Gene therapy for obstetric conditions

The first clinical trials of gene therapy in the 1990s offered the promise of a new paradigm for the treatment of genetic diseases. Over the decades that followed the challenges and setbacks which gene therapy faced often overshadowed any successes. Despite this, recent years have seen cause for renewed optimism. In 2012 Glybera™, an adeno-associated viral vector expressing lipoprotein lipase, became the first gene therapy product to receive marketing authorisation in Europe, with a licence to treat familial lipoprotein lipase deficiency. This followed the earlier licensing in China of two gene therapies: Gendicine™ for head and neck squamous cell carcinoma and Oncorine™ for late-stage nasopharyngeal cancer. By this stage over 1800 clinical trials had been, or were being, conducted worldwide, and the therapeutic targets had expanded far beyond purely genetic disorders. So far no trials of gene therapy have been carried out in pregnancy, but an increasing understanding of the molecular mechanisms underlying obstetric diseases means that it is likely to have a role to play in the future. This review will discuss how gene therapy works, its potential application in obstetric conditions and the risks and limitations associated with its use in this setting. It will also address the ethical and regulatory issues that will be faced by any potential clinical trial of gene therapy during pregnancy

Gravitational waves from an early matter era

We investigate the generation of gravitational waves due to the gravitational instability of primordial density perturbations in an early matter-dominated era which could be detectable by experiments such as LIGO and LISA. We use relativistic perturbation theory to give analytic estimates of the tensor perturbations generated at second order by linear density perturbations. We find that large enhancement factors with respect to the naive second-order estimate are possible due to the growth of density perturbations on sub-Hubble scales. However very large enhancement factors coincide with a breakdown of linear theory for density perturbations on small scales. To produce a primordial gravitational wave background that would be detectable with LIGO or LISA from density perturbations in the linear regime requires primordial comoving curvature perturbations on small scales of order 0.02 for Advanced LIGO or 0.005 for LISA, otherwise numerical calculations of the non-linear evolution on sub-Hubble scales are required.Comment: 23 pages, 2 figure

Embedded Ribbons of Graphene Allotropes: An Extended Defect Perspective

Four fundamental dimer manipulations can be used to produce a variety of localized and extended defect structures in graphene. Two-dimensional templates result in graphene allotropes, here viewed as extended defects, which can exhibit either metallic or semiconducting electrical character. \emph{Embedded allotropic ribbons}--i.e. thin swaths of the new allotropes--can also be created within graphene. We examine these ribbons and find that they maintain the electrical character of their parent allotrope even when only a few atoms in width. Such extended defects may facilitate the construction of monolithic electronic circuitry.Comment: 24 pages, 21 figure

Prehospital critical care is associated with increased survival in adult trauma patients in Scotland

Background Scotland has three prehospital critical care teams (PHCCTs) providing enhanced care support to a usually paramedic-delivered ambulance service. The effect of the PHCCTs on patient survival following trauma in Scotland is not currently known nationally. Methods National registry-based retrospective cohort study using 2011-2016 data from the Scottish Trauma Audit Group. 30-day mortality was compared between groups after multivariate analysis to account for confounding variables. Results Our data set comprised 17 157 patients, with a mean age of 54.7 years and 8206 (57.5%) of male gender. 2877 patients in the registry were excluded due to incomplete data on their level of prehospital care, leaving an eligible group of 14 280. 13 504 injured adults who received care from ambulance clinicians (paramedics or technicians) were compared with 776 whose care included input from a PHCCT. The median Injury Severity Score (ISS) across all eligible patients was 9; 3076 patients (21.5%) met the ISS>15 criterion for major trauma. Patients in the PHCCT cohort were statistically significantly (all p < 0.01) more likely to be male; be transported to a prospective Major Trauma Centre; have suffered major trauma; have suffered a severe head injury; be transported by air and be intubated prior to arrival in hospital. Following multivariate analysis, the OR for 30-day mortality for patients seen by a PHCCT was 0.56 (95% CI 0.36 to 0.86, p=0.01). Conclusion Prehospital care provided by a physician-led critical care team was associated with an increased chance of survival at 30 days when compared with care provided by ambulance clinicians

Energy landscapes of a hairpin peptide including NMR chemical shift restraints.

Methods recently introduced to improve the efficiency of protein structure prediction simulations by adding a restraint potential to a molecular mechanics force field introduce additional input parameters that can affect the performance. Here we investigate the changes in the energy landscape as the relative weight of the two contributions, force field and restraint potential, is systematically altered, for restraint functions constructed from calculated nuclear magnetic resonance chemical shifts. Benchmarking calculations were performed on a 12-residue peptide, tryptophan zipper 1, which features both secondary structure (a β-hairpin) and specific packing of tryptophan sidechains. Basin-hopping global optimization was performed to assess the efficiency with which lowest-energy structures are located, and the discrete path sampling approach was employed to survey the energy landscapes between unfolded and folded structures. We find that inclusion of the chemical shift restraints improves the efficiency of structure prediction because the energy landscape becomes more funnelled and the proportion of local minima classified as native increases. However, the funnelling nature of the landscape is reduced as the relative contribution of the chemical shift restraint potential is increased past an optimal value.This research was supported by the EPSRC and the ERC.This is the final version of the article. It first appeared from the Royal Society of Chemistry via http://dx.doi.org/10.1039/C5CP01259

Metal Abundances of Intermediate-Redshift AGN: Evidence for a Population of Lower-Metallicty Seyfert 2 Galaxies at z = 0.3-0.4

We derive oxygen abundances for two samples of Seyfert 2 (Sy2) active galactic nuclei (AGN) selected from the KPNO International Spectroscopic Survey (KISS). The two samples from KISS include 17 intermediate-redshift (0.29 < z < 0.42) Sy2s detected via their [O III] lines, and 35 low-redshift (z < 0.1), Halpha-detected Sy2s. The primary goal of this work is to explore whether the metallicity distribution of these two samples changes with redshift. To determine the oxygen abundances of the KISS galaxies, we use Cloudy to create a large number of photoionization model grids by varying the temperature of the accretion disk, the ratio of X-ray to UV continuum light, the ionization parameter, the hydrogen density, and the metallicity of the narrow-line region clouds. We link the results of these models to the observed [O III]/H-beta and [N II]/H-alpha emission-line ratios of the KISS sample on the BPT diagram, interpolating across the model grids to derive metallicity. The two redshift samples overlap substantially in terms of derived metal abundances, but we find that some of the intermediate-redshift Sy2 galaxies possess lower abundances than their local universe counterparts. Our analysis provides evidence for modest levels of chemical evolution (0.18 +/- 0.06 dex) over 3-4 Gyrs of look-back time. We compare our results to other AGN abundance derivation methods from the literature.Comment: 17 pages, 12 figures; accepted for publication in the Astrophysical Journa

The Star Formation Across Cosmic Time (SFACT) Survey. II. The First Catalog from a New Narrow-Band Survey for Emission-Line Objects

Star Formation Across Cosmic Time (SFACT) is a new narrowband survey designed to detect faint emission-line galaxies and QSOs over a broad range of redshifts. Here we present the first list of SFACT candidates from our pilot-study fields. Using the WIYN 3.5m telescope, we are able to achieve good image quality with excellent depth and routinely detect ELGs to r = 25.0. The limiting line flux of the survey is ~1.0 x 10^16 erg/s/cm^2. SFACT targets three primary emission lines: H-alpha, [O III]5007, and [O II]3727. The corresponding redshift windows allow for the detection of objects at z ~ 0-1. With a coverage of 1.50 square degrees in our three pilot-study fields, a total of 533 SFACT candidates have been detected (355 candidates per square degree). We detail the process by which these candidates are selected in an efficient and primarily automated manner, then tabulate accurate coordinates, broadband photometry, and narrowband fluxes for each source.Comment: 26 pages, 12 figures. Accepted for publication in the Astronomical Journa

Public perceptions of drinking water: A postal survey of residents with private water supplies

Background: In Canada, the legal responsibility for the condition of private water supplies, including private wells and cisterns, rests with their owners. However, there are reports that Canadians test these water supplies intermittently and that treatment of such water is uncommon. An estimated 45% of all waterborne outbreaks in Canada involve non-municipal systems. An understanding of the perceptions and needs of Canadians served by private water supplies is essential, as it would enable public health professionals to better target public education and drinking water policy. The purpose of this study was to investigate the public perceptions of private water supplies in the City of Hamilton, Ontario (Canada), with the intent of informing public education and outreach strategies within the population. Methods: A cross-sectional postal survey of 246 residences with private water supplies was conducted in May 2004. Questions pertained to the perceptions of water quality and alternative water sources, water testing behaviours and the self-identified need for further information. Results: Private wells, cisterns or both, were the source of household water for 71%, 16% and 13% of respondents, respectively. Although respondents rated their water quality highly, 80% also had concerns with its safety. The most common concerns pertained to bacterial and chemical contamination of their water supply and its potential negative effect on health. Approximately 56% and 61% of respondents used in-home treatment devices and bottled water within their homes, respectively, mainly due to perceived improvements in the safety and aesthetic qualities compared to regular tap water. Testing of private water supplies was performed infrequently: 8% of respondents tested at a frequency that meets current provincial guidelines. Two-thirds of respondents wanted more information on various topics related to private water supplies. Flyers and newspapers were the two media reported most likely to be used. Conclusion: Although respondents rated their water quality highly, the majority had concerns regarding the water from their private supply, and the use of bottled water and water treatment devices was extensive. The results of this study suggest important lines of inquiry and provide support and input for public education programs, particularly those related to private water testing, in this population

Constant Size Molecular Descriptors For Use With Machine Learning

A set of molecular descriptors whose length is independent of molecular size is developed for machine learning models that target thermodynamic and electronic properties of molecules. These features are evaluated by monitoring performance of kernel ridge regression models on well-studied data sets of small organic molecules. The features include connectivity counts, which require only the bonding pattern of the molecule, and encoded distances, which summarize distances between both bonded and non-bonded atoms and so require the full molecular geometry. In addition to having constant size, these features summarize information regarding the local environment of atoms and bonds, such that models can take advantage of similarities resulting from the presence of similar chemical fragments across molecules. Combining these two types of features leads to models whose performance is comparable to or better than the current state of the art. The features introduced here have the advantage of leading to models that may be trained on smaller molecules and then used successfully on larger molecules.Comment: 18 pages, 5 figure