342 research outputs found
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A pragmatic patient-reported outcome strategy for rare disease clinical trials: application of the EORTC item library to myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myeloid leukemia.
BackgroundNovel, pragmatic, patient-centered strategies are needed to ensure fit-for-purpose patient-reported outcomes (PRO) instruments in clinical trial research for rare diseases such as myelodysplastic syndromes (MDS), acute myeloid leukemia (AML), and chronic myelomonocytic leukemia (CMML). The objective of the current study was to select supplemental items to add to the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life-Core 30 (QLQ-C30) to ensure content coverage of all important clinical concepts in patients with higher-risk (HR) MDS, low-blast count (LB) AML, and CMML, thus, improving the instrument's ability to detect clinically meaningful treatment benefit for this context of use.MethodsOur mixed methods approach comprised literature review, clinician consultation (n = 3), and qualitative and quantitative analysis of two stages of patient interview data (n = 14, n = 18) to select library bank items to supplement a generic cancer PRO, the EORTC QLQ-C30.ResultsUnique symptom (n = 54) and impact (n = 72) concepts were organized into conceptual frameworks of treatment benefit, compared with EORTC QLQ-C30 items and conceptual gaps identified. Supplemental items (n = 13) addressing those gaps were selected from the EORTC Item Library and tested with patients. Supplemental item endorsement frequencies met World Health Organization Quality of Life criteria, suggesting good targeting and relevance for this sample. However, three supplemental items were confirmed as problematic based upon cognitive debriefing results, and expert clinical consultations. Ultimately, 10 supplemental items (n = 7 symptom; n = 3 impact) were selected for the MDS/AML/CMML context.ConclusionSupplemental items were selected to enhance the conceptual coverage of the EORTC QLQ-C30 in the areas of fatigue, shortness of breath, and functioning
Genetic mapping and developmental timing of transmission ratio distortion in a mouse interspecific backcross
<p>Abstract</p> <p>Background</p> <p>Transmission ratio distortion (TRD), defined as statistically significant deviation from expected 1:1 Mendelian ratios of allele inheritance, results in a reduction of the expected progeny of a given genotype. Since TRD is a common occurrence within interspecific crosses, a mouse interspecific backcross was used to genetically map regions showing TRD, and a developmental analysis was performed to identify the timing of allele loss.</p> <p>Results</p> <p>Three independent events of statistically significant deviation from the expected 50:50 Mendelian inheritance ratios were observed in an interspecific backcross between the <it>Mus musculus </it>A/J and the <it>Mus spretus </it>SPRET/EiJ inbred strains. At weaning <it>M. musculus </it>alleles are preferentially inherited on Chromosome (Chr) 7, while <it>M. spretus </it>alleles are preferentially inherited on Chrs 10 and 11. Furthermore, alleles on Chr 3 modify the TRD on Chr 11. All TRD loci detected at weaning were present in Mendelian ratios at mid-gestation and at birth.</p> <p>Conclusions</p> <p>Given that Mendelian ratios of inheritance are observed for Chr 7, 10 and 11 during development and at birth, the underlying causes for the interspecific TRD events are the differential post-natal survival of pups with specific genotypes. These results are consistent with the TRD mechanism being deviation from Mendelian inheritance rather than meiotic drive or segregation distortion.</p
Joint association between ambient air pollutant mixture and pediatric asthma exacerbations
Background: Exposure to air pollutants is known to exacerbate asthma, with prior studies focused on associations between single pollutant exposure and asthma exacerbations. As air pollutants often exist as a complex mixture, there is a gap in understanding the association between complex air pollutant mixtures and asthma exacerbations. We evaluated the association between the air pollutant mixture (52 pollutants) and pediatric asthma exacerbations.
Method: This study focused on children (age ≤ 19 years) who lived in Douglas County, Nebraska, during 2016–2019. A seasonal- scale joint association between the outdoor air pollutant mixture adjusting for potential confounders (temperature, precipitation, wind speed, and wind direction) in relation to pediatric asthma exacerbation-related emergency department (ED) visits was evaluated using the generalized weighted quantile sum (qWQS) regression with repeated holdout validation.
Results: We observed associations between air pollutant mixture and pediatric asthma exacerbations during spring (lagged by 5 days), summer (lag 0–5 days), and fall (lag 1–3 days) seasons. The estimate of the joint outdoor air pollutant mixture effect was higher during the summer season (adjusted-βWQS = 1.11, 95% confidence interval [CI]: 0.66, 1.55), followed by spring (adjusted-βWQS = 0.40, 95% CI: 0.16, 0.62) and fall (adjusted-βWQS = 0.20, 95% CI: 0.06, 0.33) seasons. Among the air pollutants, PM2.5, pollen, and mold contributed higher weight to the air pollutant mixture.
Conclusion: There were associations between outdoor air pollutant mixture and pediatric asthma exacerbations during the spring, summer, and fall seasons. Among the 52 outdoor air pollutant metrics investigated, PM2.5, pollen (sycamore, grass, cedar), and mold (Helminthosporium, Peronospora, and Erysiphe) contributed the highest weight to the air pollutant mixture
A deep Large Binocular Telescope view of the Canes Venatici I dwarf galaxy
We present the first deep color-magnitude diagram of the Canes Venatici I
(CVnI) dwarf galaxy from observations with the wide field Large Binocular
Camera on the Large Binocular Telescope. Reaching down to the main-sequence
turnoff of the oldest stars, it reveals a dichotomy in the stellar populations
of CVnI: it harbors an old (> 10 Gyr), metal-poor ([Fe/H] ~ -2.0) and spatially
extended population along with a much younger (~ 1.4-2.0 Gyr), 0.5 dex more
metal-rich, and spatially more concentrated population. These young stars are
also offset by 64_{-20}^{+40} pc to the East of the galaxy center. The data
suggest that this young population, which represent ~ 3-5 % of the stellar mass
of the galaxy within its half-light radius, should be identified with the
kinematically cold stellar component found by Ibata et al. (2006). CVnI
therefore follows the behavior of the other remote MW dwarf spheroidals which
all contain intermediate age and/or young populations: a complex star formation
history is possible in extremely low-mass galaxies.Comment: 4 pages, 3 figures, accepted for publication in ApJL. Minor changes,
conclusions unchange
Neighborhood Differences in COVID-19 Testing, Incidence, and Mortality in the State of Indiana
Background: COVID-19 is a highly contagious pandemic disease. This study aims to identify neighborhood-level sociodemographic, health behaviors, adherence to social distancing policies, and healthcare access factors associated with geographic variability of COVID-19 testing, case incidence, and mortality in the U.S. state of Indiana.
Methods: The study population included all Indiana residents. Geographic distribution of COVID-19 testing, positive cases, and mortality were estimated for each county and plotted using choropleth maps. Generalized bivariate and multivariable negative binomial regression were used to estimate effects of county-level factors.
Results: Higher rates of testing, case detection, and mortality were associated with a greater proportion of non-white residents. Counties with better scores in social distancing and greater proportion of older residents had lower incidence of laboratory testing. We found the highest socioeconomic tertile was associated with higher rates of cases, but no difference in testing or mortality. Improved social distancing lowered the incidence of COVID-19 testing and cases. Densely populated counties had higher testing and incidence of COVID-19 cases per capita, however, higher mortality rates were observed in rural/mixed counties.
Conclusion: Differences in COVID-19 testing, case detection, and mortality in Indiana are associated with neighborhood-level characteristics. Local contexts should be considered in COVID-19 response planning
The Subtype of GluN2 C-terminal Domain Determines the Response to Excitotoxic Insults
It is currently unclear whether the GluN2 subtype influences NMDA receptor (NMDAR) excitotoxicity. We report that the toxicity of NMDAR-mediated Ca(2+) influx is differentially controlled by the cytoplasmic C-terminal domains of GluN2B (CTD(2B)) and GluN2A (CTD(2A)). Studying the effects of acute expression of GluN2A/2B-based chimeric subunits with reciprocal exchanges of their CTDs revealed that CTD(2B) enhances NMDAR toxicity, compared to CTD(2A). Furthermore, the vulnerability of forebrain neurons in vitro and in vivo to NMDAR-dependent Ca(2+) influx is lowered by replacing the CTD of GluN2B with that of GluN2A by targeted exon exchange in a mouse knockin model. Mechanistically, CTD(2B) exhibits stronger physical/functional coupling to the PSD-95-nNOS pathway, which suppresses protective CREB activation. Dependence of NMDAR excitotoxicity on the GluN2 CTD subtype can be overcome by inducing high levels of NMDAR activity. Thus, the identity (2A versus 2B) of the GluN2 CTD controls the toxicity dose-response to episodes of NMDAR activity
WireWall – a new approach to measuring coastal wave hazard
In the UK £150bn of assets and 4 million people are at risk from coastal flooding, whilst the construction of sea wall defence schemes typically cost at least £10,000 per linear meter. With reductions in public funding, rising sea level, changing storm conditions and 3200 km of coastal defences (i.e. about £3bn), cost savings are required that do not cause a reduction in flood resistance. The design of new coastal flood defences and the setting of tolerable hazard thresholds requires site-specific information of wave overtopping during storms of varying severity. By converting an existing wave measurement technology into a prototype overtopping monitoring system "WireWall", field observations of the wave-by-wave horizontal overtopping speeds and volumes were made at our case study site Crosby, in the North West of England. The new data quantify the wave overtopping conditions observed, which varied with the wind, waves and tide, allowing better understanding of how wave hazard at Crosby changes with the local conditions
Measurement and analysis of household carbon: the case of a UK city
There is currently a lack of data recording the carbon and emissions inventory at household level. This paper presents a multi-disciplinary, bottom-up approach for estimation and analysis of the carbon emissions, and the organic carbon (OC) stored in gardens, using a sample of 575 households across a UK city. The annual emission of carbon dioxide emissions from energy used in the homes was measured, personal transport emissions were assessed through a household survey and OC stores estimated from soil sampling and vegetation surveys. The results showed that overall carbon patterns were skewed with highest emitting third of the households being responsible for more than 50% of the emissions and around 50% of garden OC storage. There was diversity in the relative contribution that gas, electricity and personal transport made to each household’s total and different patterns were observed for high, medium and low emitting households. Targeting households with high carbon emissions from one source would not reliably identify them as high emitters overall. While carbon emissions could not be offset by growing trees in gardens, there were considerable amounts of stored OC in gardens which ought to be protected. Exploratory analysis of the multiple drivers of emissions was conducted using a combination of primary and secondary data. These findings will be relevant in devising effective policy instruments for combatting city scale green-house gas emissions from domestic end-use energy demand
Global political responsibility for the conservation of albatrosses and large petrels
Migratory marine species cross political borders and enter the high seas, where the lack of an effective global management framework for biodiversity leaves them vulnerable to threats. Here, we combine 10,108 tracks from 5775 individual birds at 87 sites with data on breeding population sizes to estimate the relative year-round importance of national jurisdictions and high seas areas for 39 species of albatrosses and large petrels. Populations from every country made extensive use of the high seas, indicating the stake each country has in the management of biodiversity in international waters. We quantified the links among national populations of these threatened seabirds and the regional fisheries management organizations (RFMOs) which regulate fishing in the high seas. This work makes explicit the relative responsibilities that each country and RFMO has for the management of shared biodiversity, providing invaluable information for the conservation and management of migratory species in the marine realm
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