Methods to improve recruitment to randomised controlled trials : Cochrane systematic review and meta-analysis

Peer reviewedPublisher PD

Selective Inhibition of Plasmodium falciparum ATPase 6 by Artemisinins and Identification of New Classes of Inhibitors after Expression in Yeast

Treatment failures with artemisinin combination therapies (ACTs) threaten global efforts to eradicate malaria. They highlight the importance of identifying drug targets and new inhibitors and of studying how existing antimalarial classes work. Here, we report the successful development of a heterologous expression-based compound-screening tool. The validated drug target Plasmodium falciparum ATPase 6 (PfATP6) and a mammalian orthologue (sarco/endoplasmic reticulum calcium ATPase 1a [SERCA1a]) were functionally expressed in Saccharomyces cerevisiae, providing a robust, sensitive, and specific screening tool. Whole-cell and in vitro assays consistently demonstrated inhibition and labeling of PfATP6 by artemisinins. Mutations in PfATP6 resulted in fitness costs that were ameliorated in the presence of artemisinin derivatives when studied in the yeast model. As previously hypothesized, PfATP6 is a target of artemisinins. Mammalian SERCA1a can be mutated to become more susceptible to artemisinins. The inexpensive, low-technology yeast screening platform has identified unrelated classes of druggable PfATP6 inhibitors. Resistance to artemisinins may depend on mechanisms that can concomitantly address multitargeting by artemisinins and fitness costs of mutations that reduce artemisinin susceptibility

Organizational Alignment

There are many players in the scholarly communications space including librarians (current service/collections models), the academic institution (campus administration, research centers, colleges and departments), researchers (the professional field/discipline), and publishers of all stripes (commercial publishers, scholarly societies, university presses). What kinds of interactions do library publishers have with these various groups as they strive for organizational alignment and where are the most promising opportunities for future collaborations? This panel provides an overview of the variety of relationships library publishers engage in on and beyond their campuses to help move scholarly communications forward

Upper-Room Ultraviolet Light and Negative Air Ionization to Prevent Tuberculosis Transmission

Background Institutional tuberculosis (TB) transmission is an important public health problem highlighted by the HIV/AIDS pandemic and the emergence of multidrug- and extensively drug-resistant TB. Effective TB infection control measures are urgently needed. We evaluated the efficacy of upper-room ultraviolet (UV) lights and negative air ionization for preventing airborne TB transmission using a guinea pig air-sampling model to measure the TB infectiousness of ward air. Methods and Findings For 535 consecutive days, exhaust air from an HIV-TB ward in Lima, Perú, was passed through three guinea pig air-sampling enclosures each housing approximately 150 guinea pigs, using a 2-d cycle. On UV-off days, ward air passed in parallel through a control animal enclosure and a similar enclosure containing negative ionizers. On UV-on days, UV lights and mixing fans were turned on in the ward, and a third animal enclosure alone received ward air. TB infection in guinea pigs was defined by monthly tuberculin skin tests. All guinea pigs underwent autopsy to test for TB disease, defined by characteristic autopsy changes or by the culture of Mycobacterium tuberculosis from organs. 35% (106/304) of guinea pigs in the control group developed TB infection, and this was reduced to 14% (43/303) by ionizers, and to 9.5% (29/307) by UV lights (both p < 0.0001 compared with the control group). TB disease was confirmed in 8.6% (26/304) of control group animals, and this was reduced to 4.3% (13/303) by ionizers, and to 3.6% (11/307) by UV lights (both p < 0.03 compared with the control group). Time-to-event analysis demonstrated that TB infection was prevented by ionizers (log-rank 27; p < 0.0001) and by UV lights (log-rank 46; p < 0.0001). Time-to-event analysis also demonstrated that TB disease was prevented by ionizers (log-rank 3.7; p = 0.055) and by UV lights (log-rank 5.4; p = 0.02). An alternative analysis using an airborne infection model demonstrated that ionizers prevented 60% of TB infection and 51% of TB disease, and that UV lights prevented 70% of TB infection and 54% of TB disease. In all analysis strategies, UV lights tended to be more protective than ionizers. Conclusions Upper-room UV lights and negative air ionization each prevented most airborne TB transmission detectable by guinea pig air sampling. Provided there is adequate mixing of room air, upper-room UV light is an effective, low-cost intervention for use in TB infection control in high-risk clinical settings

Nuclear RNA sequencing of the mouse erythroid cell transcriptome.

In addition to protein coding genes a substantial proportion of mammalian genomes are transcribed. However, most transcriptome studies investigate steady-state mRNA levels, ignoring a considerable fraction of the transcribed genome. In addition, steady-state mRNA levels are influenced by both transcriptional and posttranscriptional mechanisms, and thus do not provide a clear picture of transcriptional output. Here, using deep sequencing of nuclear RNAs (nucRNA-Seq) in parallel with chromatin immunoprecipitation sequencing (ChIP-Seq) of active RNA polymerase II, we compared the nuclear transcriptome of mouse anemic spleen erythroid cells with polymerase occupancy on a genome-wide scale. We demonstrate that unspliced transcripts quantified by nucRNA-seq correlate with primary transcript frequencies measured by RNA FISH, but differ from steady-state mRNA levels measured by poly(A)-enriched RNA-seq. Highly expressed protein coding genes showed good correlation between RNAPII occupancy and transcriptional output; however, genome-wide we observed a poor correlation between transcriptional output and RNAPII association. This poor correlation is due to intergenic regions associated with RNAPII which correspond with transcription factor bound regulatory regions and a group of stable, nuclear-retained long non-coding transcripts. In conclusion, sequencing the nuclear transcriptome provides an opportunity to investigate the transcriptional landscape in a given cell type through quantification of unspliced primary transcripts and the identification of nuclear-retained long non-coding RNAs

Training the Workforce to Conduct Embedded Pragmatic Clinical Trials to Improve Care for People Living with Dementia and Their Caregivers

The National Institute on Aging IMbedded Pragmatic Alzheimer’s Disease and Alzheimer’s Disease-Related Dementias Clinical Trials (IMPACT) Collaboratory serves as a national resource for the conduct of embedded pragmatic clinical trials to improve the care of people living with dementia (PLWD) in partnership with the healthcare systems that serve them. Inherent in this objective is the need to train and support a cadre of investigators prepared to conduct this work now and in the future. The Training Core of the IMPACT Collaboratory supports the training of investigators to become experts in this field through three objectives: (1) curricula development and dissemination; (2) network generation and navigation; and (3) a career development award program. The innovative approach of the Training Core will require developing content and providing training experiences that recognize the unique challenges of research at the intersection of health systems, pragmatic trials, and PLWD and their caregivers. Ultimately, we seek to build the nation’s capacity to conduct research that bridges the gaps between efficacy studies to effectiveness research to implementation science. Although foundational resources in the methods of each of these areas are already available, few actually focus on pragmatic trials embedded within healthcare systems that focus on PLWD. To bring new interventions for PLWD from efficacy to widespread implementation, researchers must build diffusability, adaptability, heterogeneity, and scalability into the design of the intervention. In achieving these objectives, the Training Core will utilize the network of investigators, institutions, and stakeholders represented in the IMPACT Collaboratory

MISSE 6 Stressed Polymers Experiment Atomic Oxygen Erosion Data

Polymers and other oxidizable materials used on the exterior of spacecraft in the low Earth orbit (LEO) space environment can be eroded away by reaction with atomic oxygen (AO). For spacecraft design, it is important to know the LEO AO erosion yield, Ey (volume loss per incident oxygen atom), of materials susceptible to AO erosion. The Stressed Polymers Experiment was developed and flown as part of the Materials International Space Station Experiment 6 (MISSE 6) to compare the AO erosion yields of stressed and non-stressed polymers to determine if erosion is dependent upon stress while in LEO. The experiment contained 36 thin film polymer samples that were exposed to ram AO for 1.45 years. This paper provides an overview of the Stressed Polymers Experiment with details on the polymers flown, the characterization techniques used, the AO fluence, and the erosion yield results. The MISSE 6 data are compared to data for similar samples flown on previous MISSE missions to determine fluence or solar radiation effects on erosion yield

High-resolution mapping of losses and gains of Earth’s tidal wetlands

Tidal wetlands are expected to respond dynamically to global environmental change, but the extent to which wetland losses have been offset by gains remains poorly understood. We developed a global analysis of satellite data to simultaneously monitor change in three highly interconnected intertidal ecosystem types—tidal flats, tidal marshes, and mangroves—from 1999 to 2019. Globally, 13,700 square kilometers of tidal wetlands have been lost, but these have been substantially offset by gains of 9700 km2, leading to a net change of −4000 km2 over two decades. We found that 27% of these losses and gains were associated with direct human activities such as conversion to agriculture and restoration of lost wetlands. All other changes were attributed to indirect drivers, including the effects of coastal processes and climate change

Non-Hodgkin Lymphoma in Children and Adolescents: Progress Through Effective Collaboration, Current Knowledge, and Challenges Ahead

Non-Hodgkin lymphoma is the fourth most common malignancy in children, has an even higher incidence in adolescents, and is primarily represented by only a few histologic subtypes. Dramatic progress has been achieved, with survival rates exceeding 80%, in large part because of a better understanding of the biology of the different subtypes and national and international collaborations. Most patients with Burkitt lymphoma and diffuse large B-cell lymphoma are cured with short intensive pulse chemotherapy containing cyclophosphamide, cytarabine, and high-dose methotrexate. The benefit of the addition of rituximab has not been established except in the case of primary mediastinal B-cell lymphoma. Lymphoblastic lymphoma is treated with intensive, semi-continuous, longer leukemia-derived protocols. Relapses in B-cell and lymphoblastic lymphomas are rare and infrequently curable, even with intensive approaches. Event-free survival rates of approximately 75% have been achieved in anaplastic large-cell lymphomas with various regimens that generally include a short intensive B-like regimen. Immunity seems to play an important role in prognosis and needs further exploration to determine its therapeutic application. ALK inhibitor therapeutic approaches are currently under investigation. For all pediatric lymphomas, the intensity of induction/consolidation therapy correlates with acute toxicities, but because of low cumulative doses of anthracyclines and alkylating agents, minimal or no long-term toxicity is expected. Challenges that remain include defining the value of prognostic factors, such as early response on positron emission tomography/computed tomography and minimal disseminated and residual disease, using new biologic technologies to improve risk stratification, and developing innovative therapies, both in the first-line setting and for relapse