Background
Oxygen saturation monitoring for children receiving respiratory support is standard worldwide. No randomised clinical trials have compared peripheral oxygen saturation (SpO
2
) targets for ...critically ill children. The harm of interventions to raise SpO
2
to > 94% may exceed their benefits.
Methods
We undertook an open, parallel-group randomised trial of children > 38 weeks completed gestation and < 16 years of age receiving invasive or non-invasive respiratory support and supplemental oxygen who were admitted urgently to one of three paediatric intensive care units. A ‘research without prior consent’ approach was employed. Children were randomly assigned to a liberal oxygenation group (SpO
2
targets > 94%) or a conservative oxygenation group (SpO
2
= 88–92% inclusive). Outcomes were measures of feasibility: recruitment rate, protocol adherence and acceptability, between-group separation of SpO
2
and safety. The Oxy-PICU trial was registered before recruitment: ClinicalTrials.gov identifier NCT03040570.
Results
A total of 159 children met the inclusion criteria, of whom 119 (75%) were randomised between April and July 2017, representing a rate of 10 patients per month per site. The mean time to randomisation from first contact with an intensive care team was 1.9 (SD 2.2) h. Consent to continue in the study was obtained in 107 cases (90%); the children’s parents/legal representatives were supportive of the consent process. The median (interquartile range, IQR) of time-weighted individual mean SpO
2
was 94.9% (92.6–97.1) in the conservative oxygenation group and 97.5% (96.2–98.4) in the liberal group difference 2.7%, 95% confidence interval (95% CI) 1.3–4.0%,
p
< 0.001. Median (IQR) time-weighted individual mean FiO
2
was 0.28 (0.24–0.37) in the conservative group and 0.37 (0.30–0.42) in the liberal group (difference 0.08, 95% CI 0.03–0.13,
p
< 0.001). There were no significant between-group differences in length of stay, duration of organ support or mortality. Two prespecified serious adverse events (cardiac arrests) occurred, both in the liberal oxygenation group.
Conclusion
A definitive clinical trial of peripheral oxygen saturation targets is feasible in critically ill children.
Unilamellar polymer vesicles are formed when a block copolymer self-assembles to form a single bilayer structure, with a hydrophobic core and hydrophilic surfaces, and the resulting membrane folds ...over and rearranges by connecting its edges to enclose a space. The physics of self-assembly tightly specifies the wall thickness of the resulting vesicle, but, both for polymer vesicles and phospholipids, no mechanism strongly selects for the overall size, so the size distribution of vesicles tends to be very polydisperse. We report a method for the production of controlled size distributions of micrometre-sized (that is, giant) vesicles combining the 'top-down' control of micrometre-sized features (vesicle diameter) by photolithography and dewetting with the 'bottom-up' control of nanometre-sized features (membrane thickness) by molecular self-assembly. It enables the spontaneous creation of unilamellar vesicles with a narrow size distribution that could find applications in drug and gene delivery, nano- and micro-reactors, substrates for macromolecular crystallography and model systems for studies of membrane function.
We report the fabrication of high performance organic solar cells by spray‐coating the photoactive layer in air. The photovoltaic blends consist of a blend of carbazole and benzothiadiazole based ...donor–acceptor copolymers and the fullerene derivative PC70BM. Here, we formulate a number of photovoltaic inks using a range of solvent systems that we show can all be deposited by spray casting. We use a range of techniques to characterize the structure of such films, and show that spray‐cast films have comparable surface roughness to spin‐cast films and that vertical stratification that occurs during film drying reduces the concentration of PCBM towards the underlying PEDOT:PSS interface. We also show that the active layer thickness and the drying kinetics can be tuned through control of the substrate temperature. High power conversion efficiencies of 4.3%, 4.5% and 4.6% were obtained for solar cells made from a blend of PC70BM with the carbazole‐based co‐polymers PCDTBT, P2 and P1. By applying a low temperature anneal after the deposition of the cathode, the efficiency of spray‐cast solar‐cells based on a P2:PC70BM blend is increased to 5.0%. Spray coating holds significant promise as a technique capable of fabricating large‐area, high performance organic solar cells in air.
High performance organic solar cells from the blend of donor–acceptor copolymers and PC70BM were made by spray‐coating the photoactive layer in air. A high power conversion efficiency of 5% was achieved after device optimization. Neutron scattering measurements show that vertical stratification occurs during the film drying process, and the concentration of PCBM reduces towards the underlying PEDOT:PSS interface.
Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) ...represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.
Passing stars may play an important role in the evolution of our solar system. We search for close stellar encounters to the Sun among all 7.2 million stars in Gaia DR2 that have six-dimensional ...phase space data. We characterize encounters by integrating their orbits through a Galactic potential and propagating the correlated uncertainties via a Monte Carlo resampling. After filtering to remove spurious data, we find 694 stars that have median (over uncertainties) closest encounter distances within 5 pc, all occurring within 15 Myr from now. 26 of these have at least a 50% chance of coming closer than 1 pc (and 7 within 0.5 pc), all but one of which are newly discovered here. We confirm some and refute several other previously-identified encounters, confirming suspicions about their data. The closest encounter in the sample is Gl 710, which has a 95% probability of coming closer than 0.08 pc (17 000 AU). Taking mass estimates obtained from Gaia astrometry and multiband photometry for essentially all encounters, we find that Gl 710 also has the largest impulse on the Oort cloud. Using a Galaxy model, we compute the completeness of the Gaia DR2 encountering sample as a function of perihelion time and distance. Only 15% of encounters within 5 pc occurring within ±5 Myr of now have been identified, mostly due to the lack of radial velocities for faint and/or cool stars. Accounting for the incompleteness, we infer the present rate of encounters within 1 pc to be 19.7 ± 2.2 per Myr, a quantity expected to scale quadratically with the encounter distance out to at least several pc. Spuriously large parallaxes in our sample from imperfect filtering would tend to inflate both the number of encounters found and this inferred rate. The magnitude of this effect is hard to quantify.
The underlying pathology of schizophrenia (SZ) is likely as heterogeneous as its symptomatology. A variety of cortical and subcortical regions, including the prefrontal cortex, have been implicated ...in its pathology, and a number of genes have been identified as risk factors for disease development. We used in situ hybridization (ISH) to examine the expression of 58 genes in the dorsolateral prefrontal cortex (DLPFC, comprised of Brodmann areas 9 and 46) from 19 individuals with a premorbid diagnosis of SZ and 33 control individuals. Genes were selected based on: (1) previous identification as risk factors for SZ; (2) cell type markers or (3) laminar markers. Cell density and staining intensity were compared in the DLPFC, as well as separately in Brodmann areas 9 and 46. The expression patterns of a variety of genes, many of which are associated with the GABAergic system, were altered in SZ when compared with controls. Additional genes, including C8orf79 and NR4A2, showed alterations in cell density or staining intensity between the groups, highlighting the need for additional studies. Alterations were, with only a few exceptions, limited to Brodmann area 9, suggesting regional specificity of pathology in the DLPFC. Our results agree with previous studies on the GABAergic involvement in SZ, and suggest that areas 9 and 46 may be differentially affected in the disease. This study also highlights additional genes that may be altered in SZ, and indicates that these potentially interesting genes can be identified by ISH and high-throughput image analysis techniques.
The optical lightcurves of many quasars show variations of tenths of a magnitude or more on timescales of months to years. This variation often cannot be described well by a simple deterministic ...model. We perform a Bayesian comparison of over 20 deterministic and stochastic models on 6304 quasi-steller object (QSO) lightcurves in SDSS Stripe 82. We include the damped random walk (or Ornstein-Uhlenbeck OU process), a particular type of stochastic model, which recent studies have focused on. Further models we consider are single and double sinusoids, multiple OU processes, higher order continuous autoregressive processes, and composite models. We find that only 29 out of 6304 QSO lightcurves are described significantly better by a deterministic model than a stochastic one. The OU process is an adequate description of the vast majority of cases (6023). Indeed, the OU process is the best single model for 3462 lightcurves, with the composite OU process/sinusoid model being the best in 1706 cases. The latter model is the dominant one for brighter/bluer QSOs. Furthermore, a non-negligible fraction of QSO lightcurves show evidence that not only the mean is stochastic but the variance is stochastic, too. Our results confirm earlier work that QSO lightcurves can be described with a stochastic model, but place this on a firmer footing, and further show that the OU process is preferred over several other stochastic and deterministic models. Of course, there may well exist yet better (deterministic or stochastic) models, which have not been considered here.
The first part of this two-part paper demonstrated the feasibility of the direct use of data from a high resolution (25
km) Regional Climate Model (RCM) to provide inputs for a rainfall-runoff model, ...in order to obtain estimates of flood frequency. This paper uses data from a climate change experiment with the same RCM (HadRM3H) to provide estimates of change in flood frequency between the 1970s and 2080s, for 15 catchments across Great Britain. This experiment is a rerun, at twice the horizontal resolution, of one of those used by the UK Climate Impacts Programme (UKCIP) in the construction of its UKCIP02 climate change scenarios for the UK. It thus allows an exploration of the implication of these scenarios using a resolution more suited to the detailed hydrological application addressed in this paper. Despite decreases in annual average rainfall in all but one catchment, eight show an increase in flood frequency at most return periods whereas two show substantial decreases. As part I of this paper showed a distinct positive correlation between errors in annual rainfall and errors in flood frequency, the fact that flood frequency can increase despite an overall decrease in rainfall implies a marked change in the distribution of rainfall, either in terms of the probability of rainfall events and/or its seasonal cycle. Decreases in flood peaks are shown for a number of the catchments in the south and east of England, despite an increase in winter mean and extreme rainfall. Increased summer and autumn soil moisture deficits are thought to be the reason for this. Other catchments, further north or west, show an increase in flood peaks, in some cases of over 50% at the 50-year return period. Care needs to be taken when interpreting these results, as they are based on a single RCM experiment (using driving data from one GCM under a single emissions scenario). Other RCM experiments may give quite different results, and ensemble runs would ideally be required to limit sample error.
Most p53 mutations in human cancers are missense mutations resulting in a full-length mutant p53 protein. Besides losing tumor suppressor activity, some hotspot p53 mutants gain oncogenic functions. ...This effect is mediated in part, through gene expression changes due to inhibition of p63 and p73 by mutant p53 at their target gene promoters. Here, we report that the tumor suppressor microRNA let-7i is downregulated by mutant p53 in multiple cell lines expressing endogenous mutant p53. In breast cancer patients, significantly decreased let-7i levels were associated with missense mutations in p53. Chromatin immunoprecipitation and promoter luciferase assays established let-7i as a transcriptional target of mutant p53 through p63. Introduction of let-7i to mutant p53 cells significantly inhibited migration, invasion and metastasis by repressing a network of oncogenes including E2F5, LIN28B, MYC and NRAS. Our findings demonstrate that repression of let-7i expression by mutant p53 has a key role in enhancing migration, invasion and metastasis.
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