Blood eosinophils as a marker of likely corticosteroid response in children with preschool wheeze: time for an eosinophil guided clinical trial?

Childhood wheezing is common particularly in children under the age of six years and in this age-group is generally referred to as preschool wheezing. Particular diagnostic and treatment uncertainties exist in these young children due to the difficulty in obtaining objective evidence of reversible airways narrowing and inflammation. A diagnosis of asthma depends on the presence of relevant clinical signs and symptoms and the demonstration of reversible airways narrowing on lung function testing, which is difficult to perform in young children. Few treatments are available and inhaled corticosteroids are the recommended preventer treatment in most international asthma guidelines. There is however considerable controversy about its effectiveness in children with preschool wheeze and a corticosteroid responder phenotype has not been established. These diagnostic and treatment uncertainties in conjunction with the knowledge of corticosteroid side-effects, in particular the reduction of growth velocity, has resulted in a variable approach to inhaled corticosteroid prescribing by medical practitioners and a reluctance in carers to regularly administer the treatment. Identifying children who are likely responders to corticosteroid therapy would be a major benefit in the management of this condition. Eosinophils have emerged as a promising biomarker of corticosteroid responsive airways disease and evaluation of this biomarker in sputum has successfully been employed to direct management in adults with asthma. Obtaining sputum from young children is time-consuming and difficult and it is hard to justify more invasive procedures such as a bronchoscopy in young children routinely. Recently, in children, interest has shifted to assessing the value of less invasive biomarkers of likely corticosteroid response and the biomarker 'blood eosinophils' has emerged as an attractive candidate. The aim of this review is to summarise the evidence for blood eosinophils as a predictive biomarker for corticosteroid responsive disease with a particular focus on the difficult area of preschool wheeze. 

Absolute magnitudes and slope parameters of Pan-STARRS PS1 asteroids -preliminary results

We present the study of absolute magnitude (H) and slope parameter (G) of 170,000 asteroids observed by the Pan-STARRS1 telescope during the period of 15 months within its 3-year all-sky survey mission. The exquisite photometry with photometric errors below 0.04 mag and well-defined filter and photometric system allowed to derive H and G with statistical and systematic errors. Our new approach lies in the Monte Carlo technique simulating rotation periods, amplitudes, and colors, and deriving most-likely H, G and their systematic errors. Comparison of H_M by Muinonen's phase function (Muinonen et al., 2010) with the Minor Planet Center database revealed a negative offset of 0.22±0.29 meaning that Pan-STARRS1 asteroids are fainter. We showed that the absolute magnitude derived by Muinonen's function is systematically larger on average by 0.14±0.29 and by 0.30±0.16 when assuming fixed slope parameter (G=0.15, G_{12}=0.53) than Bowell's absolute magnitude (Bowell et al., 1989). We also derived slope parameters of asteroids of known spectral types and showed a good agreement with the previous studies within the derived uncertainties. However, our systematic errors on G and G_{12} are significantly larger than in previous work, which is caused by poor temporal and phase coverage of vast majority of the detected asteroids. This disadvantage will vanish when full survey data will be available and ongoing extended and enhanced mission will provide new data.

Hybrid probabilistic wind power forecasting using temporally local Gaussian process

The demand for sustainable development has resulted in a rapid growth in wind power worldwide. Despite various approaches have been proposed to improve the accuracy and to overcome the uncertainties associated with traditional methods, the stochastic and variable nature of wind still remains the most challenging issue in accurately forecasting wind power. This paper presents a hybrid deterministic-probabilistic method where a temporally local ‘moving window’ technique is used in Gaussian Process to examine estimated forecasting errors. This temporally local Gaussian Process employs less measurement data while faster and better predicts wind power at two wind farms, one in the USA and the other in Ireland. Statistical analysis on the results shows that the method can substantially reduce the forecasting error while more likely generate Gaussian-distributed residuals, particularly for short-term forecast horizons due to its capability to handle the time-varying characteristics of wind power.

The 'human revolution' in lowland tropical Southeast Asia:the antiquity and behavior of anatomically modern humans at Niah Cave (Sarawak, Borneo)

Recent research in Europe, Africa, and Southeast Asia suggests that we can no longer assume a direct and exclusive link between anatomically modern humans and behavioral modernity (the 'human revolution'), and assume that the presence of either one implies the presence of the other: discussions of the emergence of cultural complexity have to proceed with greater scrutiny of the evidence on a site-by-site basis to establish secure associations between the archaeology present there and the hominins who created it. This paper presents one such case study: Niah Cave in Sarawak on the island of Borneo, famous for the discovery in 1958 in the West Mouth of the Great Cave of a modern human skull, the 'Deep Skull,' controversially associated with radiocarbon dates of ca. 40,000 years before the present. A new chronostratigraphy has been developed through a re-investigation of the lithostratigraphy left by the earlier excavations, AMS-dating using three different comparative pre-treatments including ABOX of charcoal, and U-series using the Diffusion-Absorption model applied to fragments of bones from the Deep Skull itself. Stratigraphic reasons for earlier uncertainties about the antiquity of the skull are examined, and it is shown not to be an `intrusive' artifact. It was probably excavated from fluvial-pond-desiccation deposits that accumulated episodically in a shallow basin immediately behind the cave entrance lip, in a climate that ranged from times of comparative aridity with complete desiccation, to episodes of greater surface wetness, changes attributed to regional climatic fluctuations. Vegetation outside the cave varied significantly over time, including wet lowland forest, montane forest, savannah, and grassland. The new dates and the lithostratigraphy relate the Deep Skull to evidence of episodes of human activity that range in date from ca. 46,000 to ca. 34,000 years ago. Initial investigations of sediment scorching, pollen, palynomorphs, phytoliths, plant macrofossils, and starch grains recovered from existing exposures, and of vertebrates from the current and the earlier excavations, suggest that human foraging during these times was marked by habitat-tailored hunting technologies, the collection and processing of toxic plants for consumption, and, perhaps, the use of fire at some forest-edges. The Niah evidence demonstrates the sophisticated nature of the subsistence behavior developed by modern humans to exploit the tropical environments that they encountered in Southeast Asia, including rainforest. (c) 2006 Elsevier Ltd. All rights reserved.

A methodology to analyse the impact of offshore wind forecasting error on electricity markets

Currently wind power is dominated by onshore wind farms in the British Isles, but both the United Kingdom and the Republic of Ireland have high renewable energy targets, expected to come mostly from wind power. However, as the demand for wind power grows to ensure security of energy supply, as a potentially cheaper alternative to fossil fuels and to meet greenhouse gas emissions reduction targets offshore wind power will grow rapidly as the availability of suitable onshore sites decrease. However, wind is variable and stochastic by nature and thus difficult to schedule. In order to plan for these uncertainties market operators use wind forecasting tools, reserve plant and ancillary service agreements. Onshore wind power forecasting techniques have improved dramatically and continue to advance, but offshore wind power forecasting is more difficult due to limited datasets and knowledge. So as the amount of offshore wind power increases in the British Isles robust forecasting and planning techniques are even more critical. This paper presents a methodology to investigate the impacts of better offshore wind forecasting on the operation and management of the single wholesale electricity market in the Republic of Ireland and Northern Ireland using PLEXOS for Power Systems. © 2013 IEEE.

Electric vehicle capacity forecasting model with application to load levelling

There are many uncertainties in forecasting the charging and discharging capacity required by electric vehicles (EVs) often as a consequence of stochastic usage and intermittent travel. In terms of large-scale EV integration in future power networks this paper develops a capacity forecasting model which considers eight particular uncertainties in three categories. Using the model, a typical application of EVs to load levelling is presented and exemplified using a UK 2020 case study. The results presented in this paper demonstrate that the proposed model is accurate for charge and discharge prediction and a feasible basis for steady-state analysis required for large-scale EV integration.

Cellular signalling effects in high precision radiotherapy

Radiotherapy is commonly planned on the basis of physical dose received by the tumour and surrounding normal tissue, with margins added to address the possibility of geometric miss. However, recent experimental evidence suggests that intercellular signalling results in a given cell's survival also depending on the dose received by neighbouring cells. A model of radiation-induced cell killing and signalling was used to analyse how this effect depends on dose and margin choices. Effective Uniform Doses were calculated for model tumours in both idealised cases with no delivery uncertainty and more realistic cases incorporating geometric uncertainty. In highly conformal irradiation, a lack of signalling from outside the target leads to reduced target cell killing, equivalent to under-dosing by up to 10% compared to large uniform fields. This effect is significantly reduced when higher doses per fraction are considered, both increasing the level of cell killing and reducing margin sensitivity. These effects may limit the achievable biological precision of techniques such as stereotactic radiotherapy even in the absence of geometric uncertainties, although it is predicted that larger fraction sizes reduce the relative contribution of cell signalling driven effects. These observations may contribute to understanding the efficacy of hypo-fractionated radiotherapy.

Absolute magnitudes and slope parameters for 250,000 asteroids observed by Pan-STARRS PS1 - preliminary results

We present the results of a Monte Carlo technique to calculate the absolute magnitudes (H) and slope parameters (G) of about 240,000 asteroids observed by the Pan-STARRS1 telescope during the first 15 months of its 3-year all-sky survey mission. The system's exquisite photometry with photometric errors asteroids rotation period, amplitude and color to derive the most-likely H and G, but its major advantage is in estimating realistic statistical+systematic uncertainties and errors on each parameter. The method was confirmed by comparison with the well-established and accurate results for about 500 asteroids provided by Pravec et al. (2012) and then applied to determining H and G for the Pan-STARRS1 asteroids using both the Muinonen et al. (2010) and Bowell et al. (1989) phase functions. Our results confirm the bias in MPC photometry discovered by ( Jurić et al., 2002).

Superluminous Supernovae as Standardizable Candles and High-Redshift Distance Probes

We investigate the use of type Ic superluminous supernovae (SLSN Ic) as standardizable candles and distance indicators. Their appeal as cosmological probes stems from their remarkable peak luminosities, hot blackbody temperatures, and bright rest-frame ultraviolet emission. We present a sample of 16 published SLSN, from redshifts 0.1 to 1.2, and calculate accurate K corrections to determine uniform magnitudes in 2 synthetic rest-frame filter bandpasses with central wavelengths at 400 nm and 520 nm. At 400 nm, we find an encouragingly low scatter in their uncorrected, raw mean magnitudes with M(400) = -21.86 ± 0.35 mag for the full sample of 16 objects. We investigate the correlation between their decline rates and peak magnitude and find that the brighter events appear to decline more slowly. In a manner similar to the Phillips relation for type Ia SNe (SNe Ia), we define a ΔM 20 decline relation. This correlates peak magnitude and decline over 20 days and can reduce the scatter in standardized peak magnitudes to ±0.22 mag. We further show that M(400) appears to have a strong color dependence. Redder objects are fainter and also become redder faster. Using this peak magnitudecolor evolution relation, a surprisingly low scatter of between ±0.08 mag and ±0.13 mag can be found in peak magnitudes, depending on sample selection. However, we caution that only 8 to 10 objects currently have enough data to test this peak magnitudecolor evolution relation. We conclude that SLSN Ic are promising distance indicators in the high-redshift universe in regimes beyond those possible with SNe Ia. Although the empirical relationships are encouraging, the unknown progenitor systems, how they may evolve with redshift, and the uncertain explosion physics are of some concern. The two major measurement uncertainties are the limited numbers of low-redshift, well-studied objects available to test these relationships and internal dust extinction in the host galaxies.

Cosmological Constraints from Measurements of Type Ia Supernovae Discovered During the First 1.5 Yr of the Pan-STARRS1 Survey

We present griz_P1 light curves of 146 spectroscopically confirmed Type Ia supernovae (SNe Ia; 0.03 < z < 0.65) discovered during the first 1.5 yr of the Pan-STARRS1 Medium Deep Survey. The Pan-STARRS1 natural photometric system is determined by a combination of on-site measurements of the instrument response function and observations of spectrophotometric standard stars. We find that the systematic uncertainties in the photometric system are currently 1.2% without accounting for the uncertainty in the Hubble Space Telescope Calspec definition of the AB system. A Hubble diagram is constructed with a subset of 113 out of 146 SNe Ia that pass our light curve quality cuts. The cosmological fit to 310 SNe Ia (113 PS1 SNe Ia + 222 light curves from 197 low-z SNe Ia), using only supernovae (SNe) and assuming a constant dark energy equation of state and flatness, yields w = -1.120^+0.360_-0.206(Stat)^+0.269_0.291(Sys). When combined with BAO+CMB(Planck)+H₀, the analysis yields Ω_M = 0.280^+0.013_0.012 and w = -1.166^+0.072_-0.069 including all identified systematics. The value of w is inconsistent with the cosmological constant value of -1 at the 2.3σ level. Tension endures after removing either the baryon acoustic oscillation (BAO) or the H₀ constraint, though it is strongest when including the H₀ constraint. If we include WMAP9 cosmic microwave background (CMB) constraints instead of those from Planck, we find w = -1.124^+0.083_-0.065, which diminishes the discord to <2σ. We cannot conclude whether the tension with flat ΛCDM is a feature of dark energy, new physics, or a combination of chance and systematic errors. The full Pan-STARRS1 SN sample with ∼three times as many SNe should provide more conclusive results.

An Adaptive Predictive Control Strategy for RMPPT under Partially Shaded Conditions

As one of key technologies in photovoltaic converter control, Maximum Power Point Tracking (MPPT) methods can keep the power conversion efficiency as high as nearly 99% under the uniform solar irradiance condition. However, these methods may fail when shading conditions occur and the power loss can over as much as 70% due to the multiple maxima in curve in shading conditions v.s. single maximum point in uniformly solar irradiance. In this paper, a Real Maximum Power Point Tracking (RMPPT) strategy under Partially Shaded Conditions (PSCs) is introduced to deal with this kind of problems. An optimization problem, based on a predictive model which will change adaptively with environment, is developed to tracking the global maxima and corresponding adaptive control strategy is presented. No additional circuits are required to obtain the environment uncertainties. Finally, simulations show the effectiveness of proposed method.

Progress towards improving chronologies for marine sediment records.

The North Atlantic has played a key role in abrupt climate changes due to the sensitivity of the Atlantic Meridional Overturning Circulation (AMOC) to the location and strength of deep water formation. It is crucial for modelling future climate change to understand the role of the AMOC in the rapid warming and gradual cooling cycles known as Dansgaard-Oescher (DO) events which are recorded in the Greenland ice cores. However, palaeoceanographic research into DO events has been hampered by the uncertainty in timing due largely to the lack of a precise chronological time frame for marine records. While tephrochronology provides links to the Greenland ice core records at a few points, radiocarbon remains the primary dating method for most marine cores. Due to variations in the atmospheric and oceanic 14C concentration, radiocarbon ages must be calibrated to provide calendric ages. The IntCal Working Group provides a global estimate of ocean 14C ages for calibration of marine radiocarbon dates, but the variability of the surface marine reservoir age in the North Atlantic particularly during Heinrich or DO events, makes calibration uncertain. In addition, the current Marine09 radiocarbon calibration beyond around 15 ka BP is largely based on 'tuning' to the Hulu Cave isotope record, so that the timing of events may not be entirely synchronous with the Greenland ice cores. The use of event-stratigraphy and independent chronological markers such as tephra provide the scope to improve marine radiocarbon reservoir age estimates particularly in the North Atlantic where a number of tephra horizons have been identified in both marine sediments and the Greenland ice cores. Quantification of timescale uncertainties is critical but statistical techniques which can take into account the differential dating between events can improve the precision. Such techniques should make it possible to develop specific marine calibration curves for selected regions.

Core outcome sets and trial registries

Some reasons for registering trials might be considered as self-serving, such as satisfying the requirements of a journal in which the researchers wish to publish their eventual findings or publicising the trial to boost recruitment. Registry entries also help others, including systematic reviewers, to know about ongoing or unpublished studies and contribute to reducing research waste by making it clear what studies are ongoing. Other sources of research waste include inconsistency in outcome measurement across trials in the same area, missing data on important outcomes from some trials, and selective reporting of outcomes. One way to reduce this waste is through the use of core outcome sets: standardised sets of outcomes for research in specific areas of health and social care. These do not restrict the outcomes that will be measured, but provide the minimum to include if a trial is to be of the most use to potential users. We propose that trial registries, such as ISRCTN, encourage researchers to note their use of a core outcome set in their entry. This will help people searching for trials and those worried about selective reporting in closed trials. Trial registries can facilitate these efforts to make new trials as useful as possible and reduce waste. The outcomes section in the entry could prompt the researcher to consider using a core outcome set and facilitate the specification of that core outcome set and its component outcomes through linking to the original core outcome set. In doing this, registries will contribute to the global effort to ensure that trials answer important uncertainties, can be brought together in systematic reviews, and better serve their ultimate aim of improving health and well-being through improving health and social care.

Accumulating research: a systematic account of how cumulative meta-analyses would have provided knowledge, improved health, reduced harm and saved resources

BACKGROUND: "Cumulative meta-analysis" describes a statistical procedure to calculate, retrospectively, summary estimates from the results of similar trials every time the results of a further trial in the series had become available. In the early 1990 s, comparisons of cumulative meta-analyses of treatments for myocardial infarction with advice promulgated through medical textbooks showed that research had continued long after robust estimates of treatment effects had accumulated, and that medical textbooks had overlooked strong, existing evidence from trials. Cumulative meta-analyses have subsequently been used to assess what could have been known had new studies been informed by systematic reviews of relevant existing evidence and how waste might have been reduced.

METHODS AND FINDINGS: We used a systematic approach to identify and summarise the findings of cumulative meta-analyses of studies of the effects of clinical interventions, published from 1992 to 2012. Searches were done of PubMed, MEDLINE, EMBASE, the Cochrane Methodology Register and Science Citation Index. A total of 50 eligible reports were identified, including more than 1,500 cumulative meta-analyses. A variety of themes are illustrated with specific examples. The studies showed that initially positive results became null or negative in meta-analyses as more trials were done; that early null or negative results were over-turned; that stable results (beneficial, harmful and neutral) would have been seen had a meta-analysis been done before the new trial; and that additional trials had been much too small to resolve the remaining uncertainties.

CONCLUSIONS: This large, unique collection of cumulative meta-analyses highlights how a review of the existing evidence might have helped researchers, practitioners, patients and funders make more informed decisions and choices about new trials over decades of research. This would have led to earlier uptake of effective interventions in practice, less exposure of trial participants to less effective treatments, and reduced waste resulting from unjustified research.

Multifocal remitting-relapsing cerebral demyelination twenty years following allogeneic bone marrow transplantation

We report a case study of a female who received an allogeneic bone marrow transplantation (BMT) from a sex-mismatched related donor and who, after a twenty-year interval, developed an acute fulminant biopsy-proven demyelinating disorder of cerebral white matter which followed a remitting-relapsing chronic course. In situ hybridization studies using Y-chromosome-specific markers revealed Y-chromosome-positive mononuclear cells in biopsy samples of white matter. Magnetic resonance imaging (MRI) studies of the asymptomatic healthy male donor showed multiple white matter lesions. These observations suggest that donor lymphocytes were sensitized to central nervous system (CNS) antigens prior to or at the time of transplantation but remained dormant for 20 years before becoming activated to cause widespread demyelination.