5,962 research outputs found

    Test evaluation trials present different challenges for trial managers compared to Intervention trials

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    Introduction Test evaluation trials present different challenges for trial managers compared to intervention trials. There has been very little research on the management of test evaluation trials and how this impacts on trial success, in comparison with intervention trials. Evaluations of medical tests present specific challenges, because they are a pivot point bridging the complexities of pathways prompting testing with treatment decision-making. We systematically explored key differences in the trial design and management of test evaluation trials compared to intervention trials at the different stages of study design and delivery. We identified challenges in test evaluation trials that were more pronounced than in intervention trials, based on experience from 10 test evaluation trials. Methods We formed a focus group of 7 trial managers and a statistician who had been involved in the day-to-day management of both test evaluation trials and intervention trials. We used discussion and content analysis to group challenges from 10 trials into a structured thematic format. The trials covered a range of medical conditions, diagnostic tests, clinical pathways and conditions including chronic kidney disease, chronic pelvic pain, colitis, detrusor over-activity, group B streptococcal colonisation, tuberculosis and colorectal, lung, ovarian and thyroid cancers. Results We identified 10 common themes underlying challenges that are more pronounced in test evaluation compared to intervention trials. We illustrate these themes with examples from 10 trials, including with 31 specific challenges we experienced. The themes were ethics/governance; accessing patient populations; recruitment; patient preference; test processes, clinical pathways and samples storage; uncertainty of diagnostic results; verifying diagnosis (reference standard); follow-up; adverse effects; and diagnostic impact. Conclusion We present 10 common themes, including 31 challenges, in test evaluation trials that will be helpful to others designing and managing future test evaluation trials. Proactive identification of potential challenges at the design and planning stages of test evaluation trials will enable strategies to improve trial design and management that may be different from standard strategies used for intervention trials. Future work could extend this topic to include challenges for other trial stakeholders including participants, clinicians, statisticians and funders

    Effective mobilities in pseudomorphic Si/SiGe/Si p-channel metal-oxide-semiconductor field-effect transistors with thin silicon capping layers

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    The room-temperature effective mobilities of pseudomorphic Si/Si0.64Ge0.36/Si p-metal-oxidesemiconductor field effect transistors are reported. The peak mobility in the buried SiGe channel increases with silicon cap thickness. It is argued that SiO2/Si interface roughness is a major source of scattering in these devices, which is attenuated for thicker silicon caps. It is also suggested that segregated Ge in the silicon cap interferes with the oxidation process, leading to increased SiO2/Si interface roughness in the case of thin silicon caps

    Analysis of independent cohorts of outbred CFW mice reveals novel loci for behavioral and physiological traits and identifies factors determining reproducibility

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    Combining samples for genetic association is standard practice in human genetic analysis of complex traits, but is rarely undertaken in rodent genetics. Here, using 23 phenotypes and genotypes from two independent laboratories, we obtained a sample size of 3,076 commercially available outbred mice and identified 70 loci, more than double the number of loci identified in the component studies. Fine-mapping in the combined sample reduced the number of likely causal variants, with a median reduction in set size of 51%, and indicated novel gene associations, including Pnpo, Ttll6 and GM11545 with bone mineral density, and Psmb9 with weight. However replication at a nominal threshold of 0.05 between the two component studies was low, with less than a third of loci identified in one study replicated in the second. In addition to overestimates in the effect size in the discovery sample (Winner's Curse), we also found that heterogeneity between studies explained the poor replication, but the contribution of these two factors varied among traits. Leveraging these observations we integrated information about replication rates, study-specific heterogeneity, and Winner's Curse corrected estimates of power to assign variants to one of four confidence levels. Our approach addresses concerns about reproducibility, and demonstrates how to obtain robust results from mapping complex traits in any genome-wide association study

    Methane emissions are predominantly responsible for record-breaking atmospheric methane growth rates in 2020 and 2021

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    The global atmospheric methane growth rates reported by NOAA for 2020 and 2021 are the largest since systematic measurements began in 1983. To explore the underlying reasons for these anomalous growth rates, we use newly available methane data from the Japanese Greenhouse gases Observing SATellite (GOSAT) to estimate methane surface emissions. Relative to baseline values in 2019, we find that a significant global increase in methane emissions of 27.0 ± 11.3 and 20.8 ± 11.4 Tg is needed to reproduce observed atmospheric methane in 2020 and 2021, respectively, assuming fixed climatological values for OH. We see the largest annual increases in methane emissions during 2020 over Eastern Africa (14 ± 3 Tg), tropical Asia (3 ± 4 Tg), tropical South America (5 ± 4 Tg), and temperate Eurasia (3 ± 3 Tg), and the largest reductions are observed over China (−6 ± 3 Tg) and India (−2 ± 3 Tg). We find comparable emission changes in 2021, relative to 2019, except for tropical and temperate South America where emissions increased by 9 ± 4 and 4 ± 3 Tg, respectively, and for temperate North America where emissions increased by 5 ± 2 Tg. The elevated contributions we saw in 2020 over the western half of Africa (−5 ± 3 Tg) are substantially reduced in 2021, compared to our 2019 baseline. We find statistically significant positive correlations between anomalies of tropical methane emissions and groundwater, consistent with recent studies that have highlighted a growing role for microbial sources over the tropics. Emission reductions over India and China are expected in 2020 due to the Covid-19 lockdown but continued in 2021, which we do not currently understand. To investigate the role of reduced OH concentrations during the Covid-19 lockdown in 2020 on the elevated atmospheric methane growth in 2020–2021, we extended our inversion state vector to include monthly scaling factors for OH concentrations over six latitude bands. During 2020, we find that tropospheric OH is reduced by 1.4 ± 1.7 % relative to the corresponding 2019 baseline value. The corresponding revised global growth of a posteriori methane emissions in 2020 decreased by 34 % to 17.9 ± 13.2 Tg, relative to the a posteriori value that we inferred using fixed climatological OH values, consistent with sensitivity tests using the OH climatology inversion using reduced values for OH. The counter statement is that 66 % of the global increase in atmospheric methane during 2020 was due to increased emissions, particularly from tropical regions. Regional flux differences between the joint methane–OH inversion and the OH climatology inversion in 2020 are typically much smaller than 10 %. We find that OH is reduced by a much smaller amount during 2021 than in 2020, representing about 10 % of the growth of atmospheric methane in that year. Therefore, we conclude that most of the observed increase in atmospheric methane during 2020 and 2021 is due to increased emissions, with a significant contribution from reduced levels of OH.</p

    The evolution, diversity, and host associations of rhabdoviruses.

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    Metagenomic studies are leading to the discovery of a hidden diversity of RNA viruses. These new viruses are poorly characterized and new approaches are needed predict the host species these viruses pose a risk to. The rhabdoviruses are a diverse family of RNA viruses that includes important pathogens of humans, animals, and plants. We have discovered thirty-two new rhabdoviruses through a combination of our own RNA sequencing of insects and searching public sequence databases. Combining these with previously known sequences we reconstructed the phylogeny of 195 rhabdovirus sequences, and produced the most in depth analysis of the family to date. In most cases we know nothing about the biology of the viruses beyond the host they were identified from, but our dataset provides a powerful phylogenetic approach to predict which are vector-borne viruses and which are specific to vertebrates or arthropods. By reconstructing ancestral and present host states we found that switches between major groups of hosts have occurred rarely during rhabdovirus evolution. This allowed us to propose seventy-six new likely vector-borne vertebrate viruses among viruses identified from vertebrates or biting insects. Based on currently available data, our analysis suggests it is likely there was a single origin of the known plant viruses and arthropod-borne vertebrate viruses, while vertebrate- and arthropod-specific viruses arose at least twice. There are also few transitions between aquatic and terrestrial ecosystems. Viruses also cluster together at a finer scale, with closely related viruses tending to be found in closely related hosts. Our data therefore suggest that throughout their evolution, rhabdoviruses have occasionally jumped between distantly related host species before spreading through related hosts in the same environment. This approach offers a way to predict the most probable biology and key traits of newly discovered viruses.BL and FMJ are supported by a NERC grant (NE/L004232/1), a European Research Council grant (281668, DrosophilaInfection), a Junior Research Fellowship from Christ’s College, Cambridge (BL). GGRM is supported by an MRC studentship. The metagenomic sequencing of viruses from D. immigrans, D. tristis and S. deflexa was supported by a Wellcome Trust fellowship (WT085064) to DJO.This is the final version of the article. It first appeared from Oxford University Press via http://dx.doi.org/10.1093/ve/vev01

    The added value of satellite observations of methane for understanding the contemporary methane budget

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    Surface observations have recorded large and incompletely understood changes to atmospheric methane (CH(4)) this century. However, their ability to reveal the responsible surface sources and sinks is limited by their geographical distribution, which is biased towards the northern midlatitudes. Data from Earth-orbiting satellites designed specifically to measure atmospheric CH(4) have been available since 2009 with the launch of the Japanese Greenhouse gases Observing SATellite (GOSAT). We assess the added value of GOSAT to data collected by the US National Oceanic and Atmospheric Administration (NOAA), which have been the lynchpin for knowledge about atmospheric CH(4) since the 1980s. To achieve that we use the GEOS-Chem atmospheric chemistry transport model and an inverse method to infer a posteriori flux estimates from the NOAA and GOSAT data using common a priori emission inventories. We find the main benefit of GOSAT data is from its additional coverage over the tropics where we report large increases since the 2014/2016 El Niño, driven by biomass burning, biogenic emissions and energy production. We use data from the European TROPOspheric Monitoring Instrument to show how better spatial coverage and resolution measurements allow us to quantify previously unattainable diffuse sources of CH(4), thereby opening up a new research frontier. This article is part of a discussion meeting issue ‘Rising methane: is warming feeding warming? (part 1)’
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