sites. Follow-up was in accordance with standard clinical care and included regular outpatient review and radiological surveillance. Local control, progression-free survival and overall survival are presented. RESULTS Data for 14 patients with 18 treated lesions were included. The median patient age was 15 years (range 5–20 years). Nine patients were treated for local recurrence and five for metastatic lesions. All patients had already undergone multiple previous treatments. Eleven patients had undergone previous radiotherapy. The median interval between the completion of initial radiotherapy and reirradiation was 29.0 months (range 0.2–49.5 months). The median follow-up was 3.4 years (range 0.28–6.4 years). The 1-year local control rate was 78.6% and the 2-year local control rate was 57.1%. Overall median survival was 58.4 months (95% confidence interval 33.8–82.9 months). Cumulative biologically effective doses (BED) over 200 Gy were associated with late toxicity (P = 0.04). CONCLUSION Radical doses of short-course hypofractionated radiotherapy can achieve excellent local control and may contribute to the prolongation of overall survival. There is a need for prospective trials exploring the use of ablative radiotherapy in metastatic disease in paediatric/teenage and young adult patients in order to establish safe and effective treatment schedules

High Precision and High Yield Fabrication of Dense Nanoparticle Arrays onto DNA Origami at Statistically Independent Binding Sites

High precision, high yield, and high density self-assembly of nanoparticles into arrays is essential for nanophotonics. Spatial deviations as small as a few nanometers can alter the properties of near-field coupled optical nanostructures. Several studies have reported assemblies of few nanoparticle structures with controlled spacing using DNA nanostructures with variable yield. Here, we report multi-tether design strategies and attachment yields for homo- and hetero-nanoparticle arrays templated by DNA origami nanotubes. Nanoparticle attachment yield via DNA hybridization is comparable with streptavidin-biotin binding. Independent of the number of binding sites, \u3e97% site-occupation was achieved with four tethers and 99.2% site-occupation is theoretically possible with five tethers. The interparticle distance was within 2 nm of all design specifications and the nanoparticle spatial deviations decreased with interparticle spacing. Modified geometric, binomial, and trinomial distributions indicate that site-bridging, steric hindrance, and electrostatic repulsion were not dominant barriers to self-assembly and both tethers and binding sites were statistically independent at high particle densities

Semiology, clustering, periodicity and natural history of seizures in an experimental occipital cortical epilepsy model

Focal neocortical epilepsy is a common form of epilepsy and there is a need to develop animal models that allow the evaluation of novel therapeutic strategies to treat this type of epilepsy. Tetanus toxin (TeNT) injection into the rat visual cortex induces focal neocortical epilepsy without preceding status epilepticus. The latency to first seizure ranged from 3 to 7 days. Seizure duration was bimodal, with both short (approximately 30 s) and long-lasting (>100 s) seizures occurring in the same animals. Seizures were accompanied by non-motor features such as behavioural arrest, or motor seizures with or without evolution to generalized tonic-clonic seizures. Seizures were more common during the sleep phase of a light-dark cycle. Seizure occurrence was not random, and tended to cluster with significantly higher probability of recurrence within 24 h of a previous seizure. Across animals, the number of seizures in the first week could be used to predict the number of seizures in the following 3 weeks. The TeNT model of occipital cortical epilepsy is a model of acquired focal neocortical epilepsy that is well-suited for preclinical evaluation of novel anti-epileptic strategies. We provide here a detailed analysis of the epilepsy phenotypes, seizure activity, electrographic features and the semiology. In addition, we provide a predictive framework that can be used to reduce variation and consequently animal use in preclinical studies of potential treatments

Breaking into the conversation: cultural value and the role of the South African National Arts Festival from apartheid to democracy

The paper examines the value of the South African National Arts Festival (NAF) in the transition to democracy using theories of cultural capital. NAF history from 1974 to 2004 is used to argue that the Festival provided an important arena for the expression of political resistance in the 1980s and, to some degree, continues to do so today. It is concluded that an important part of the value of the arts is their ability to provide a forum for debating the goals and values of society and that individualistic utility theory is not always successful in measuring such social value

Measurements of double-helicity asymmetries in inclusive J/ψJ/\psi production in longitudinally polarized p+pp+p collisions at s=510\sqrt{s}=510 GeV

We report the double helicity asymmetry, $A_{LL}^{J/\psi}$, in inclusive $J/\psi$ production at forward rapidity as a function of transverse momentum $p_T$ and rapidity $|y|$. The data analyzed were taken during $\sqrt{s}=510$ GeV longitudinally polarized $p$$+$$p$ collisions at the Relativistic Heavy Ion Collider (RHIC) in the 2013 run using the PHENIX detector. At this collision energy, $J/\psi$ particles are predominantly produced through gluon-gluon scatterings, thus $A_{LL}^{J/\psi}$ is sensitive to the gluon polarization inside the proton. We measured $A_{LL}^{J/\psi}$ by detecting the decay daughter muon pairs $\mu^+ \mu^-$ within the PHENIX muon spectrometers in the rapidity range $1.2<|y|<2.2$. In this kinematic range, we measured the $A_{LL}^{J/\psi}$ to be $0.012 \pm 0.010$~(stat)~$\pm$~$0.003$(syst). The $A_{LL}^{J/\psi}$ can be expressed to be proportional to the product of the gluon polarization distributions at two distinct ranges of Bjorken $x$: one at moderate range $x \approx 0.05$ where recent RHIC data of jet and $\pi^0$ double helicity spin asymmetries have shown evidence for significant gluon polarization, and the other one covering the poorly known small-$x$ region $x \approx 2\times 10^{-3}$. Thus our new results could be used to further constrain the gluon polarization for $x< 0.05$.Comment: 335 authors, 10 pages, 4 figures, 3 tables, 2013 data. Version accepted for publication by Phys. Rev. D. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm

Nuclear dependence of the transverse single-spin asymmetry in the production of charged hadrons at forward rapidity in polarized p+pp+p, p+p+Al, and p+p+Au collisions at sNN=200\sqrt{s_{_{NN}}}=200 GeV

We report on the nuclear dependence of transverse single-spin asymmetries (TSSAs) in the production of positively-charged hadrons in polarized $p^{\uparrow}+p$, $p^{\uparrow}+$Al and $p^{\uparrow}+$Au collisions at $\sqrt{s_{_{NN}}}=200$ GeV. The measurements have been performed at forward rapidity ($1.4<\eta<2.4$) over the range of $1.8<p_{T}<7.0$ GeV$/c$ and $0.1<x_{F}<0.2$. We observed a positive asymmetry $A_{N}$ for positively-charged hadrons in \polpp collisions, and a significantly reduced asymmetry in $p^{\uparrow}$+$A$ collisions. These results reveal a nuclear dependence of charged hadron $A_N$ in a regime where perturbative techniques are relevant. These results provide new opportunities to use \polpA collisions as a tool to investigate the rich phenomena behind TSSAs in hadronic collisions and to use TSSA as a new handle in studying small-system collisions.Comment: 303 authors from 66 institutions, 9 pages, 2 figures, 1 table. v1 is version accepted for publication in Physical Review Letters. Plain text data tables for the points plotted in figures for this and previous PHENIX publications are (or will be) publicly available at http://www.phenix.bnl.gov/papers.htm