A checklist for clinical trials in rare disease: Obstacles and anticipatory actions-lessons learned from the FOR-DMD trial

Background: Trials in rare diseases have many challenges, among which are the need to set up multiple sites in different countries to achieve recruitment targets and the divergent landscape of clinical trial regulations in those countries. Over the past years, there have been initiatives to facilitate the process of international study set-up, but the fruits of these deliberations require time to be operationally in place. FOR-DMD (Finding the Optimum Steroid Regimen for Duchenne Muscular Dystrophy) is an academic-led clinical trial which aims to find the optimum steroid regimen for Duchenne muscular dystrophy, funded by the National Institutes of Health (NIH) for 5 years (July 2010 to June 2015), anticipating that all sites (40 across the USA, Canada, the UK, Germany and Italy) would be open to recruitment from July 2011. However, study start-up was significantly delayed and recruitment did not start until January 2013. Method: The FOR-DMD study is used as an example to identify systematic problems in the set-up of international, multi-centre clinical trials. The full timeline of the FOR-DMD study, from funding approval to site activation, was collated and reviewed. Systematic issues were identified and grouped into (1) study set-up, e.g. drug procurement; (2) country set-up, e.g. competent authority applications; and (3) site set-up, e.g. contracts, to identify the main causes of delay and suggest areas where anticipatory action could overcome these obstacles in future studies. Results: Time from the first contact to site activation across countries ranged from 6 to 24 months. Reasons of delay were universal (sponsor agreement, drug procurement, budgetary constraints), country specific (complexity and diversity of regulatory processes, indemnity requirements) and site specific (contracting and approvals). The main identified obstacles included (1) issues related to drug supply, (2) NIH requirements regarding contracting with non-US sites, (3) differing regulatory requirements in the five participating countries, (4) lack of national harmonisation with contracting and the requirement to negotiate terms and contract individually with each site and (5) diversity of languages needed for study materials. Additionally, as with many academic-led studies, the FOR-DMD study did not have access to the infrastructure and expertise that a contracted research organisation could provide, organisations often employed in pharmaceutical-sponsored studies. This delay impacted recruitment, challenged the clinical relevance of the study outcomes and potentially delayed the delivery of the best treatment to patients. Conclusion: Based on the FOR-DMD experience, and as an interim solution, we have devised a checklist of steps to not only anticipate and minimise delays in academic international trial initiation but also identify obstacles that will require a concerted effort on the part of many stakeholders to mitigate

Polyimide based amorphous silicon solar modules

Requirements for space power are increasingly emphasizing lower costs and higher specific powers. This results from new fiscal constraints, higher power requirements for larger applications, and the evolution toward longer distance missions such as a Lunar or Mars base. The polyimide based a-Si modules described are being developed to meet these needs. The modules consist of tandem a-Si solar cell material deposited directly on a roll of polyimide. A laser scribing/printing process subdivides the deposition into discrete cell strips which are series connected to produce the required voltage without cutting the polymer backing. The result is a large, monolithic, blanket type module approximately 30 cm wide and variable in length depending on demand. Current production modules have a specific power slightly over 500 W/Kg with room for significant improvement. Costs for the full blanket modules range from $30/Watt to$150/Watt depending on quantity and engineering requirements. Work to date focused on the modules themselves and adjusting them for the AMO spectrum. Work is needed yet to insure that the modules are suitable for the space environment

A comparison of collision cross section values obtained via travelling wave ion mobility-mass spectrometry and ultra high performance liquid chromatography-ion mobility-mass spectrometry : application to the characterisation of metabolites in rat urine

A comprehensive Collision Cross Section (CCS) library was obtained via Travelling Wave Ion Guide mobility measurements through direct infusion (DI). The library consists of CCS and Mass Spectral (MS) data in negative and positive ElectroSpray Ionisation (ESI) mode for 463 and 479 endogenous metabolites, respectively. For both ionisation modes combined, TWCCSN2 data were obtained for 542 non-redundant metabolites. These data were acquired on two different ion mobility enabled orthogonal acceleration QToF MS systems in two different laboratories, with the majority of the resulting TWCCSN2 values (from detected compounds) found to be within 1% of one another. Validation of these results against two independent, external TWCCSN2 data sources and predicted TWCCSN2 values indicated to be within 1-2% of these other values. The same metabolites were then analysed using a rapid reversed-phase ultra (high) performance liquid chromatographic (U(H)PLC) separation combined with IM and MS (IM-MS) thus providing retention time (tr), m/z and TWCCSN2 values (with the latter compared with the DI-IM-MS data). Analytes for which TWCCSN2 values were obtained by U(H)PLC-IM-MS showed good agreement with the results obtained from DI-IM-MS. The repeatability of the TWCCSN2 values obtained for these metabolites on the different ion mobility QToF systems, using either DI or LC, encouraged the further evaluation of the U(H)PLC-IM-MS approach via the analysis of samples of rat urine, from control and methotrexate-treated animals, in order to assess the potential of the approach for metabolite identification and profiling in metabolic phenotyping studies. Based on the database derived from the standards 63 metabolites were identified in rat urine, using positive ESI, based on the combination of tr, TWCCSN2 and MS data.</p

Tomographic image of melt storage beneath Askja Volcano, Iceland using local microseismicity

We use P wave and S wave arrivals from microseismic earthquakes to construct 3-D tomographic Vp and Vs images of the magma storage region beneath Askja's central volcano in the Northern Volcanic Zone of Iceland. A distinctive ellipsoidal low-velocity anomaly, with both Vp and Vsvelocities 8-12% below the background, is imaged at 6-11 km depth beneath the caldera. The presence of a shallow magma chamber is corroborated by geodetic and gravity studies. The small Vp/Vs anomaly suggests a lack of pervasive melt. We interpret this anomaly as a region of multiple sills, some frozen but hot, others containing partial melt. A second, smaller low-velocity anomaly beneath the main magma storage region may represent a magma migration pathway. This interpretation is supported by the close proximity to the anomaly of clusters of deep, magmatically induced earthquakes. However, the location and shape of this deep anomaly are poorly constrained by the current data set

On Non-Abelian Symplectic Cutting

We discuss symplectic cutting for Hamiltonian actions of non-Abelian compact groups. By using a degeneration based on the Vinberg monoid we give, in good cases, a global quotient description of a surgery construction introduced by Woodward and Meinrenken, and show it can be interpreted in algebro-geometric terms. A key ingredient is the `universal cut' of the cotangent bundle of the group itself, which is identified with a moduli space of framed bundles on chains of projective lines recently introduced by the authors.Comment: Various edits made, to appear in Transformation Groups. 28 pages, 8 figure

Expansion of Thaumarchaeota habitat range is correlated with horizontal transfer of ATPase operons.

Thaumarchaeota are responsible for a significant fraction of ammonia oxidation in the oceans and in soils that range from alkaline to acidic. However, the adaptive mechanisms underpinning their habitat expansion remain poorly understood. Here we show that expansion into acidic soils and the high pressures of the hadopelagic zone of the oceans is tightly linked to the acquisition of a variant of the energy-yielding ATPases via horizontal transfer. Whereas the ATPase genealogy of neutrophilic Thaumarchaeota is congruent with their organismal genealogy inferred from concatenated conserved proteins, a common clade of V-type ATPases unites phylogenetically distinct clades of acidophilic/acid-tolerant and piezophilic/piezotolerant species. A presumptive function of pumping cytoplasmic protons at low pH is consistent with the experimentally observed increased expression of the V-ATPase in an acid-tolerant thaumarchaeote at low pH. Consistently, heterologous expression of the thaumarchaeotal V-ATPase significantly increased the growth rate of E. coli at low pH. Its adaptive significance to growth in ocean trenches may relate to pressure-related changes in membrane structure in which this complex molecular machine must function. Together, our findings reveal that the habitat expansion of Thaumarchaeota is tightly correlated with extensive horizontal transfer of atp operons

Safeguarding freshwater life beyond 2020: Recommendations for the new global biodiversity framework from the European experience

Plans are currently being drafted for the next decade of action on biodiversity-both the post-2020 Global Biodiversity Framework of the Convention on Biological Diversity (CBD) and Biodiversity Strategy of the European Union (EU). Freshwater biodiversity is disproportionately threatened and underprioritized relative to the marine and terrestrial biota, despite supporting a richness of species and ecosystems with their own intrinsic value and providing multiple essential ecosystem services. Future policies and strategies must have a greater focus on the unique ecology of freshwater life and its multiple threats, and now is a critical time to reflect on how this may be achieved. We identify priority topics including environmental flows, water quality, invasive species, integrated water resources management, strategic conservation planning, and emerging technologies for freshwater ecosystem monitoring. We synthesize these topics with decades of first-hand experience and recent literature into 14 special recommendations for global freshwater biodiversity conservation based on the successes and setbacks of European policy, management, and research. Applying and following these recommendations will inform and enhance the ability of global and European post-2020 biodiversity agreements to halt and reverse the rapid global decline of freshwater biodiversity

Maximal Temperature in Flux Compactifications

Thermal corrections have an important effect on moduli stabilization leading to the existence of a maximal temperature, beyond which the compact dimensions decompactify. In this note, we discuss generality of our earlier analysis and apply it to the case of flux compactifications. The maximal temperature is again found to be controlled by the supersymmetry breaking scale, T_{crit} \sim \sqrt{m_{3/2} M_P}.Comment: 10 pages, 10 figures. v2:comment and references adde

Farm-scale tradeoffs between legume use as forage versus green manure: the case of Canavalia Brasiliensis

This is an Author’s Accepted Manuscript of an article published in Agroecology and Sustainable Food Systems, 2014, available online: http://www.tandfonline.com/ http://dx.doi.org/10.1080/21683565.2013.82866