Biphosphonate-Mediated Gene Vector Delivery from the Metal Surfaces of Stents

The clinical use of metallic expandable intravascular stents has resulted in imporved therapeutic outcomes for coronary artery disease. However, arterial reobstruction after stenting, in-stent restenosis, remains an important problem. Gene therapy to treat in-stent restenosis by using gene vector delivery from the metallic stent surfaces has never been demonstrated. The present studies investigated the hypothesis that metal-biphosphonate binding can enable site-specific gene vector delivery from metal surfaces. Polyallylamine biphosphonate (PAA-BP) was synthesized by using Michael addition methodology. Exposure to aqueous solutions of PAA-BP resulted in the formation of a monomolecular biphosphonate later on metal alloy surfaces (steel, nitinol, and cobalt-chromium), as demonstrated by x-ray photoelectron spectroscopy. Surface-bound PAA-BP enabled adenoviral (Ad) tethering due to covalent thiol-binding of either anti-Ad antibody or a recombinant Ad-receptor protein, D1. In arterial smooth muscle cell cultures, alloy samples configured with surface-tethered Ad were demonstrated to achieve site-specific transduction with a reporter gene, (GFP). Rat carotid stent angioplasties using metal stents exposed to aqueous PAA-BP and derivatized with anti-knob antibody or D1 resulted in extensive localized Ad-GFP expression in the arterial wall. In a separate study with a model therapeutic vector, Ad-inducible nitric oxide synthase (iNOS) attached to the biphosphonate-treated metal stent surface via D1, significant inhibition of restenosis was demonstrated (neointimal/media ration 1.68 ± 0.27 and 3.4 ± 0.35; Ad-iNOS vs. control, P \u3c 0.01). Is is concluded that effective gene vector delivery from metallic stent surfaces can be achieved using this approach

Global Development and Climate Change: A Game Theory Approach

The increasing concern with climate change is one of the main issues of our time, and thus we aim to theoretically and mathematically analyse its causes. However our approach follows a different stream of thought, presenting the reasoning and decision-making processes between technical and moral solutions. We have resorted to game theory models in order to demonstrate cooperative and non-cooperative scenarios, ranging from the traditional to the evolutionary within game theory. In doing so we are able to glimpse the development of modern society and a paradigm shift regarding human control over nature and to what extent it is harmful to the sustainability of our environment and the survival of future generations. Merging different fields of knowledge, we present a theoretical-philosophical approach, combined with empirical-mathematical solutions taking into account the agent-based behaviour guided blindly by instrumental rationality

Constraining the 21 cm brightness temperature of the IGM at z = 6.6 around LAEs with the murchison widefield array

The locations of Ly α-emitting galaxies (LAEs) at the end of the Epoch of Reionization (EoR) are expected to correlate with regions of ionized hydrogen, traced by the redshifted 21 cm hyperfine line. Mapping the neutral hydrogen around regions with detected and localized LAEs offers an avenue to constrain the brightness temperature of the Universe within the EoR by providing an expectation for the spatial distribution of the gas, thereby providing prior information unavailable to power spectrum measurements. We use a test set of 12 h of observations from the Murchison Widefield Array (MWA) in extended array configuration, to constrain the neutral hydrogen signature of 58 LAEs, detected with the Subaru Hypersuprime Cam in the Silverrush survey, centred on z = 6.58. We assume that detectable emitters reside in the centre of ionized H II bubbles during the end of reionization, and predict the redshifted neutral hydrogen signal corresponding to the remaining neutral regions using a set of different ionized bubble radii. A pre-whitening matched filter detector is introduced to assess detectability. We demonstrate the ability to detect, or place limits upon, the amplitude of brightness temperature fluctuations, and the characteristic H II bubble size. With our limited data, we constrain the brightness temperature of neutral hydrogen to ΔTB B = 15 ± 2h-1 cMpc

Comparing generic drug markets in Europe and the United States: prices, volumes, and spending

Our study indicates that there are opportunities for cost savings in generic drug markets in Europe and the United States. Regulators should make it easier for generic drugs to reach the market. Regulators and payers should apply measures to stimulate price competition among generic drugmakers and to increase generic drug use. To meaningfully evaluate policy options, it is important to analyze historical context and understand why similar initiatives failed previously. Context: Rising drug prices are putting pressure on health care budgets. Policymakers are assessing how they can save money through generic drugs. Methods: We compared generic drug prices and market shares in 13 European countries, using data from 2013, to assess the amount of variation that exists between countries. To place these results in context, we reviewed evidence from recent studies on the prices and use of generics in Europe and the United States. We also surveyed peer‐reviewed studies, gray literature, and books published since 2000 to (1) outline existing generic drug policies in European countries and the United States; (2) identify ways to increase generic drug use and to promote price competition among generic drug companies; and (3) explore barriers to implementing reform of generic drug policies, using a historical example from the United States as a case study. Findings: The prices and market shares of generics vary widely across Europe. For example, prices charged by manufacturers in Switzerland are, on average, more than 2.5 times those in Germany and more than 6 times those in the United Kingdom, based on the results of a commonly used price index. The proportion of prescriptions filled with generics ranges from 17% in Switzerland to 83% in the United Kingdom. By comparison, the United States has historically had low generic drug prices and high rates of generic drug use (84% in 2013), but has in recent years experienced sharp price increases for some off‐patent products. There are policy solutions to address issues in Europe and the United States, such as streamlining the generic drug approval process and requiring generic prescribing and substitution where such policies are not yet in place. The history of substitution laws in the United States provides insights into the economic, political, and cultural issues influencing the adoption of generic drug policies. Conclusions: Governments should apply coherent supply‐ and demand‐side policies in generic drug markets. An immediate priority is to convince more physicians, pharmacists, and patients that generic drugs are bioequivalent to branded products. Special‐interest groups continue to obstruct reform in Europe and the United States

Career Resourcing and the Process of Professional Emergence

We theorize a career resourcing process that explains how individuals can create a new profession. Using historical archives, we trace the emergence of health services research as a new research profession through the career actions of early practitioners. We find that career resourcing can lead to the institutionalization of a new profession by: 1) a process of accretion, where people pursuing fulfilling careers generate resources that contribute to institutionalization, or 2) institutional work to deliberately build the professional community and infrastructure. We contribute to research on institutional change by specifying career actions that can lead to the institutionalization of a new profession, and by developing theory that accounts for the motivations and the means of individuals to act in ways that result in the institutionalization of a new profession

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk.

Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (≥140 mm Hg systolic blood pressure or  ≥90 mm Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events. This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention

Genetic associations at 53 loci highlight cell types and biological pathways relevant for kidney function.

Reduced glomerular filtration rate defines chronic kidney disease and is associated with cardiovascular and all-cause mortality. We conducted a meta-analysis of genome-wide association studies for estimated glomerular filtration rate (eGFR), combining data across 133,413 individuals with replication in up to 42,166 individuals. We identify 24 new and confirm 29 previously identified loci. Of these 53 loci, 19 associate with eGFR among individuals with diabetes. Using bioinformatics, we show that identified genes at eGFR loci are enriched for expression in kidney tissues and in pathways relevant for kidney development and transmembrane transporter activity, kidney structure, and regulation of glucose metabolism. Chromatin state mapping and DNase I hypersensitivity analyses across adult tissues demonstrate preferential mapping of associated variants to regulatory regions in kidney but not extra-renal tissues. These findings suggest that genetic determinants of eGFR are mediated largely through direct effects within the kidney and highlight important cell types and biological pathways

High Incidence of Sympathetic Ophthalmia after Contact and Noncontact Neodymium:YAG Cyclotherapy

Background: Two cases of sympathetic ophthalmia occurring after noncontact neodymium:YAG (Nd:YAG) cyclotherapy have previously been reported. In each case, the patient had undergone filtering surgery in the exciting eye. Although in each case Nd:YAG cyclotherapy was the last surgery performed, the inciting event of sympathetic ophthalmia was unclear. Methods: The authors studied three additional patients who developed sympathetic ophthalmia after Nd:YAG cyclotherapy for glaucoma. Results: Two patients developed sympathetic ophthalmia 4 months after noncontact Nd:YAG cyclotherapy, and 1 patient developed sympathetic ophthalmia 18 months after contact Nd:YAG cyclotherapy. All patients had previous cataract extractions but no filtering surgery in the exciting eye. Clinical features included chronic iridocyclitis, choroidal folds, Dalen-Fuchs nodules, and optic disc edema. Combining these cases with the two previously reported cases, the incidence of sympathetic ophthalmia at our institution thus far is 5.8% (4 of 69) and 0.67% (1 of 150) after noncontact and contact Nd:YAG cyclotherapy, respectively. Conclusions: The incidence of sympathetic ophthalmia after Nd:YAG cyclotherapy is high compared with other ocular procedures. The clinician should vigilantly monitor patients after Nd:YAG cyclotherapy and report additional cases that may have occurred at other institutions