Achieving orphan designation for placental insufficiency: annual incidence estimations in Europe

Objective To determine whether a novel therapy for placental insufficiency could achieve orphan drug status by estimating the annual incidence of placental insufficiency, defined as an estimated fetal weight below the 10th centile in the presence of abnormal umbilical artery Doppler velocimetry, per 10 000 European Union (EU ) population as part of an application for European Medicines Agency (EMA ) orphan designation. Design Incidence estimation based on literature review and published national and EU statistics. Setting and population European Union. Methods Data were drawn from published literature, including national and international guidelines, international consensus statements, cohort studies and randomised controlled trials, and published national and EU statistics, including birth rates and stillbirth rates. Rare disease databases were also searched. Results The proportion of affected pregnancies was estimated as 3.17% (95% CI 2.93–3.43%), using a weighted average of the results from two cohort studies. Using birth rates from 2012 and adjusting for a pregnancy loss rate of 1/100 gave an estimated annual incidence of 3.33 per 10 000 EU population (95% CI 3.07–3.60 per 10 000 EU population). This fell below the EMA threshold of 5 per 10 000 EU population. Conclusions Maternal vascular endothelial growth factor gene therapy for placental insufficiency was granted EMA orphan status in 2015 after we demonstrated that it is a rare, life‐threatening or chronically debilitating and currently untreatable disease. Developers of other potential obstetric therapies should consider applying for orphan designation, which provides financial and regulatory benefits

Shear behaviour of crushed concrete and bricks

Demolition waste materials mainly consist of concrete and bricks and arise from the demolition of existing structures and buildings. Environmental and economical reasons make their recycling necessary, but to date, their use is curtailed due to the lack of research in determining their properties. This paper reports on the efforts to understand the behavioural characteristics of three types of recycled material to determine their potential for engineering fill applications. For this purpose, their physical and mechanical characteristics were extensively investigated. Two types of crushed concrete, one obtained straight after demolition and the other processed to industry specifications, and one type of crushed brick were tested. An extensive large-scale shear box test regime was employed to determine the shear strength behaviour of the materials. The influence of the normal stress on the peak friction angle, the shear stress– horizontal displacement relationship and horizontal displacement– vertical displacement behaviour of the materials are discussed in this paper. The results showed that the behaviour of the three recycled materials during shear testing was similar to the behaviour exhibited by natural granular materials from literature. In conclusion, the shear box test results have shown that the specific demolition waste products exhibit considerable shear strength and can be utilised in construction as low-level engineering fill

All-Silicon spherical-Mie-resonator photodiode with spectral response in the infrared region

[EN] Silicon is the material of choice for visible light photodetection and solar cell fabrication. However, due to the intrinsic band gap properties of silicon, most infrared photons are energetically useless. Here, we show the first example of a photodiode developed on a micrometre scale sphere made of polycrystalline silicon whose photocurrent shows the Mie modes of a classical spherical resonator. The long dwell time of resonating photons enhances the photocurrent response, extending it into the infrared region well beyond the absorption edge of bulk silicon. It opens the door for developing solar cells and photodetectors that may harvest infrared light more efficiently than silicon photovoltaic devices that are so far developed.The authors acknowledge financial support from the following projects: FIS2009-07812, MAT2012-35040, network ‘Nanophotonics for Energy Efficiency’ Grant agreement 248855, TEC2012-34397, Consolider 2007-0046 Nanolight, AGAUR 2009 SGR 549 and the PROMETEO/2010/043. We also acknowledge the fruitful discussions with Professor Javier Garcı´a de Abajo.Garín Escrivá, M.; Fenollosa Esteve, R.; Alcubilla, R.; Shi, L.; Marsal, LF.; Meseguer Rico, FJ. (2014). All-Silicon spherical-Mie-resonator photodiode with spectral response in the infrared region. Nature Communications. 5:2-6. https://doi.org/10.1038/ncomms4440S265Schockley, W. & Queisser, H. J. Detailed balance limit of efficiency of pn junction solar cells. J. Appl. Phys. 32, 510–519 (1961).Cao, L. et al. Engineering light absorption in semiconductor nanowire devices. Nat. Mater. 8, 643–647 (2009).Kelzenberg, M. D. et al. Enhanced absorption and carrier collection in Si wire arrays for photovoltaic applications. Nat. Mater. 9, 239–244 (2010).Ünlü, M. S. & Strite, S. Resonant cavity enhanced photonic devices. J. Appl. Phys. 78, 607–639 (1995).Xu, Q., Schmidt, B., Pradhan, S. & Lipson, M. Micrometre-scale silicon electro-optic modulator. Nature 435, 325–327 (2005).Serpengüzel, A., Kurt, A. & Ayaz, U. K. Silicon microspheres for electronic and photonic integration. Photon. Nanostructur.: Fundam. Appl. 6, 179–182 (2008).Kim, S. K. et al. Tuning light absorption in core/shell silicon nanowire photovoltaic devices through morphological design. Nano Lett. 12, 4971–4976 (2012).Yu, L. et al. Bismuth-catalyzed and doped silicon nanowires for one-pump-down fabrication of radial junction solar cells. Nano Lett. 12, 4153–4158 (2012).Fan, Z. et al. Three-dimensional nanopillar-array photovoltaics on low-cost and flexible substrates. Nat. Mater. 8, 648–653 (2009).Wallentin, J. et al. InP Nanowire array solar cells achieving 13.8% efficiency by exceeding the ray optics limit. Science 339, 1057–1060 (2013).Krogstrup, P. et al. Single-nanowire solar cells beyond the Shockley–Queisser limit. Nat. Photon. 7, 306–310 (2013).Fenollosa, R., Meseguer, F. & Tymczenko, M. Silicon colloids: from microcavities to photonic sponges. Adv. Mater. 20, 95–98 (2008).Pell, L. E., Schricker, A. D., Mikulec, F. V. & Korgel, B. A. Synthesis of amorphous silicon colloids by trisilane thermolysis in high temperature supercritical solvents. Langmuir 20, 6546–6548 (2004).Shi, L. et al. Monodisperse silicon nanocavities and photonic crystals with magnetic response in the optical region. Nat. Commun. 4, a.n.1904 (2013).Levine, J. D., Hotchkiss, G. B. & Wammerbacher, M. D. Basic properties of the spheral solar cell. Proc. 22nd IEEE PVSC p1045IEEE: Las Vegas, (1991).Breen, T. L., Tien, J., Oliver, S. R. J., Hadzic, T. & Whitesides, G. M. Design and self-assembly of open, regular, 3D mesostructures. Science 284, 948–951 (1999).Gracias, D. H., Tien, J., Breen, T. L., Hsu, C. & Whitesides, G. M. Forming electrical networks in three dimensions by self-assembly. Science 289, 1170–1172 (2000).Gumennik, A. et al. Silicon-in-silica spheres via axial thermal gradient in-fibre capillary instabilities. Nat. Commun. 4, a.n.2216 (2013).Yamamoto, K. et al. Thin-film poly-Si solar cells on glass substrate fabricated at low temperature. Appl. Phys. A 69, 179–185 (1999).Cesare, G., de, Caputo, D. & Tucci, M. Electrical properties of ITO/crystalline-silicon contact at different deposition temperatures. IEEE Electron Dev. Lett. 33, 327–329 (2012).Eversole, J. D., Lin, H.-B., Huston, A. L. & Campillo, A. J. Spherical-cavity-mode assignments of optical resonances in microdoplets using elastic scattering. J. Opt. Soc. Am. A 7, 2159–2168 (1990).Poruba, A. et al. Optical absorption and light scattering in microcrystalline silicon thin films and solar cells. J. Appl. Phys. 88, 148–160 (2000)

Cobalt and Nickel Nanopillars on Aluminium Substrates by Direct Current Electrodeposition Process

A fast and cost-effective technique is applied for fabricating cobalt and nickel nanopillars on aluminium substrates. By applying an electrochemical process, the aluminium oxide barrier layer is removed from the pore bottom tips of nanoporous anodic alumina templates. So, cobalt and nickel nanopillars are fabricated into these templates by DC electrodeposition. The resulting nanostructure remains on the aluminium substrate. In this way, this method could be used to fabricate a wide range of nanostructures which could be integrated in new nanodevices

Autoimmune diseases and pregnancy: analysis of a series of cases

BACKGROUND: An autoimmune disease is characterized by tissue damage, caused by self-reactivity of different effector mechanisms of the immune system, namely antibodies and T cells. All autoimmune diseases, to some extent, have implications for fertility and obstetrics. Currently, due to available treatments and specialised care for pregnant women with autoimmune disease, the prognosis for both mother and child has improved significantly. However these pregnancies are always high risk. The purpose of this study is to analyse the fertility/pregnancy process of women with systemic and organ-specific autoimmune diseases and assess pathological and treatment implications. METHODS: The authors performed an analysis of the clinical records and relevant obstetric history of five patients representing five distinct autoimmune pathological scenarios, selected from Autoimmune Disease Consultation at the Hospital of Braga, and reviewed the literature. RESULTS: The five clinical cases are the following: Case 1-28 years old with systemic lupus erythematosus, and clinical remission of the disease, under medication with hydroxychloroquine, prednisolone and acetylsalicylic acid, with incomplete miscarriage at 7 weeks of gestation without signs of thrombosis. Case 2-44 years old with history of two late miscarriages, a single preterm delivery (33 weeks) and multiple thrombotic events over the years, was diagnosed with antiphospholipid syndrome after acute myocardial infarction. Case 3-31 years old with polymyositis, treated with azathioprine for 3 years with complete remission of the disease, took the informed decision to get pregnant after medical consultation and full weaning from azathioprine, and gave birth to a healthy term new-born. Case 4-38 years old pregnant woman developed Behcet's syndrome during the final 15 weeks of gestation and with disease exacerbation after delivery. Case 5-36 years old with autoimmune thyroiditis diagnosed during her first pregnancy, with difficult control over the thyroid function over the years and first trimester miscarriage, suffered a second miscarriage despite clinical stability and antibody regression. CONCLUSIONS: As described in literature, the authors found a strong association between autoimmune disease and obstetric complications, especially with systemic lupus erythematosus, antiphospholipid syndrome and autoimmune thyroiditis

Defining Smallness for Gestational Age in the Early Years of the Danish Medical Birth Registry

Background: Being born small for gestational age (SGA) is associated with decreased insulin sensitivity and increased blood pressure in childhood, but the association with clinical disease in early adulthood is less certain. The Danish Medical Birth Registry has registered all births in Denmark since 1973, but due to variable data quality, data is most often used only from 1981 onwards, and birth registers in other countries may have similar problems for the early years. We wanted to examine whether the data can be used for identification of children born SGA and used in future research. Methodology/Principal Findings: All persons born between 1974 and 1996 were identified in the Danish Medical Birth Registry (n = 1.704.890). Immigrants and children without data on gestational age and birth weight were excluded, and a total of 1.348.106 children were included in the analysis. The difference between the different variables used in the history of the registry were examined, and the quality of data in the birth registry from 1974-1981 was examined and compared to subsequent years. Data on birth weight and gestational age in the early years of the registry is inconsistent, and the identification of children born SGA is inaccurate, with 49 % false-positives. The biggest source of error is due to the rough and inaccurate intervals used for gestational age. By using –3 standard deviations as a cut-off for the identification of children born SGA, the number of false-positives was reduced to 9%, while the amount of false-negatives were increased. Conclusion: Choosing –3 standard deviations for identifying children born SGA is a viable, though not optimal solution fo

Analysis of bias stress on thin-film transistors obtained by Hot-Wire Chemical Vapour Deposition

The stability under gate bias stress of unpassivated thin film transistors was studied by measuring the transfer and output characteristics at different temperatures. The active layer of these devices consisted of in nanocrystalline silicon deposited at 125°C by Hot-Wire Chemical Vapour Deposition. The dependence of the subthreshold activation energy on gate bias for different gate bias stresses is quite different from the one reported for hydrogenated amorphous silicon. This behaviour has been related to trapped charge in the active layer of the thin film transistor.Peer ReviewedPostprint (published version

β-Phase Morphology in Ordered Poly(9,9-dioctylfluorene) Nanopillars by Template Wetting Method

An efficient method based in template wetting is applied for fabrication of ordered Poly(9,9-dioctylfluorene) (PFO) nanopillars with β-phase morphology. In this process, nanoporous alumina obtained by anodization process is used as template. PFO nanostructures are prepared under ambient conditions via infiltration of the polymeric solution into the pores of the alumina with an average pore diameter of 225 nm and a pore depth of 500 nm. The geometric features of the resulting structures are characterized with environmental scanning electron microscopy (ESEM), luminescence fluorimeter (PL) and micro μ-X-ray diffractometer (μ-XRD). The characterization demonstrates the β-phase of the PFO in the nanopillars fabricated. Furthermore, the PFO nanopillars are characterized by Raman spectroscopy to study the polymer conformation. These ordered nanostructures can be used in optoelectronic applications such as polymer light-emitting diodes, sensors and organic solar cells

DAS-28-based EULAR response and HAQ improvement in rheumatoid arthritis patients switching between TNF antagonists

<p>Abstract</p> <p>Introduction</p> <p>No definitive data are available regarding the value of switching to an alternative TNF antagonist in rheumatoid arthritis patients who fail to respond to the first one. The aim of this study was to evaluate treatment response in a clinical setting based on HAQ improvement and EULAR response criteria in RA patients who were switched to a second or a third TNF antagonist due to failure with the first one.</p> <p>Methods</p> <p>This was an observational, prospective study of a cohort of 417 RA patients treated with TNF antagonists in three university hospitals in Spain between January 1999 and December 2005. A database was created at the participating centres, with well-defined operational instructions. The main outcome variables were analyzed using parametric or non-parametric tests depending on the level of measurement and distribution of each variable.</p> <p>Results</p> <p>Mean (± SD) DAS-28 on starting the first, second and third TNF antagonist was 5.9 (± 2.0), 5.1 (± 1.5) and 6.1 (± 1.1). At the end of follow-up, it decreased to 3.3 (± 1.6; Δ = -2.6; p > 0.0001), 4.2 (± 1.5; Δ = -1.1; p = 0.0001) and 5.4 (± 1.7; Δ = -0.7; p = 0.06). For the first TNF antagonist, DAS-28-based EULAR response level was good in 42% and moderate in 33% of patients. The second TNF antagonist yielded a good response in 20% and no response in 53% of patients, while the third one yielded a good response in 28% and no response in 72%. Mean baseline HAQ on starting the first, second and third TNF antagonist was 1.61, 1.52 and 1.87, respectively. At the end of follow-up, it decreased to 1.12 (Δ = -0.49; p < 0.0001), 1.31 (Δ = -0.21, p = 0.004) and 1.75 (Δ = -0.12; p = 0.1), respectively. Sixty four percent of patients had a clinically important improvement in HAQ (defined as ≥ -0.22) with the first TNF antagonist and 46% with the second.</p> <p>Conclusion</p> <p>A clinically significant effect size was seen in less than half of RA patients cycling to a second TNF antagonist.</p