A case‐study of cold‐air pool evolution in hilly terrain using field measurements from COLPEX

A case‐study investigation of cold‐air pool (CAP) evolution in hilly terrain is conducted using field measurements made during IOP 16 of the COLd‐air Pool EXperiment (COLPEX). COLPEX was designed to study cold‐air pooling in small‐scale valleys typical of the UK (∼100–200 m deep, ∼1 km wide). The synoptic conditions during IOP 16 are typical of those required for CAPs to form during the night, with high pressure, clear skies and low ambient winds. Initially a CAP forms around sunset and grows uninterrupted for several hours. However, starting 4 hr after sunset, a number of interruptions to this steady cooling rate occur. Three episodes are highlighted from the observations and the cause of disruption attributed to (a) wave activity, in the form of gravity waves and/or Kelvin–Helmholtz (KH) instability, (b) increases in the above‐valley winds resulting from the development of a nocturnal low‐level jet (NLLJ), (c) shear‐induced mixing resulting from instability of the NLLJ. A weakly stable residual layer provides the conditions for wave activity during Episode 1. This residual layer is eroded by a developing NLLJ from the top down during Episode 2. The sustained increase in winds at hill‐top levels – attributed to the NLLJ – continue to disrupt the CAP through Episode 3. Although cooling is interrupted, the CAP is never completely eroded during the night. Complete CAP break‐up occurs some 3.5 hr after local sunrise. This case‐study highlights a number of meteorological phenomena that can disrupt CAP evolution even in ideal CAP conditions. These processes are unlikely to be sufficiently represented by current operational weather forecast models and can be challenging even for high‐resolution research models

Regulatory evaluation of Glybera in Europe-two committees, one mission

publishersversionPeer reviewe

The Epidemics of Donations: Logistic Growth and Power-Laws

This paper demonstrates that collective social dynamics resulting from individual donations can be well described by an epidemic model. It captures the herding behavior in donations as a non-local interaction between individual via a time-dependent mean field representing the mass media. Our study is based on the statistical analysis of a unique dataset obtained before and after the tsunami disaster of 2004. We find a power-law behavior for the distributions of donations with similar exponents for different countries. Even more remarkably, we show that these exponents are the same before and after the tsunami, which accounts for some kind of universal behavior in donations independent of the actual event. We further show that the time-dependent change of both the number and the total amount of donations after the tsunami follows a logistic growth equation. As a new element, a time-dependent scaling factor appears in this equation which accounts for the growing lack of public interest after the disaster. The results of the model are underpinned by the data analysis and thus also allow for a quantification of the media influence

Multi-photon ionisation spectroscopy for rotational state preparation of N+2

In this paper we investigate the 2 + 1′ resonance enhanced multi-photon ionisation (REMPI) of molecular nitrogen via the a1Πg(v = 6) intermediate state and analyse its feasibility to generate molecular nitrogen ions in a well defined ro-vibrational state. This is an important tool for high precision experiments based on trapped molecular ions, and is crucial for studying the time variation of the fundamental constant mp/me using N+2. The transition is not reported in the literature and detailed spectral analysis has been conducted to extract the molecular constants of the intermediate state. By carefully choosing the intermediate ro-vibrational state, the ionisation laser wavelength and controlling the excitation laser pulse energy, unwanted formation of rotationally excited molecular ions can be suppressed and ro-vibrational ground state ions can be generated with high purity

A statistical framework to evaluate virtual screening

<p>Abstract</p> <p>Background</p> <p>Receiver operating characteristic (ROC) curve is widely used to evaluate virtual screening (VS) studies. However, the method fails to address the "early recognition" problem specific to VS. Although many other metrics, such as RIE, BEDROC, and pROC that emphasize "early recognition" have been proposed, there are no rigorous statistical guidelines for determining the thresholds and performing significance tests. Also no comparisons have been made between these metrics under a statistical framework to better understand their performances.</p> <p>Results</p> <p>We have proposed a statistical framework to evaluate VS studies by which the threshold to determine whether a ranking method is better than random ranking can be derived by bootstrap simulations and 2 ranking methods can be compared by permutation test. We found that different metrics emphasize "early recognition" differently. BEDROC and RIE are 2 statistically equivalent metrics. Our newly proposed metric SLR is superior to pROC. Through extensive simulations, we observed a "seesaw effect" – overemphasizing early recognition reduces the statistical power of a metric to detect true early recognitions.</p> <p>Conclusion</p> <p>The statistical framework developed and tested by us is applicable to any other metric as well, even if their exact distribution is unknown. Under this framework, a threshold can be easily selected according to a pre-specified type I error rate and statistical comparisons between 2 ranking methods becomes possible. The theoretical null distribution of SLR metric is available so that the threshold of SLR can be exactly determined without resorting to bootstrap simulations, which makes it easy to use in practical virtual screening studies.</p

Chemotherapy-induced oral mucositis is associated with detrimental bacterial dysbiosis.

BACKGROUND: Gastrointestinal mucosal injury (mucositis), commonly affecting the oral cavity, is a clinically significant yet incompletely understood complication of cancer chemotherapy. Although antineoplastic cytotoxicity constitutes the primary injury trigger, the interaction of oral microbial commensals with mucosal tissues could modify the response. It is not clear, however, whether chemotherapy and its associated treatments affect oral microbial communities disrupting the homeostatic balance between resident microorganisms and the adjacent mucosa and if such alterations are associated with mucositis. To gain knowledge on the pathophysiology of oral mucositis, 49 subjects receiving 5-fluorouracil (5-FU) or doxorubicin-based chemotherapy were evaluated longitudinally during one cycle, assessing clinical outcomes, bacterial and fungal oral microbiome changes, and epithelial transcriptome responses. As a control for microbiome stability, 30 non-cancer subjects were longitudinally assessed. Through complementary in vitro assays, we also evaluated the antibacterial potential of 5-FU on oral microorganisms and the interaction of commensals with oral epithelial tissues. RESULTS: Oral mucositis severity was associated with 5-FU, increased salivary flow, and higher oral granulocyte counts. The oral bacteriome was disrupted during chemotherapy and while antibiotic and acid inhibitor intake contributed to these changes, bacteriome disruptions were also correlated with antineoplastics and independently and strongly associated with oral mucositis severity. Mucositis-associated bacteriome shifts included depletion of common health-associated commensals from the genera Streptococcus, Actinomyces, Gemella, Granulicatella, and Veillonella and enrichment of Gram-negative bacteria such as Fusobacterium nucleatum and Prevotella oris. Shifts could not be explained by a direct antibacterial effect of 5-FU, but rather resembled the inflammation-associated dysbiotic shifts seen in other oral conditions. Epithelial transcriptional responses during chemotherapy included upregulation of genes involved in innate immunity and apoptosis. Using a multilayer epithelial construct, we show mucositis-associated dysbiotic shifts may contribute to aggravate mucosal damage since the mucositis-depleted Streptococcus salivarius was tolerated as a commensal, while the mucositis-enriched F. nucleatum displayed pro-inflammatory and pro-apoptotic capacity. CONCLUSIONS: Altogether, our work reveals that chemotherapy-induced oral mucositis is associated with bacterial dysbiosis and demonstrates the potential for dysbiotic shifts to aggravate antineoplastic-induced epithelial injury. These findings suggest that control of oral bacterial dysbiosis could represent a novel preventive approach to ameliorate oral mucositis

Current anti-doping policy: a critical appraisal

BACKGROUND: Current anti-doping in competitive sports is advocated for reasons of fair-play and concern for the athlete's health. With the inception of the World Anti Doping Agency (WADA), anti-doping effort has been considerably intensified. Resources invested in anti-doping are rising steeply and increasingly involve public funding. Most of the effort concerns elite athletes with much less impact on amateur sports and the general public. DISCUSSION: We review this recent development of increasingly severe anti-doping control measures and find them based on questionable ethical grounds. The ethical foundation of the war on doping consists of largely unsubstantiated assumptions about fairness in sports and the concept of a "level playing field". Moreover, it relies on dubious claims about the protection of an athlete's health and the value of the essentialist view that sports achievements reflect natural capacities. In addition, costly antidoping efforts in elite competitive sports concern only a small fraction of the population. From a public health perspective this is problematic since the high prevalence of uncontrolled, medically unsupervised doping practiced in amateur sports and doping-like behaviour in the general population (substance use for performance enhancement outside sport) exposes greater numbers of people to potential harm. In addition, anti-doping has pushed doping and doping-like behaviour underground, thus fostering dangerous practices such as sharing needles for injection. Finally, we argue that the involvement of the medical profession in doping and anti-doping challenges the principles of non-maleficience and of privacy protection. As such, current anti-doping measures potentially introduce problems of greater impact than are solved, and place physicians working with athletes or in anti-doping settings in an ethically difficult position. In response, we argue on behalf of enhancement practices in sports within a framework of medical supervision. SUMMARY: Current anti-doping strategy is aimed at eradication of doping in elite sports by means of all-out repression, buttressed by a war-like ideology similar to the public discourse sustaining international efforts against illicit drugs. Rather than striving for eradication of doping in sports, which appears to be an unattainable goal, a more pragmatic approach aimed at controlled use and harm reduction may be a viable alternative to cope with doping and doping-like behaviour

A theoretical entropy score as a single value to express inhibitor selectivity

<p>Abstract</p> <p>Background</p> <p>Designing maximally selective ligands that act on individual targets is the dominant paradigm in drug discovery. Poor selectivity can underlie toxicity and side effects in the clinic, and for this reason compound selectivity is increasingly monitored from very early on in the drug discovery process. To make sense of large amounts of profiling data, and to determine when a compound is sufficiently selective, there is a need for a proper quantitative measure of selectivity.</p> <p>Results</p> <p>Here we propose a new theoretical entropy score that can be calculated from a set of IC₅₀data. In contrast to previous measures such as the 'selectivity score', Gini score, or partition index, the entropy score is non-arbitary, fully exploits IC₅₀data, and is not dependent on a reference enzyme. In addition, the entropy score gives the most robust values with data from different sources, because it is less sensitive to errors. We apply the new score to kinase and nuclear receptor profiling data, and to high-throughput screening data. In addition, through analyzing profiles of clinical compounds, we show quantitatively that a more selective kinase inhibitor is not necessarily more drug-like.</p> <p>Conclusions</p> <p>For quantifying selectivity from panel profiling, a theoretical entropy score is the best method. It is valuable for studying the molecular mechanisms of selectivity, and to steer compound progression in drug discovery programs.</p

Variations in influenza vaccination coverage among the high-risk population in Sweden in 2003/4 and 2004/5: a population survey

<p>Abstract</p> <p>Background</p> <p>In Sweden, the vaccination campaign is the individual responsibility of the counties, which results in different arrangements. The aim of this study was to find out whether influenza vaccination coverage rates (VCRs) had increased between 2003/4 and 2004/5 among population at high risk and to find out the influence of personal preferences, demographic characteristics and health care system characteristics on VCRs.</p> <p>Methods</p> <p>An average sample of 2500 persons was interviewed each season (2003/4 and 2004/5). The respondents were asked whether they had had an influenza vaccination, whether they suffered from chronic conditions and the reasons of non-vaccination. For every county the relevant health care system characteristics were collected via a questionnaire sent to the medical officers of communicable diseases.</p> <p>Results</p> <p>No difference in VCR was found between the two seasons. Personal invitations strongly increased the chance of having had a vaccination. For the elderly, the number of different health care professionals in a region involved in administering vaccines decreased this chance.</p> <p>Conclusion</p> <p>Sweden remained below the WHO-recommendations for population at high risk due to disease. To meet the 2010 WHO-recommendation further action may be necessary to increase vaccine uptake. Increasing the number of personal invitations and restricting the number of different administrators responsible for vaccination may be effective in increasing VCRs among the elderly.</p