1,644 research outputs found
Carbon monoxide poisoning in a patient with carbon dioxide retention: a therapeutic challenge.
We present the case of a 70 year-old man with carbon monoxide poisoning following a house fire. A significant smoking history and likely underlying chronic lung pathology complicated treatment, as due to symptomatic retention of carbon dioxide we were unable to use high-flow oxygen to facilitate the elimination of carbon monoxide. We suggest that patients with risk factors for obstructive lung disease be monitored extremely carefully during treatment for carbon monoxide toxicity
A third trial oversight committee: Functions, benefits and issues
BACKGROUND/AIMS:
Clinical trial oversight is central to the safety of participants and production of robust data. The United Kingdom Medical Research Council originally set out an oversight structure comprising three committees in 1998. The first committee, led by the trial team, is hands-on with trial conduct/operations (‘Trial Management Group’) and essential. The second committee (Data Monitoring Committee), usually completely independent of the trial, reviews accumulating trial evidence and is used by most later phase trials. The Independent Data Monitoring Committee makes recommendations to the third oversight committee. The third committee, (‘Trial Steering Committee’), facilitates in-depth interactions of independent and non-independent trial members and gives broader oversight (blinded to comparative analysis). We investigated the roles and functioning of the third oversight committee with multiple research methods. We reflect upon these findings to standardise the committee’s remit and operation and to potentially increase its usage.
METHODS:
We utilised findings from our recent published suite of research on the third oversight committee to inform guideline revision. In brief, we conducted a survey of 38 United Kingdom–registered Clinical Trials Units, reviewed a cohort of 264 published trials, observed 8 third oversight committee meetings and interviewed 52 trialists. We convened an expert panel to discuss third oversight committees. Subsequently, we interviewed nine patient/lay third committee members and eight committee Chairs.
RESULTS:
In the survey, most Clinical Trials Units required a third committee for all their trials (27/38, 71%) with independent members (ranging from 1 to 6). In the survey and interviews, the independence of the third committee was valued to make unbiased consideration of Independent Data Monitoring Committee recommendations and to advise on trial progress, protocol changes and recruitment issues in conjunction with the trial leadership. The third committee also advised funders and sponsors about trial continuation and represented patients and the public by including lay members. Of the cohort of 264 published trials, 144 reported a ‘steering’ committee (55%), but the independence of these members was not described so these may have been internal Trial Management Groups. Around two thirds of papers (60%) reported having an Independent Data Monitoring Committee and 26.9% neither a steering nor an Independent Data Monitoring Committee. However, before revising the third committee charter (Terms of Reference), greater standardisation is needed around defining member independence, composition, primacy of decision-making, interactions with other committees and the lifespan.
CONCLUSION:
A third oversight committee has benefits for trial oversight and conduct, and a revised charter will facilitate greater standardisation and wider adoption
Recommended from our members
The impact and significance of tephra deposition on a Holocene forest environment in the North Cascades, Washington, USA
High-resolution palaeoecological analyses (stratigraphy, tephra geochemistry, radiocarbon dating, pollen and ordination) were used to reconstruct a Holocene vegetation history of a watershed in the Pacific Northwest of America to evaluate the effects and duration of tephra deposition on a forest environment and the significance of these effects compared to long-term trends. Three tephra deposits were detected and evaluated: MLF-T158 and MLC-T324 from the climactic eruption of Mount Mazama, MLC-T480 from a Late Pleistocene eruption of Mount Mazama and MLC-T485 from a Glacier Peak eruption. Records were examined from both the centre and fringe of the basin to elucidate regional and local effects. The significance of tephra impacts independent of underlying long-term trends was confirmed using partial redundancy analysis. Tephra deposition from the climactic eruption of Mount Mazama approximately 7600 cal. years BP caused a significant local impact, reflected in the fringe location by changes to open habitat vegetation (Cyperaceae and Poaceae) and changes in aquatic macrophytes (Myriophyllum spicatum, Potamogeton, Equisetum and the alga Pediastrum). There was no significant impact of the climactic Mazama tephra or other tephras detected on the pollen record of the central core. Changes in this core are potentially climate driven. Overall, significant tephra fall was demonstrated through high resolution analyses indicating a local effect on the terrestrial and aquatic environment, but there was no significant impact on the regional forest dependent of underlying environmental changes
The parabola theorem on continued fractions
Using geometric methods borrowed from the theory of Kleinian groups, we interpret the parabola theorem on continued fractions in terms of sequences of Möbius transformations. This geometric approach allows us to relate the Stern–Stolz series, which features in the parabola theorem, to the dynamics of certain sequences of Möbius transformations acting on three-dimensional hyperbolic space. We also obtain a version of the parabola theorem in several dimensions
Somatic mutations in facial skin from countries of contrasting skin cancer risk
The incidence of keratinocyte cancer (basal cell and squamous cell carcinomas of the skin) is 17-fold lower in Singapore than the UK1-3, despite Singapore receiving 2-3 times more ultraviolet (UV) radiation4,5. Aging skin contains somatic mutant clones from which such cancers develop6,7. We hypothesized that differences in keratinocyte cancer incidence may be reflected in the normal skin mutational landscape. Here we show that, compared to Singapore, aging facial skin from populations in the UK has a fourfold greater mutational burden, a predominant UV mutational signature, increased copy number aberrations and increased mutant TP53 selection. These features are shared by keratinocyte cancers from high-incidence and low-incidence populations8-13. In Singaporean skin, most mutations result from cell-intrinsic processes; mutant NOTCH1 and NOTCH2 are more strongly selected than in the UK. Aging skin in a high-incidence country has multiple features convergent with cancer that are not found in a low-risk country. These differences may reflect germline variation in UV-protective genes
From Nonspecific DNA–Protein Encounter Complexes to the Prediction of DNA–Protein Interactions
©2009 Gao, Skolnick. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.doi:10.1371/journal.pcbi.1000341DNA–protein interactions are involved in many essential biological activities. Because there is no simple mapping code between DNA base pairs and protein amino acids, the prediction of DNA–protein interactions is a challenging problem. Here, we present a novel computational approach for predicting DNA-binding protein residues and DNA–protein interaction modes without knowing its specific DNA target sequence. Given the structure of a DNA-binding protein, the method first generates an ensemble of complex structures obtained by rigid-body docking with a nonspecific canonical B-DNA. Representative models are subsequently selected through clustering and ranking by their DNA–protein interfacial energy. Analysis of these encounter complex models suggests that the recognition sites for specific DNA binding are usually favorable interaction sites for the nonspecific DNA probe and that nonspecific DNA–protein interaction modes exhibit some similarity to specific DNA–protein binding modes. Although the method requires as input the knowledge that the protein binds DNA, in benchmark tests, it achieves better performance in identifying DNA-binding sites than three previously established methods, which are based on sophisticated machine-learning techniques. We further apply our method to protein structures predicted through modeling and demonstrate that our method performs satisfactorily on protein models whose root-mean-square Ca deviation from native is up to 5 Å from their native structures. This study provides valuable structural insights into how a specific DNA-binding protein interacts with a nonspecific DNA sequence. The similarity between the specific DNA–protein interaction mode and nonspecific interaction modes may reflect an important sampling step in search of its specific DNA targets by a DNA-binding protein
Thermotomaculum hydrothermale gen. nov., sp. nov., a novel heterotrophic thermophile within the phylum Acidobacteria from a deep-sea hydrothermal vent chimney in the Southern Okinawa Trough
http://www.godac.jamstec.go.jp/darwin/cruise/natsushima/nt08-13/
Splice-Modulating Oligonucleotide QR-110 Restores CEP290 mRNA and Function in Human c.2991+1655A>G LCA10 Models.
Leber congenital amaurosis type 10 (LCA10) is a severe inherited retinal dystrophy associated with mutations in CEP290. The deep intronic c.2991+1655A>G mutation in CEP290 is the most common mutation in LCA10 individuals and represents an ideal target for oligonucleotide therapeutics. Here, a panel of antisense oligonucleotides was designed to correct the splicing defect associated with the mutation and screened for efficacy and safety. This identified QR-110 as the best-performing molecule. QR-110 restored wild-type CEP290 mRNA and protein expression levels in CEP290 c.2991+1655A>G homozygous and compound heterozygous LCA10 primary fibroblasts. Furthermore, in homozygous three-dimensional iPSC-derived retinal organoids, QR-110 showed a dose-dependent restoration of mRNA and protein function, as measured by percentage and length of photoreceptor cilia, without off-target effects. Localization studies in wild-type mice and rabbits showed that QR-110 readily reached all retinal layers, with an estimated half-life of 58 days. It was well tolerated following intravitreal injection in monkeys. In conclusion, the pharmacodynamic, pharmacokinetic, and safety properties make QR-110 a promising candidate for treating LCA10, and clinical development is currently ongoing.This study was funded by ProQR. iPSC work in the Cheetham lab is also supported by the Wellcome Trust, Fight for Sight, RP Fighting Blindness, and Moorfields Eye Charity
Evolutionary dynamics and biogeography of Musaceae reveal a correlation between the diversification of the banana family and the geological and climatic history of Southeast Asia
Article PurchasedTropical Southeast Asia, which harbors most of the Musaceae biodiversity, is one of the most species-rich regions in the world. Its high degree of endemism is shaped by the region's tectonic and climatic history, with large differences between northern Indo-Burma and the Malayan Archipelago. Here, we aim to find a link between the diversification and biogeography of Musaceae and geological history of the Southeast Asian subcontinent. The Musaceae family (including five Ensete, 45 Musa and one Musella species) was dated using a large phylogenetic framework encompassing 163 species from all Zingiberales families. Evolutionary patterns within Musaceae were inferred using ancestral area reconstruction and diversification rate analyses. All three Musaceae genera - Ensete, Musa and Musella - originated in northern Indo-Burma during the early Eocene. Musa species dispersed from 'northwest to southeast' into Southeast Asia with only few back-dispersals towards northern Indo-Burma. Musaceae colonization events of the Malayan Archipelago subcontinent are clearly linked to the geological and climatic history of the region. Musa species were only able to colonize the region east of Wallace's line after the availability of emergent land from the late Miocene onwards
Asteroseismology and Interferometry
Asteroseismology provides us with a unique opportunity to improve our
understanding of stellar structure and evolution. Recent developments,
including the first systematic studies of solar-like pulsators, have boosted
the impact of this field of research within Astrophysics and have led to a
significant increase in the size of the research community. In the present
paper we start by reviewing the basic observational and theoretical properties
of classical and solar-like pulsators and present results from some of the most
recent and outstanding studies of these stars. We centre our review on those
classes of pulsators for which interferometric studies are expected to provide
a significant input. We discuss current limitations to asteroseismic studies,
including difficulties in mode identification and in the accurate determination
of global parameters of pulsating stars, and, after a brief review of those
aspects of interferometry that are most relevant in this context, anticipate
how interferometric observations may contribute to overcome these limitations.
Moreover, we present results of recent pilot studies of pulsating stars
involving both asteroseismic and interferometric constraints and look into the
future, summarizing ongoing efforts concerning the development of future
instruments and satellite missions which are expected to have an impact in this
field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume
14, Issue 3-4, pp. 217-36
- …