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

Georgia Abortion Law and Our Commitment to Patients

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/153775/1/art41143.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/153775/2/art41143_am.pd

Abandonment of Unaweep Canyon (1.4–0.8 Ma), western Colorado: Effects of stream capture and anomalously rapid Pleistocene river incision

Cosmogenic-burial and U-series dating, identification of fluvial terraces and lacustrine deposits, and river-profile reconstructions show that capture of the Gunnison River by the Colorado River and abandonment of Unaweep Canyon occurred between 1.4-0.8 Ma. This event led to a rapid pulse of incision unlike any documented in the Rocky Mountains. Following abandonment of Unaweep Canyon by the ancestral Gunnison River, a wave of incision propagated upvalley rapidly through Mancos Shale at rates of ~90-440 km/Ma. The Gunnison River removed 400-500 km3 of erodible Mancos Shale and incised up to 360 m deep in 0.17-0.76 My (incision rates of ~470-2250 m/Ma). Prior to canyon abandonment, long-term (~11-1 Ma) Gunnison River incision averaged ~100 m/Ma. The wave of incision also caused the subsequent capture of the Bostwick-Shinn Park River by the ancestral Uncompahgre River ca. 0.87-0.64 Ma, at a location ~70 km upvalley from Unaweep Canyon. This event led to similarly rapid (up to ~500 m/Ma) but localized river incision. As regional river incision progressed, the juxtaposition of resistant Precambrian bedrock and erodible Mancos Shale within watersheds favored the development of significant relief between adjacent stream segments, which led to stream piracy. The response of rivers to the abandonment of Unaweep Canyon illustrates how the mode and tempo of long-term fluvial incision are punctuated by short-term geomorphic events such as stream piracy. These short-term events can trigger significant landscape changes, but the effects are more localized relative to regional climatically- or tectonically-driven events. Powered byThis is an author's peer-reviewed final manuscript, as accepted by the publisher. The published article is copyrighted by the Geological Society of America and can be found at: http://geosphere.gsapubs.org/.Keywords: Stream piracy, Gunnison River, Knickpoint, Fluvial incision, Unaweep Canyo

BioTIME: A database of biodiversity time series for the Anthropocene.

MotivationThe BioTIME database contains raw data on species identities and abundances in ecological assemblages through time. These data enable users to calculate temporal trends in biodiversity within and amongst assemblages using a broad range of metrics. BioTIME is being developed as a community-led open-source database of biodiversity time series. Our goal is to accelerate and facilitate quantitative analysis of temporal patterns of biodiversity in the Anthropocene.Main types of variables includedThe database contains 8,777,413 species abundance records, from assemblages consistently sampled for a minimum of 2 years, which need not necessarily be consecutive. In addition, the database contains metadata relating to sampling methodology and contextual information about each record.Spatial location and grainBioTIME is a global database of 547,161 unique sampling locations spanning the marine, freshwater and terrestrial realms. Grain size varies across datasets from 0.0000000158 km2 (158 cm2) to 100 km2 (1,000,000,000,000 cm2).Time period and grainBioTIME records span from 1874 to 2016. The minimal temporal grain across all datasets in BioTIME is a year.Major taxa and level of measurementBioTIME includes data from 44,440 species across the plant and animal kingdoms, ranging from plants, plankton and terrestrial invertebrates to small and large vertebrates.Software format.csv and .SQL

Validation practices for satellite based earth observation data across communities

Assessing the inherent uncertainties in satellite data products is a challenging task. Different technical approaches have been developed in the Earth Observation (EO) communities to address the validation problem which results in a large variety of methods as well as terminology. This paper reviews state-of-the-art methods of satellite validation and documents their similarities and differences. First the overall validation objectives and terminologies are specified, followed by a generic mathematical formulation of the validation problem. Metrics currently used as well as more advanced EO validation approaches are introduced thereafter. An outlook on the applicability and requirements of current EO validation approaches and targets is given

New East Manchester: urban renaissance or urban opportunism?

In this paper we ask how a shrinking city responds when faced with a perforated urban fabric. Drawing on Manchester’s response to its perforated eastern flank - and informed by a parallel study of Leipzig - we use the city’s current approach to critique urban regeneration policy in England. Urban renaissance holds out the promise of delivering more sustainable - that is more compact, more inclusive and more equitable - cities. However, the Manchester study demonstrated that the attempt to stem population loss from the city is at best fragile, despite a raft of policies now in place to support urban renaissance in England. It is argued here that Manchester like Leipzig is likely to face an ongoing battle to attract residents back from their suburban hinterlands. This is especially true of the family market that we identify as being an important element for long-term sustainable population growth in both cities. We use the case of New East Manchester to consider how discourses linked to urban renaissance – particularly those that link urbanism with greater densities - rule out some of the options available to Leipzig, namely, managing the long-term perforation of the city. We demonstrate that while Manchester is inevitably committed to the urban renaissance agenda, in practice New East Manchester demonstrates a far more pragmatic – but equally unavoidable – approach. This we attribute to the gap between renaissance and regeneration described by Amin et al (2000) who define the former as urbanism for the middle class and the latter as urbanism for the working class. While this opportunistic approach may ultimately succeed in producing development on the ground, it will not address the fundamental, and chronic, problem; the combination of push and pull that sees families relocating to suburban areas. Thus, if existing communities in East Manchester are to have their area buoyed up – or sustained - by incomers, and especially families, with greater levels of social capital and higher incomes urban policy in England will have to be challenged

The importance of monsoon precipitation for foundation tree species across the semiarid Southwestern U.S.

Forest dynamics in arid and semiarid regions are sensitive to water availability, which is becoming increasingly scarce as global climate changes. The timing and magnitude of precipitation in the semiarid southwestern U.S. (“Southwest”) has changed since the 21st century began. The region is projected to become hotter and drier as the century proceeds, with implications for carbon storage, pest outbreaks, and wildfire resilience. Our goal was to quantify the importance of summer monsoon precipitation for forested ecosystems across this region. We developed an isotope mixing model in a Bayesian framework to characterize summer (monsoon) precipitation soil water recharge and water use by three foundation tree species (Populus tremuloides [aspen], Pinus edulis [piñon], and Juniperus osteosperma [Utah juniper]). In 2016, soil depths recharged by monsoon precipitation and tree reliance on monsoon moisture varied across the Southwest with clear differences between species. Monsoon precipitation recharged soil at piñon-juniper (PJ) and aspen sites to depths of at least 60 cm. All trees in the study relied primarily on intermediate to deep (10-60 cm) moisture both before and after the onset of the monsoon. Though trees continued to primarily rely on intermediate to deep moisture after the monsoon, all species increased reliance on shallow soil moisture to varying degrees. Aspens increased reliance on shallow soil moisture by 13% to 20%. Utah junipers and co-dominant ñons increased their reliance on shallow soil moisture by about 6% to 12%. Nonetheless, approximately half of the post-monsoon moisture in sampled piñon (38-58%) and juniper (47-53%) stems could be attributed to the monsoon. The monsoon contributed lower amounts to aspen stem water (24-45%) across the study area with the largest impacts at sites with recent precipitation. Therefore, monsoon precipitation is a key driver of growing season moisture that semiarid forests rely on across the Southwest. This monsoon reliance is of critical importance now more than ever as higher global temperatures lead to an increasingly unpredictable and weaker North American Monsoon

Left Hemisphere Specialization for Oro-Facial Movements of Learned Vocal Signals by Captive Chimpanzees

The left hemisphere of the human brain is dominant in the production of speech and signed language. Whether similar lateralization of function for communicative signal production is present in other primates remains a topic of considerable debate. In the current study, we examined whether oro-facial movements associated with the production of learned attention-getting sounds are differentially lateralized compared to facial expressions associated with the production of species-typical emotional vocalizations in chimpanzees.Still images captured from digital video were used to quantify oro-facial asymmetries in the production of two attention-getting sounds and two species-typical vocalizations in a sample of captive chimpanzees. Comparisons of mouth asymmetries during production of these sounds revealed significant rightward biased asymmetries for the attention-getting sounds and significant leftward biased asymmetries for the species-typical sounds.These results suggest that the motor control of oro-facial movements associated with the production of learned sounds is lateralized to the left hemisphere in chimpanzees. Furthermore, the findings suggest that the antecedents for lateralization of human speech may have been present in the common ancestor of chimpanzees and humans approximately 5 mya and are not unique to the human lineage

Stretching the spines of gymnasts: a review

Gymnastics is noted for involving highly specialized strength, power, agility and flexibility. Flexibility is perhaps the single greatest discriminator of gymnastics from other sports. The extreme ranges of motion achieved by gymnasts require long periods of training, often occupying more than a decade. Gymnasts also start training at an early age (particularly female gymnasts), and the effect of gymnastics training on these young athletes is poorly understood. One of the concerns of many gymnastics professionals is the training of the spine in hyperextension-the ubiquitous 'arch' seen in many gymnastics positions and movements. Training in spine hyperextension usually begins in early childhood through performance of a skill known as a back-bend. Does practising a back-bend and other hyperextension exercises harm young gymnasts? Current information on spine stretching among gymnasts indicates that, within reason, spine stretching does not appear to be an unusual threat to gymnasts' health. However, the paucity of information demands that further study be undertaken