Abstract. Both climate forcing and climate sensitivity persist as stubborn uncertainties limiting the extent to which climate models can provide actionable scientific scenarios for climate change. A key, explicit control on cloud–aerosol interactions, the largest uncertainty in climate forcing, is the vertical velocity of cloud-scale updrafts. Model-based studies of climate sensitivity indicate that convective entrainment, which is closely related to updraft speeds, is an important control on climate sensitivity. Updraft vertical velocities also drive many physical processes essential to numerical weather prediction. Vertical velocities and their role in atmospheric physical processes have been given very limited attention in models for climate and numerical weather prediction. The relevant physical scales range down to tens of meters and are thus frequently sub-grid and require parameterization. Many state-of-science convection parameterizations provide mass fluxes without specifying vertical velocities, and parameterizations that do provide vertical velocities have been subject to limited evaluation against what have until recently been scant observations. Atmospheric observations imply that the distribution of vertical velocities depends on the areas over which the vertical velocities are averaged. Distributions of vertical velocities in climate models may capture this behavior, but it has not been accounted for when parameterizing cloud and precipitation processes in current models. New observations of convective vertical velocities offer a potentially promising path toward developing process-level cloud models and parameterizations for climate and numerical weather prediction. Taking account of the scale dependence of resolved vertical velocities offers a path to matching cloud-scale physical processes and their driving dynamics more realistically, with a prospect of reduced uncertainty in both climate forcing and sensitivity.


Respiratory diseases are among the leading causes of morbidity and mortality worldwide, representing a major unmet medical need. New chemical entities rarely make it into the clinic to treat respiratory diseases, which is partially due to a lack of adequate predictive disease models and the limited availability of human lung tissues to model respiratory disease. Human pluripotent stem cells (hPSCs) may help fill this gap by serving as a scalable human in vitro model. In addition, human in vitro models of rare genetic mutations can be generated using hPSCs. hPSC-derived epithelial cells and organoids have already shown great potential for the understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. These potentials can also be applied to other hPSC-derived lung cell types in the future. In this review, we will discuss how hPSCs have brought, and may continue to bring, major changes to the field of respiratory diseases by understanding the molecular mechanisms of the pathology and by finding efficient therapeutics. Human pluripotent stem cells may help to develop animal-free, fully human in vitro models to advance our understanding of disease mechanisms, for finding new potential targets by using high-throughput screening platforms, and for personalised treatments. https://bit.ly/3cahaqz


Abstract. Sahid ZD, Syukur M, Maharijaya A, Nurcholis W. 2021. Polyphenol content and pharmacological activities of Capsicum frutescens and C. chinense genotypes. Biodiversitas 22: 3838-3843. Chili is a horticultural crop with potential as a functional food crop. This is because chili has beneficial biochemical parameters such as antioxidants, phenolics, flavonoids, and ?-glucosidase inhibitors. This study evaluated the biochemical parameters in twelve genotypes of two chili species (Capsicum frutescens and Capsicum chinense). Information from this research can be used as a reference in chili plant breeding activities which are directed as functional food plants. The method of measuring biochemical parameters using an ELISA reader with a modified method. Samples were measured with a microplate and repeated three times. The results that emerged from the ELISA reader were then converted with Microsoft Excel and analyzed using the R program. The results showed that the Capsicum chinense species (Habanero Fransisca) had the highest ?-glucosidase inhibitory activity (52.52%) compared to other genotypes of the Capsicum frutescens species. The highest TPC (19.42), TFC (2.51), and antioxidant FRAP (117.27) were shown by the pure line genotype F8 285290-290-2-2-4-4-1. The biochemical content of the chili genotypes tested was divided into three major groups. This grouping is not affected based on the species used. The correlation between antioxidants using the FRAP method with TFC (0.69) and TPC (0.83) is positive and significantly different. In conclusion, information on biochemical content can be used as a basis for developing genotypes, especially for the purposes of plant breeding activities in the future.


recent burst in technology which followed the advent of genomic arrays has led to better understanding of the complex inter-relationship between microbes, their hosts and the environment. In addition, holistic approaches to study physiology have made it possible to evaluate the contribution of multiple elements on a single platform. Biology of viruses and their interaction with the host, the pathological consequences of virus infection to the host, and the environmental and host genetic influences on all these are areas of intense investigation. Recent transcriptome and proteome analyses have unearthed a wealth of information on how viruses replicate, survive in the host, spread and cause disease and how the host responds to infection. In this review, we summarize some of the advances in genomic, proteomic and systems biology approaches to understand virus-host interaction and pathogenesis of viral diseases. These studies have broad and important implications for the identification of anti-viral targets and for rational design of clinical interventions.


A prokaryotic ubiquitin-like protein modulates the function of ferritin so that bacteria can grow under iron-limiting conditions. Some bacteria possess a ubiquitin-like protein called Pup (prokaryotic ubiquitin-like protein), which can be covalently attached to target proteins to tag them for proteasomal degradation. However, not all pupylated proteins are degraded, and some bacteria that have pupylation machinery do not have proteasomes, implying that pupylation must have additional roles. Küberl et al. found that pupylation enabled Corynebacterium glutamicum, a bacterium that lacks a proteasome, to adapt to iron-limiting conditions. Although C. glutamicum Δpup mutants grew well on various carbon and nitrogen sources and under conditions of nitrogen stress, these pupylation-defective mutants did not grow as well as wild-type (WT) cells in iron-poor medium. The total cellular iron content, which includes both free and bound iron, was the same in Δpup mutants and WT cells, but the mutant cells had less free iron than WT cells, indicating that iron in the mutant cells was sequestered. Transcriptomic profiling was consistent with hypersensitivity to iron limitation of the Δpup mutants and included increased abundance of transcripts stimulated by low-iron conditions. In WT cells under normal growth conditions, the iron storage protein ferritin (Ftn) was pupylated on Lys78, and mutating this to Ala prevented pupylation of Ftn in WT cells. Under iron-limiting conditions, C. glutamicum Δftn cells expressing this mutant form of Ftn exhibited the same growth defect as Δpup mutants. As expected, pupylation did not cause degradation of Ftn, because the abundance of Ftn did not differ between Δpup and WT C. glutamicum under iron-limiting conditions. Although C. glutamicum lacks a complete proteasome, the proteasomal subunit homolog ARC, which unfolds pupylated proteins, is present, and ARC was required for growth under iron-limiting conditions. Thus, pupylation may enable unfolding of Ftn to release stored iron. A. Küberl, T. Polen, M. Bott, The pupylation machinery is involved in iron homeostasis by targeting the iron storage protein ferritin. Proc. Natl. Acad. Sci. U.S.A. 113, 4806–4811 (2016). [PubMed]


There comes a time in many a Caribbean traveller's voyages when all those gorgeous beaches framed by palms and etched by azure seas may blend into one lovely, hazy memory, a record playing the same tune. Was that Bahamas or Barbados? Have I seen the Virgins or the Saints? Not so, once you have touched down on the ABCs: Aruba, Bonaire and Curacao. From Curacao's historical renaissance to Aruba's endless sandy fun to Bonaire's well-finned waters, this part of the world overflows with unexpected delights and engaging surroundings. Like three sisters, Aruba, Bonaire and Curacao share in familial traits but are each uniquely endowed. Taste one or savour all three. The only thing you can expect is an unquenchable thirst for more.


BACKGROUND AND AIMS
Recent mounting evidence suggest that probiotics supplementation can have a positive effect on mood and psychological symptoms such as stress and anxiety disorders. The majority of studies, however, rely on animal models, while clinical data are still inconsistent. In this systematic review, we examined if and to which extent probiotics can influence psychological stress and anxiety disorders.

METHODS
The search of online databases Medline, PubMed, Scopus, Web of Science and clinical trials.gov provided relevant studies up to November 2019. We included double blind, randomized and placebo controlled or prospective studies, as well as studies measuring preclinical psychological symptoms of perceived stress and anxiety, before and after supplementation with a probiotic.

RESULTS
Twelve studies met the inclusion criteria (3 on stress, 4 on anxiety, and 5 both on stress and anxiety), accounting for 1,521 participants. The improvement of stress, anxiety, and stress-anxiety was reported in 1/3, 3/4, and 2/5 studies, respectively.

CONCLUSIONS
Available studies suggest that probiotics may improve psychological symptoms associated particularly with anxiety. Further research needs to investigate whether probiotics also improve psychological stress disturbances.


We first prove, informally but constructively, that Z is a ring without zero-divisors. Then, using Per Martin-Lof's type theory, we establish the same result formally. This is done following the informal reasoning closely. The proofs are automatically checked by using the proof-checker ``TWB'' developed by us at SICS. In the proofs we use only the basic set-theoretic axioms in type theory.


ABSTRACT Between the 1920s and 1930s, the translation of foreign contemporary novels into Italian was encouraged by publishers, meeting the needs of a new readership, which was larger and more heterogeneous than before the war. However, the sharp rise in the number of imported novels provoked strong disapproval. In a context of heightened nationalism and cultural autocracy, translation was considered a polluting, anti-patriotic and servile practice. The censorship that took place, however, was mostly implemented via a tacit compromise between the publishers and the regime, rather than by repressive institutional actions. In order to protect themselves from sanctions and requisitions, publishers and translators often deleted potentially unpleasant elements from the texts, including topics such as abortion, suicide, pacifism, sexuality, women's emancipation or episodes belittling Italy. The analysis of German popular fiction translated into Italian in this period suggests that popular literature was translated with a high degree of manipulation. This may be ascribed to the low cultural status accorded to this type of literature and the modernity of the themes it contained. Furthermore, while 'high literature' catered to a niche readership, the widespread circulation of popular literature made it seem more dangerous and thus more subject to censorship.


Sequential processes can encounter faults as a result of improper ordering of subsets of the events. In order to reveal faults caused by the relative ordering of t or fewer of v events, for some fixed t, a test suite must provide tests so that every ordering of every set of t or fewer events is exercised. Such a test suite is equivalent to a sequence covering array, a set of permutations on v events for which every subsequence of t or fewer events arises in at least one of the permutations. Equivalently it is a (different) set of permutations, a completely t-scrambling set of permutations, in which the images of every set of t chosen events include each of the t! possible "patterns." In event sequence testing, minimizing the number of permutations used is the principal objective. By developing a connection with covering arrays, lower bounds on this minimum in terms of the minimum number of rows in covering arrays are obtained. An existing bound on the largest v for which the minimum can equal t! is improved. A conditional expectation algorithm is developed to generate sequence covering arrays whose number of permutations never exceeds a specified logarithmic function of v when t is fixed, and this method is shown to operate in polynomial time. A recursive product construction is established when t = 3 to construct sequence covering arrays on vw events from ones on v and w events. Finally computational results are given for t ∈{ 3, 4, 5} to demonstrate the utility of the conditional expectation algorithm and the product construction.


The sexually transmitted pathogen, Neisseria gonorrhoeae, undergoes natural transformation at high frequency. This property has led to the rapid dissemination of antibiotic resistance markers and to the panmictic structure of the gonococcal population. However, high‐frequency transformation also makes N. gonorrhoeae one of the easiest bacterial species to manipulate genetically in the laboratory. Techniques have been developed that result in transformation frequencies >50%, allowing the identification of mutants by screening and without selection. Constructs have been created to take advantage of this high‐frequency transformation, facilitating genetic mutation, complementation, and heterologous gene expression. Techniques are described for genetic manipulation of N. gonorrhoeae, as well as for growth of this fastidious organism. Curr. Protoc. Microbiol. 23:4A.2.1‐4A.2.24. © 2011 by John Wiley & Sons, Inc.


This paper presents a new approach of applying partial least squares (PLS) method combined with a physical principle based on dominant factor. The characteristic line intensity of the specific element was taken to build up the dominant factor to reflect the major elemental concentration and PLS approach was then applied to further improve the model accuracy. The deviation evolution of characteristic line intensity from the ideal condition was depicted and according to the deviation understanding, efforts were taken to model the non-linear self-absorption and inter-element interference effects to improve the accuracy of dominant factor model. With a dominant factor to carry the main quantitative information, the novel multivariate model combines advantages of both the conventional univariate and PLS models and partially avoids the overuse of the unrelated noise in the spectrum for PLS application. The dominant factor makes the combination model more robust over a wide concentration range and PLS application improves the model accuracy for samples with matrices within the calibration sample set. Results show that RMSEP of the final dominant factor based PLS model decreased to 2.33% from 5.25% when using the conventional PLS approach with full spectral information. Furthermore, with the development in understanding the physics of the laser-induced plasma, there is potential to easily improve the accuracy of the dominant factor model as well as the proposed novel multivariate model.


The design of sensitive online healthcare systems must balance the requirements of privacy and accountability for the good of individuals, organizations, and society. Via a design science research approach, we build and evaluate a sophisticated software system for the online provision of psychosocial healthcare to distributed and vulnerable populations. Multidisciplinary research capabilities are embedded within the system to investigate the effectiveness of online treatment protocols. Throughout the development cycles of the system, we build an emergent design theory of scrutiny that applies a multi-layer protocol to support governance of privacy and accountability in sensitive online applications. The design goal is to balance stakeholder privacy protections with the need to provide for accountable interventions in critical and well-defined care situations. The research implications for the development and governance of online applications in numerous privacy-sensitive application areas are explored


The doubling constant of a metric space (X, d) is the smallest value /spl lambda/ such that every ball in X can be covered by /spl lambda/ balls of half the radius. The doubling dimension of X is then defined as dim (X) = log/sub 2//spl lambda/. A metric (or sequence of metrics) is called doubling precisely when its doubling dimension is bounded. This is a robust class of metric spaces which contains many families of metrics that occur in applied settings. We give tight bounds for embedding doubling metrics into (low-dimensional) normed spaces. We consider both general doubling metrics, as well as more restricted families such as those arising from trees, from graphs excluding a fixed minor, and from snowflaked metrics. Our techniques include decomposition theorems for doubling metrics, and an analysis of a fractal in the plane according to T. J. Laakso (2002). Finally, we discuss some applications and point out a central open question regarding dimensionality reduction in L/sub 2/.


Introduction Mainly case reports have shown that N. meningitidis, typically a resident of the oropharynx and the causative agent of meningococcal meningitis and meningococcemia, is capable of invading and colonising the urogenital tract. This can result in urethritis, akin to the syndrome caused by N. gonorrhoeae, the etiologic agent of gonorrhoea. Recently, meningococcal strains associated with outbreaks of urethritis were reported to share genetic characteristics with gonococcus, raising the question of the extent to which these strains contain features that promote adaptation to the genitourinary niche, making them "gonococcus-like" and distinguishing them from other N. meningitidis. Methods A total of 31 urethritis-associated N. meningitidis, representing multiple serogroups and independently collected over a decade and 3 continents, underwent genome sequencing and analysis. The genomes were compared with serogroup-matched N. meningitidis strains isolated from carriage and invasive disease and N. gonorrhoeae strains isolated from men with urethritis. Results Intact nitrite reductase (AniA), disrupted factor-H binding protein (fHbp), and the lack of capsule are features previously speculated to promote urogenital colonisation. However, we found that a considerable number (n=11) of meningococcal urethritis isolates harbour mutations in AniA predicted to result in truncated peptides and a minority (n=4) of these isolates contained alleles associated with frameshifted fHbp. We noted substantial diversity in the capsule biosynthetic locus, including intact, disrupted, and absent capsules, indicating urogenital colonisation is possible across a range of capsular phenotypes. Conclusion The meningococcal urethritis strains in this study do not share the allelic patterns of AniA, fHbp, or the capsule locus previously reported for urethritis-associated N. meningitidis. The allelic patterns likely reflect diversity in the underlying meningococcal population, rather than novel adaptation to the urogenital tract.


Optical properties of two-layer antireflection systems are discussed. Theory is applied to study the optical performance of bismuth-oxide/magnesium-fluoride bilayers. The theoretical study includes graphs and numerical tables showing the spectral reflectances for different glass substrates, the effect of film-thickness mismatching and the spectral reflectance for plane-polarized incident light.


Regional seismic studies of the Earth's deep mantle indicate the presence of P- and S-wave reflectors at the top of the D′′ layer. Such reflectors appear to be laterally intermittent, occur at a range of depths, and produce waveforms whose amplitude and polarity differ at different locations. A number of possible explanations for D′′ reflections have been proposed, including: a phase change from perovskite to post-perovskite; thermal or thermochemical discontinuities generated by subducted slabs; alignment of anisotropic minerals and global or small-scale chemical heterogeneity arising perhaps from core–mantle interactions or primitive material. However, some of the observed heterogeneity in D′′ structure may be related to lack of consistency between the style, quality and number of seismic observations in different regions, as well as complexity in wave propagation due to 3-D structure. In this study, we present a compilation of observations of D′′ reflections for regions in which (1) a reflector is seen in both P- and S-wave arrivals and (2) consistent array seismology techniques have been applied to infer the properties of the reflectors. Using a recent Monte Carlo thermodynamic modelling method to convert changes in chemistry and mineralogy into changes in seismic velocity, we compare the fit of different isotropic thermochemical structures to the observed seismic properties of D′′ reflections, namely the polarity and amplitude of the waveforms. Our results indicate that it may be possible to discriminate between different possible origins for D′′ reflections on the basis of polarity observations alone. Amplitude measurements may provide further constraints but must be treated with caution due to a large number of factors, which can influence waveform amplitudes. In regions such as the Caribbean, which are characterized by high-amplitude, negative polarity P waveforms and positive polarity S waveforms, a phase change from perovskite to post-perovskite provides the most likely explanation for the discontinuity. However, in other regions, notably Siberia and the central Pacific, P- and S waveforms both display a positive polarity, and multiple explanations for the discontinuity are possible, including subduction-related chemical heterogeneity and anisotropy.


In the mid-1950s, much Canadian literature was out of print, making it relatively inaccessible to readers, including those studying the subject in schools and universities. When English professor Malcolm Ross approached Toronto publisher Jack McClelland in 1952 to propose a Canadian literary reprint series, it was still the accepted wisdom among publishers that Canadian literature was of insufficient interest to the educational market to merit any great publishing risks. Eventually convinced by Ross that a latent market for Canadian literary reprints did indeed exist, McClelland & Stewart launched the New Canadian Library (NCL) series in 1958, with Ross as its general editor. In 2008, the NCL will celebrate a half-century of publication. In New Canadian Library, Janet B. Friskney takes the reader through the early history of the NCL series, focusing on the period up to 1978 when Malcolm Ross retired as general editor. A wealth of archival resources, published reviews, and the NCL volumes themselves are used to survey the working relationship between Ross and McClelland, as well as the collaborative participation of those who, through the middle decades of the twentieth century, were committed to studying and nurturing Canada's literary heritage. To place the New Canadian Library in its proper historical context, Friskney examines the simultaneous development of Canadian literary studies as a legitimate area of research and teaching in academe and acknowledges the NCL as a milestone in Canadian publishing history.


UNLABELLED
Cessation of tobacco use, whether smoked or smokeless, is amongst the most significant actions a patient can take to secure their health--both oral and general. The potential role of the dental team in assisting this process is now well recognized, but the degree to which this occurs in practice is uncertain. The UK National Health Service has devoted substantial resources to the development of stop-smoking services. This article describes how the contribution of dentists and dental care professionals fits with wider public health tobacco cessation and control measures.

CLINICAL RELEVANCE
This article presents an update on the impact of tobacco use on health and outlines current evidence on treating tobacco use and dependence. It also highlights the role of the dental team in helping patients to stop smoking, in light of wider developments in the provision of stop-smoking services.


The development of efficient organic-based photovoltaic devices is a vibrant area of research with the potential of providing a cheap source of sustainable energy to society. The attainable power conversion efficiencies could be strongly enhanced via the singlet fission (SF) mechanism, a quantum mechanical phenomenon that potentially doubles the number of electron–hole pairs in a photoexcitation process by splitting a high energy singlet into two triplets. Biradicaloid molecules are particularly appealing for SF applications due to the possibility of controlling the balance between open-shell and closed-shell resonance structures via chemical modifications, which open new opportunities to fine tune the singlet and triplet excitation energies, and thus maximize the SF efficiency. Recently, we have shown that doping acenes with boron (B) or nitrogen (N) atoms leads to a large modulation in its biradicaloid nature at the ground-state. Herein, this previous study is extended to the case of asymmetric substitutions by introducing a BN-pair in a tetracene molecule to form azaborine analogues of acenes. The consequences of the chemical doping on the excitonic properties of tetracene are investigated through high-level multireference calculations. From a pool of 60 proposed BN-tetracene chromophores, we identify 15 new promising candidates for SF as they satisfy the energy level matching conditions involving the low-lying singlet and triplet states of a monomer. Still, some of these compounds show good chemical stability as evidenced by their modest biradical character. These results are interpreted in terms of aromaticity changes, charge transfer effects and exciton properties. More generally, this study shows how the energetics of singlet fission materials can be dramatically altered by using fairly simple chemical substitutions and provides detailed insight into the underlying relationships between the molecular structure, the electronic structure, and the excited state energies.


Extensive efforts to restrain the rise in health care costs have not had a pronounced impact. The health care system in the United States has undergone significant changes, and as we entered the 1990s, a shift toward managed care was gathering momentum. Nevertheless, spending on medical care continues to rise by nearly 10 percent a year, thus increasing the percentage of GNP these costs represent. With substantial progress in lowering the rise of health care costs unlikely in the near future, the debate over some form of national program is bound to intensify.


Large areas of one-dimensional ZnO nanostructures (nanorods and nanowires) were prepared by simple solvothermal method. The synthesis involves a template-less and surfactant free aqueous methods. In this study, Zn metal sheet was used as both Zn2+ ion source for the growth of ZnO nano-structures and substrate for oxide film. The mixed solvent of 1-propanol with water was used as solvents for nanorods and ethylene glycol with water was for nanowires. The solvothermal treatment of a zinc metal plate with the solvents at the temperature of 125 oC for 10 hours resulted in the 1-D ZnO nanostructures, which were grown on the Zn metal sheet. The synthesized ZnO was well aligned on whole area of substrate and the nanorods were 150 nm in diameter and 3 μm in lengths, respectively.


This investigation analyzes the growth of small companies which were involved in a business incubation scheme. We use a descriptive design, including participation of 44 incubated companies in a Business Incubation Program Empreser, at Hermosillo, Sonora in the year 2010, and the same number of companies not included in the program. We find the main growth development indicators (SEBRAE) are organization, position, and innovation in activities.


Background The control of Ebola virus disease (EVD) outbreaks relies on rapid diagnosis and prompt action, a daunting task in limited-resource contexts. This study develops prediction scores that can help healthcare workers improve their decision-making at the triage-point of EVD suspect-cases during EVD outbreaks. Methods We computed accuracy measurements of EVD predictors to assess their diagnosing ability compared with the reference standard GeneXpert® results, during the eastern DRC EVD outbreak. We developed predictive scores using the Spiegelhalter-Knill-Jones approach and constructed a clinical prediction score (CPS) and an extended clinical prediction score (ECPS). We plotted the receiver operating characteristic curves (ROCs), estimated the area under the ROC (AUROC) to assess the performance of scores, and computed net benefits (NB) to assess the clinical utility (decision-making ability) of the scores at a given cut-off. We performed decision curve analysis (DCA) to compare, at a range of threshold probabilities, prediction scores' decision-making ability and to quantify the number of unnecessary isolation. Results The analysis was done on data from 10432 subjects, including 651 EVD cases. The EVD prevalence was 6.2% in the whole dataset, 14.8% in the subgroup of suspects who fitted the WHO Ebola case definition, and 3.2% for the set of suspects who did not fit this case definition. The WHO clinical definition yielded 61.6% sensitivity and 76.4% specificity. Fatigue, difficulty in swallowing, red eyes, gingival bleeding, hematemesis, confusion, hemoptysis, and a history of contact with an EVD case were predictors of EVD. The AUROC for ECPS was 0.88 (95%CI: 0.86–0.89), significantly greater than this for CPS, 0.71 (95%CI: 0.69–0.73) (p < 0.0001). At -1 point of score, the CPS yielded a sensitivity of 85.4% and specificity of 42.3%, and the ECPS yielded sensitivity of 78.8% and specificity of 81.4%. The diagnostic performance of the scores varied in the three disease contexts (the whole, fitting or not fitting the WHO case definition data sets). At 10% of threshold probability, e.g. in disease-adverse context, ECPS gave an NB of 0.033 and a net reduction of unnecessary isolation of 67.1%. Using ECPS as a joint approach to isolate EVD suspects reduces the number of unnecessary isolations by 65.7%. Conclusion The scores developed in our study showed a good performance as EVD case predictors since their use improved the net benefit, i.e., their clinical utility. These rapid and low-cost tools can help in decision-making to isolate EVD-suspicious cases at the triage point during an outbreak. However, these tools still require external validation and cost-effectiveness evaluation before being used on a large scale.


The aim of this study is to illustrate the advantage of using computational fluid dynamics (CFD) in order to help manage fire-fighting operations on the field. The jet streams from a water nozzle in an open field are investigated in terms of essential hydraulics characteristics such as overall shape patterns and throw. The model developed by CFD is also based on the measures taken in an open field test programme for characterizing the nozzle of a robot kit designed for fire-fighting operations in hostile environments. The observations made during the tests are used in two ways: one way is to try to feed information to the CFD model on the hydraulics in the jet issuing from the nozzle, the other way is to compare the overall outcome from the CFD model to the results obtained in the test programme. The first part of the study describes the features of the nozzle set up (geometry, positioning, pressures), the open field environment of the tests (space, wind), the outcome observed (stream shape, flow rate, throw). The second part of the study describes the CFD model in terms of specific characteristics of the nozzle (emerging shape patterns), of the numerical domain set (global dimensions and wind influence) and in terms of the outcome obtained (stream shape, flow rate, throw). The comparison between the tests results and the numerical results completes the study and forms the basis for a proposed combined use of information gained from real and associated virtual environment, which can be of help in managing fire-fighting activities.


A four-field system of equations has been recently derived from the compressible magnetohydrodynamic (MHD) equations to describe turbulence in the solar wind. These equations apply to a plasma permeated by a spatially varying mean magnetic field when the plasma beta is of the order unity or less. In the presence of spatial inhomogeneities, the four-field equations predict pressure fluctuations of the order of the Mach number of the turbulence, as observed by Helios 1 and 2. It is shown that inhomogeneities that occur only in the form of pressure-balanced structures cannot account for density fluctuations as large as the Mach number of the turbulence. Numerical predictions from the four-field and compressible MHD equations are compared using the same initial condition. The comparison shows that the predictions of the four-field model are qualitatively consistent with the predictions of the compressible MHD model and suggests that the four-field model is a viable model of compressible turbulence in the solar wind.


The Chemical Oxygen Demand (COD) end value of effluent discharged from a bioreactor into the environment is a critical indicator of its capacity to pollute the environment. A comparative parametric analysis of COD removal rate using three different biogas digesters is presented. The three bioreactors are Upflow Anaerobic Sludge Blanket (UASB), Upflow Bioreactor with Central Substrate Dispenser (UBCSD), and Continuous Stirred-Tank Reactor (CSTR) known as Module I, Module II and Module III respectively. In order to select the most fitting bioreactor type among the three considered, experimentation was carried out using organic municipal waste (OMW) as substrate. A 10-day hydraulic retention time (HRT) was used, while cattle rumen microbes were used to improve digestion rate. UBCSD showed the highest level of percentage COD removal of 95.2%, followed by the CSTR with a value of 80.8%; while the UASB offered the lowest level of percentage COD removal of 79.0%. This outcome indicates that effluent from the UBCSD digested substrate is more suitable and safer for use as organic fertilizer in agricultural practices. It similarly implies that a bioreactor with enhanced mixing capacity is safer for digestion.


The electronic information revolution and the use of computers as an essential part of everyday life are now more widespread than ever before, as the Internet is exploited for the speedy transfer of data and business. Hotel/hospitality websites are growing in use worldwide, and they present popular business channels on the Internet. However, they need to be continuously evaluated and monitored to measure their levels of efficiency, effectiveness and user satisfaction, ultimately to improve quality and profit. Also, users have become the most important factor impacting on the success of these websites; if they are produced and are then deemed not useful by the end-users; the result is a failed business. Thus, nobody can use them and the stakeholders cannot make money. To assess the success of hotel/hospitality sites; usability criteria should be considered to ensure that users can find their way quickly and easily to complete their tasks effectively. This paper aims to use user testing and the thinking aloud protocol to evaluate two interfaces of hotel/hospitality sites to examine how their usability problems significantly impede user performance. The results show that usability is the main factor affecting users' performance, and that it is the best attribute for measuring the extent to which hotel/hospitality sites meet the requirements of their users and marketing strategy. Also, this study emphasizes to the one important concept in marketing which is related to usability concept is to understand the online user behaviour to deliver effective online user experiences, consequently, to achieve good e-marketing strategy. Because in this study, a high percentage of users failed in completing their tasks to reserve rooms for their journey. Thus, stakeholders fail in achieving the most important goal of their e-marketing strategy.


Experimentation of a wireless network protocol over the air is of significant interest. However, it is more rarely performed than simulation because of the difficulties in coding and debugging as well as lack of scalability and repeatability. In this article, the concept of a code-reuse platform making use of a simulation code directly for real experiments is revisited as an efficient and easy means of experimentation. Furthermore, an architecture and key components of an idealistic code-reuse platform are suggested, and then CommonCode, the most advanced codereuse platform, is proposed. Through extensive simulations and experiments using Common-Code for the same codes, we demonstrate that CommonCode is valid and accurate in terms of protocol performance, and simultaneously fast and easy in terms of protocol development.


As the elderly population is now the fastest growing age group in the United States, there is an imminent need to understand the molecular mechanisms of aging and develop new approaches to counter aging and the maladies that come with it. Modulation of metabolism, either by dietary restriction or pharmacologic or genetic alteration of metabolic pathways, can extend lifespan and delay age-related diseases in evolutionarily diverse organisms. Here we demonstrate, for the first time, a role for alpha-ketoglutarate (alpha-KG) in the regulation of aging. Alpha-KG serves many functions in the cell, including being an intermediate of the tricarboxylic acid cycle, a precursor for several amino acids, and a substrate for alpha-KG-dependent oxygenases. We show that alpha-KG extends the mean lifespan of adult Caenorhabditis elegans by about 50%, and provide evidence to suggest that this is not due to the metabolism of alpha-KG into other metabolites. Other metabolites have been shown to extend lifespan as well, but without a well defined mechanism. Research on small molecules in aging has been hindered by the inability to identify drug targets. We use a label-free, unbiased drug target identification strategy termed DARTS (drug affinity responsive target stability) to uncover a new binding target of alpha-KG, the beta subunit of the ATP synthase. We reveal that alpha-KG inhibits ATP synthase in in vitro and in vivo assays using both worm and mammalian models. Consistently, genetic or pharmacological inhibition of ATP synthase yields the same phenotypes as alpha-KG: increased lifespan, decreased ATP levels, lower oxygen consumption rates, elevated levels of reactive oxygen species, and reduced target of rapamycin signaling. However, unlike genetic inhibition of ATP synthase, alpha-KG does not induce the mitochondrial unfolded protein response, cause larval arrest, or slow pharyngeal pumping rates. Remarkably, alpha-KG does not further increase the lifespan of dietary restricted animals and is elevated during starvation, a testament to it being a key regulator of dietary restriction mediated lifespan extension. Like dietary restriction, alpha-KG also induces autophagy, and we provide evidence to suggest that autophagy may play an essential role for the longevity of alpha-KG treated animals. Our findings posit alpha-KG as a key regulator of metabolic pathways in response to nutrient status, and suggest new strategies for the prevention and treatment of aging and age-related diseases.


Divide and Choose among two agents, and the Diminishing Share (DS) and Moving Knife (MK) algorithms among many, elicit parsimonious information to guarantee to each a Fair Share, worth at least 1/n-th of the whole manna. Our n-person Divide and Choose (D&C) rule, unlike DS and MK, works if the manna has subjectively good and bad parts. If utilities are additive over indivisible items, it implements the canonical "Fair Share up to one item" approximation. The D&C rule also offers one interpretation of the Fair Share when utilities are neither additive nor monotonic . Under a mild continuity assumption, it guarantees to each agent her minMax utility: that of her best share in the worst possible partition. This is lower than her Maxmin utility: that of her worst share in the best possible partition. When the manna is unanimously good, or unanimously bad, better guarantees than minMax are feasible. Our Bid & Choose rules fix an additive benchmark measure of shares, and ask agents to bid the smallest size of a share they find acceptable. The resulting Guarantee is between the minMax and Maxmin utilities


Ontologies are commonly used for annotating textual data mainly based on human language technologies [1]. This research focuses on manual extensions of ontologies to support the annotation of business news. Experiments were conducted on a well known Cyc ontology and using Cyc annotator on two business news datasets. We show that the proposed extensions of ontology results in annotation with better coverage of terms that are relevant for the business domain. The results of identifying financial terms in business news using the original Cyc ontology show the average precision of 56% and recall of 41% in case of Reuters news and the average precision of 69% and the recall of 57% in case of Yahoo financial news. Using the proposed extension results with increased performance, the average precision of 82% and average recall of 73% for Yahoo financial news and average precision of 84% and average recall of 63% for Reuters news.


The wireless sensor networks (WSN) are emerging as autonomous monitoring platform consisting of small, low-power and inexpensive devices. A typical device within WSN comprises of three major components: a sensing circuit, single-threaded processor, and wireless transmitter-receiver circuit; moreover, the three components operate on AA batteries. The coverage problem in WSN is to place sensor devices (nodes) in a service area so that the entire service area is sensed. A major concern in WSN is to maximize the coverage of the service area while in turn maximizing the lifespan of WSN. Because of the low-cost design and finite lifespan of the sensor nodes, many sensors fail to operate due to either a malfunction or power run-out. This paper presents the coverage restoration problem, which addresses the following question: how to restore the covered area of a failed sensor without adding or moving sensors? We have modeled the restoration coverage problem as a decision tree that estimates all possible restoration scenarios when a randomly set of sensors is failed. The longest path in the decision tree represents the longest possible restoration of a given WSN. Our initial experiments demonstrate how feasible to find the best restoration paths in a short time.


The solubility of calcium titanate in CaCl2 melt was investigated above 1373 K, and electrodeposition of Ti metal in the melt was attempted. Many pits were formed on the surface of sintered CaTiO3 compact by the immersion in CaCl2 melt above 1373 K. The weight of the compact decreased with the increase in the immersion time, and the decrease got faster with the increase in temperature. Cathodic current in cyclic voltammetry increased with the addition of CaTiO3 powder in the bath, and the increase in the cathodic currents depended on the bath temperature and the added amount of CaTiO3. From the results by the electrochemical measurement, the solubilities of CaTiO3 in CaCl2 melt were estimated about 7 mol% at 1573 K, and less than 1 mol% at 1373 K. Metallic Ti was detected by XRD analysis in the electrodeposit obtained by potentio-static electrolysis in the bath containing CaTiO3 above 1373 K, but the amount of Ti metal seemed a little. The similar results were obtained in CaCl2 melt containing Ca3Ti2O7 though the detailed study has not been completed. It was concluded that calcium titanate was soluble in molten CaCl2 above 1373 K, and that the CaCl2 bath containing calcium titanate could be applied to Ti electrolysis. [doi:10.2320/matertrans.MK201615]


The effects of applied tensile stress on the microstructural stability of a third generation single crystal superalloy DD10 have been investigated under stressed and un-stressed thermal exposure at 980 °C. The results indicated that μ phase precipitated in the dendrite core after both stressed and un-stressed thermal exposure at 980 °C for 450 h. The μ phase formation, γ′ coarsening and rafting processes were promoted by the applied tensile stress. However, the precipitation of μ phase was not sensitive to the magnitude of applied tensile stress. Meanwhile, the applied tensile stress did not affect the type and morphology of the topologically close packed (TCP) phase. It is suggested that the interaction of the applied tensile stress and the misfit stress decreased the lattice misfit between μ phase and γ matrix and promoted the formation of μ phase.


The paper analyses research output of the journal IJIDT using bibliometric approach for five years from 2011 to 2015. The journal publishes 259 research papers during the study period and published papers were examined and analyzed for distribution of articles, authorship pattern, the degree of collaboration, and geographical distribution of articles etc. Conclusions have been drawn from the analysis and found that two authorship patterns are prevalent with 0.63 Degree of Collaboration, India as the top most contributor of the articles for the journal and amongst foreign countries, Saudi Arabia is the highest contributor. Karnataka is the highest contributor amongst the Indian States and Union Territories. Journal Articles were found the most prevalent source of information for writing research papers and used as a citation. Calculated half-life of the journal citations found to be 8 years.


Fifty years ago Gideon promised that an attorney would vindicate the constitutional rights of any accused too poor to afford an attorney. But Gideon also promised more. Writ small, Gideon promised to protect individual defendants; writ large, Gideon promised to protect our system of constitutional criminal procedure. Much has been written about Gideon''s broken promise to our poor; this Essay is about Gideon''s broken promise to our system. With its army of zealous public defenders, Gideon should have produced litigation that vigorously protected the core structures of our adversary trial system. Instead, courts have converted Gideon representation into a Gideon defendant''s de facto relinquishment of important Sixth Amendment rights. As a result, counsel –– not client –– controls the invocation and exercise of the adversary procedures. And, even as to those Sixth Amendment rights still within a defendant''s exclusive control, Strickland eviscerates a defendant''s capacity to seek redress when counsel precludes the exercise of a fundamental right. As a result, Gideon has increasingly become an enforcer of the status quo –– a cog in the systemic machine that grinds continually toward under-enforcement of Sixth Amendment adversary rights.


Background: In clinical neurophysiology, threshold tracking studies are used to evaluate the functionality of a muscle through studying the functionality of its motor units (MUs) that govern the muscle. The functionality of an MU can be quantified by estimation of its excitability properties via MU's stimulus-response curve. In this study, we aim to develop a model-based approach to estimate MU's threshold mean and its activation range as indications of MU's excitability. This is a different approach from routine strategies in neurophysiology, which are mostly subjective. Methods: To assess the excitability of a single MU, needle electromyography examination was used to obtain the axonal activity of that MU. To improve estimation, the examination was repeated several times on individuals. Replication of experiment introduces serial correlation between observations. We account for this correlation by using a mixed-effects model. We investigate the appropriateness of classical logistic mixed-effects model and its Bayesian formulation for estimation purpose. Results: Both classical and Bayesian models can obtain a reliable estimation of MU's threshold. However, we found Bayesian approach to provide a better estimate of MU's activation range. Moreover, if data contain outliers both classical and Bayesian methods are vulnerable to some extent. Conclusions: Compared to the classical approach, Bayesian method is more flexible in dealing with overdispersion and provides more robust estimation of MU's parameters.


It is a great pleasure to be introducing this set of four thematic papers, which arose from the symposium 'The Micropalaeontological Record of Global Change' at the Third International Palaeontological Congress (IPC3) last year (28 June–3 July, 2010). Co-hosted by the Natural History Museum and Imperial College, London, IPC3 was brought to the UK under the auspices of the Palaeontological Association, thanks to the efforts of many but most notably Prof. Dick Aldridge, who chaired the IPC3 organizing committee. With Dick's own strong micropalaeontological interests, and this unique opportunity for the UK's palaeontological societies to join together as hosts to such a major international event, The Micropalaeontology Society (TMS) gave IPC3 its whole-hearted support.

It is, perhaps, difficult to express the particular benefits and unique quality of a given scientific gathering; reports fill the pages of society newsletters, for repeat attendees at regular meetings their general feel becomes dissipated across half-remembered backgrounds of host institutions, cities and post-conference outcrops. To me, IPC3 felt like something different. The idea of the International Palaeontological Congress in itself is a new initiative. I remember hearing of plans for IPC2 in Beijing during my PhD studies. There were murmurs of excitement through the palaeontological community and a totting up of costs amongst the research students. As a very junior micropalaeontologist with a palaeoceanographic bent, IPC2 was a curiosity, and I was happy enough to watch my vertebrate palaeontologist office-mate go with moderate interest but little envy. IPC3, however, was different. Here was the world-leading palaeontological gathering, right on our doorstep – for me, in my very institution.

IPC3, and specifically the TMS support of its organization and scientific programme, expressed a number of strengths, achievements and, dare I say it, creative tensions within the UK palaeontological community. First, it was an expression of the …


This article sets forth a new model for knowledge generation in applied and professional psychology -- the pragmatic case study (PCS) method. Drawing from both psychology's traditional/quantitative and alternative/qualitative approaches, the PCS method involves the creation of systematic, peer-reviewed case studies in psychotherapy (and in all other areas of applied psychology) that follow D. Peterson's "disciplined inquiry" epistemological model. The studies are designed to be organized into "journal-databases," like Pragmatic Case Studies in Psychotherapy (PCSP), which combine (a) individual studies; (b) articles that address epistemological, theoretical, methodological, logistical, economic, political and ethical issues in the PCS method; and (c) substantive cross-case analyses of groups of individual cases already published in the database. To lay out the model's arguments, the article is divided into four major sections that consider, respectively: (1) a discussion of the relevant historical and philosophical context from which the PCS model emerges; (2) a proposal for an initial set of methodological guidelines for ensuring rigorous quality in each case study; (3) an illustrative application of the model to cognitive-behavioral efficacy research; and (4) an exploration of the implications of the model. Throughout, the emphasis is upon creating an integrative, pragmatic alternative for gaining new useful knowledge in our discipline.


Medium and Large Data Center (DC) are large energy consumers, with increasing power density, mainly with the singular growth of usage of the WWW and the recent development of the "cloud" computing. The DC's owners, managers and operators have been primarily concerned with power and cooling, due to the important role of these resources in the operating costs and investments in facilities infrastructure. The environmental aspect of energy, ostensively consumed, is also a concern. This article lists and presents the key drivers of this concern and a brief description of a method and an indicator for the measurement of energy efficiency, widely used in DCs, the PUE (Power Usage Effectiveness). Technologies are also discussed, addressing sources of inefficiencies and losses, in regard to the possibilities of control and mitigation, opening the discussion for the development of methods for the energy efficiency optimizing, without affecting the reliability of the facilities (operational risk), that is the main characteristic of the infrastructure of a mission critical facility. Keywords: Data Center, Energy, Efficiency, PUE


The ESR method shows that variation of lysin concentration in the maiz enzyme resulting from the Opaque-2 mutation correlates with the number of paramagnetic centres in seed fractions. Increase of the lysin concentration brings about a quick rise of the ESR amplitude in the enzyme fraction of aleyrone layer and a decrease of the ESR amplitude in the seed germ.


Nuclear fusion is considered to be a valuable, alternative renewable energy supply. Operation of nuclear fusion plasmas is accomplished through the tokamak concept, which combines toroidal and poloidal coils to confine the plasma magnetically. Tokamak plasmas typically constitute high-order nonlinear distributed systems, which suffer from a large number of instabilities or off-normal events requiring actively controlled stabilization. As a result many fusion related control problems arise, which all demand a dedicated control approach, differing from standard feedback control to more innovative solutions. As an example of such a fusion related control problem, the active stabilization and suppression of so-called Tearing Modes (TMs) or magnetic islands in a tokamak plasma is considered. Enhanced efficiency of a tokamak, requires higher plasma beta, plasma shaping and larger devices. Higher beta operation, however, leads to the manifestation of TMs. Localized injection of electron cyclotron (EC) waves has demonstrated its feasibility to stabilize TMs. Efficient, flexible and well-localized heating and current drive by EC waves can be achieved applying a mechanical Electron Cyclotron Resonance Heating (ECRH) launcher system. The work reported primarily focuses on the mechanics and control of such a system with a 2 rotational degrees of freedom (DOF) steer-able mirror, operated at TEXTOR. The dynamics of this instrument are measured and modeled in terms of Frequency Response Function (FRF) estimation and equations of motion. Nonlinear system behavior (mainly induced by friction) is characterized and modeled. The impact of external disturbances is considered. This identification procedure allows design and implementation of a cascaded control strategy for improved actuation of the mechanical launcher and also provides information on the physical limitations of the system. The report additionally presents proposals, from a control engineering perspective, for future development of real-time TM control scenarios dedicated to the TEXTOR ECRH installation. It is clarified that modeling, experiments and simulation can be adopted to design controllers, which improve the functionality of the system in real-time feedback controlled suppression and stabilization of magnetic islands.


Nicotine enhances the value of environmental stimuli and rewards, and reward enhancement can maintain nicotine consumption. Stimulants such as d-amphetamine are misused more by women and are commonly co-used with nicotine. d-Amphetamine potentiates nicotine's effects in human and animal research. To date, there are no published studies examining this interaction in a reward-enhancement task. The current study sought to investigate the reward-enhancing effects of nicotine alongside and coadministered with d-amphetamine. Further, we evaluated the persistence of reward enhancement across ratio and temporal schedules of reinforcement. We used 10 male and 10 female Sprague–Dawley rats. Enhancement was assessed within subjects by examining active lever pressing for a visual stimulus reinforcer on variable ratio 3, variable interval 30 s and variable time 30 s – variable ratio 3 schedules. Before 1-h sessions, rats received one injection of saline, 0.1 or 0.3 mg/kg d-amphetamine and one of saline or 0.4 mg/kg nicotine, making six possible drug combinations (saline + saline, saline + nicotine, 0.1 d-amphetamine + aline, 0.1 d-amphetamine + nicotine, 0.3 d-amphetamine + saline and 0.3 d-amphetamine + nicotine) experienced in a randomized order by each rat. When d-amphetamine was coadministered with nicotine, we found an interaction effect on reward enhancement that persisted across schedules of reinforcement. Males and females exhibited reward enhancement by 0.3 d-amphetamine, while only females showed reward enhancement by 0.1 d-amphetamine. Further, females responded more for the visual stimulus than males in all d-amphetamine conditions. Future studies should assess how reward enhancement is involved in high nicotine-amphetamine comorbidity rates and enhanced amphetamine misuse in women.


BACKGROUND AND PURPOSE
Treatment doses of heparins are not recommended for acute ischemic stroke. Despite this, their use in this setting is widespread. We investigated whether subgroups of patients with acute ischemic stroke and atrial fibrillation, identified by clinical, hemostatic (d-dimer, prothombin fragments(1+2) [F(1+2)], soluble fibrin monomer), or inflammatory (C-reactive protein [CRP]) variables might have a differential response to low molecular weight heparin (LMWH) over aspirin. In addition, we sought to identify factors associated with a poor clinical outcome at 3 months.

METHODS
We conducted a post hoc subgroup analysis of a randomized, placebo-controlled, double-blind trial (Heparin in Acute Embolic Stroke Trial) designed to test the hypothesis that treatment doses of LMWH (dalteparin; 100 IU/kg BID) would be superior to aspirin (160 mg per day) in patients with acute ischemic stroke and atrial fibrillation. For the current analysis, 431 participants were included. The primary outcome measure was a poor outcome at 3 months, defined as death or dependency in activities of daily living. Using regression analysis, we determined whether any of the chosen variables were associated with a differential response to dalteparin (treatment interaction) or with poor outcome.

RESULTS
In the multivariable logistic regression model, none of the clinical, hemostatic, or inflammatory variables were associated with a significant treatment interaction. Stroke severity (odds ratio [OR], 1.09 [95% CI, 1.07 to 1.12]), increasing age (OR, 1.09 [CI, 1.05 to 1.14]), CRP level (OR, 1.32 [CI, 1.04 to 1.66]), and F(1+2) level (OR, 1.77 [CI, 1.07 to 2.91]) were independently associated with a poor outcome at 3 months.

CONCLUSIONS
Our study does not support the use of treatment doses of LMWH in any of the studied subgroups of patients with acute ischemic stroke and atrial fibrillation. Age, stroke severity, CRP, and F(1+2) were predictive of poor outcome at 3 months.


Around the world, the electricity industry is in the process of undergoing a fundamental transition. Twenty years ago, electricity was primarily generated at large, industrial-scale generating plants, and transported in one direction to consumers via the transmission and distribution networks. The large generators were typically closely integrated into the operation of the transmission and distribution networks. Electricity consumers, on the other hand, were treated as essentially passive. This paradigm has changed and will change further. Around the world, a number of regions have chosen to introduce competition and competitive markets into the generation of electricity. In most of these regions, the operation of generation and transmission is coordinated through market mechanisms. This required a substantial change in the way the electricity industry is organised and operated.


Aims Novelty preference or sensation seeking is an important trait related to initiating and maintaining risky behaviours, including substance abuse. Here we introduce a novel or familiar prime (image) preceding a risk choice and focus on behavioural and imaging correlates to the prime that might predict risk seeking in healthy volunteers. We aim to investigate whether novel or familiar primes affect judgments of risk. We hypothesize that subjects would be more risk seeking following a novel relative to familiar stimulus and that subjects who are more novelty seeking will have increased striatal and hippocampal activity to the novel stimulus. Methods We adapted a risk-taking task involving acceptance or rejection of a 50:50 choice of gain or loss which was preceded by a familiar (pre-test familiarization) or novel face prime. Neutral expression faces of males and females from The Karolinska Directed Emotional Faces database were used as primes. Subjects were tested behaviourally and scanned using functional MRI as they were performing a different version of the same task. Results Twenty-four healthy volunteers were recruited for the behavioral study and eighteen for the fMRI study. We show enhanced risk taking following novel relative to familiar images and particularly for the low gain condition. Subjects had faster reaction times to the prime when accepting rather than rejecting the risky choice. We further show that right putamen activity to novel versus familiar primes were positively correlated with risk taking choices. Conclusions Novelty appears to have a contextually enhancing effect on augmenting risky choices possibly mediated via putaminal activity. These findings highlight the role of context in risk taking and have important implications for a wide range of behaviours including substance abuse.


This paper describes a technique for modeling single-event upsets due to ionizing radiation in a partially depleted silicon-on-insulator (SOI) MOSFET device. Two current pulses are used, one connected between the drain and body of the device, and the other connected between the body and source of the device. The physical representation of these two current sources is described in detail. Circuit modeling is verified against drift-diffusion field solver modeling and hardware experiments. The effects of manufacturing variation and operating condition variation on the qCrit of circuit storage elements are explored


Proper training of military personnel, at all levels, has never been more crucial. In this article, we describe the application of virtual environment technology to a novel and complex task-the military checkpoint. In the process, we also address differences between an immersive virtual environment training system and a destop version.


We present a version of GMI (Gomory mixed-integer) cuts in a way so that they are derived with respect to a "dual form" mixed-integer optimization problem and applied on the standard-form primal side as columns, using the primal simplex algorithm. This follows the general scheme of He and Lee, who did the case of Gomory pure-integer cuts. Our input mixed-integer problem is not in standard form, and so our cuts are derived rather differently from how they are normally derived. A convenient way to develop GMI cuts is from MIR (mixed-integer rounding) cuts, which are developed from 2-dimensional BMI (basic mixed-integer) cuts, which involve a nonnegative continuous variable and an integer variable. The non-negativity of the continuous variable is not the right tool for us, as our starting point (the "dual form" mixed-integer optimization problem) has no non-negativity. So we work out a different 2-dimensional starting point, a pair of somewhat arbitrary inequalities in one continuous and one integer variable. In the end, we follow the approach of He and Lee, getting now a finitely converging primal simplex column-generation algorithm for mixed-integer optimization problems.


This paper explores the registered sexual offender (RSO) residency requirements, restrictions, and issues within Broward, Miami-Dade, and Monroe counties in Florida. While Florida statute 775.215 does not allow RSOs to live within 1,000 feet of a school, childcare facility, park, or playground, county and local ordinances often impose more restrictive residency requirements.  Because of these requirements as well as more extensive residency restrictions on a county and city level, RSOs abiding by the requirements often end up living in clusters and/or colonies like the infamous Julia Tuttle Causeway cluster.  As a result, these restrictions create clusters of SROs within socially disorganized areas, higher levels of transient SROs, and SROs who abscond and fail to report.  This paper examines, though the use of ArcGIS 10.3, the number of registered RSOs that violate the state statute by where they live; and investigates the hot spots and residency clusters where they are in violation as well as in regulation as it pertains to the statute.  Using the baseline of 1,000 feet, there are 905 RSOs (31% of the overall total RSOs) violating Florida statute within the tri-county area of Broward, Miami-Dade, and Monroe counties.


Randomized clinical trials (RCTs) like those conducted by the FDA provide medical practitioners with average effects of treatments, and are generally more desirable than observational studies due to their control of unobserved confounders (UCs), viz., latent factors that influence both treatment and recovery. However, recent results from causal inference have shown that randomization results in a subsequent loss of information about the UCs, which may impede treatment efficacy if left uncontrolled in practice (Bareinboim, Forney, and Pearl 2015). Our paper presents a novel experimental design that can be noninvasively layered atop past and future RCTs to not only expose the presence of UCs in a system, but also reveal patient- and practitioner-specific treatment effects in order to improve decision-making. Applications are given to personalized medicine, second opinions in diagnosis, and employing offline results in online recommender systems.


Especially with the evaluation of non-listed (medium-sized) companies, the following problems and significant restrictions pertaining to the applicability of the CAPM must be taken into account when determining cost of capital. 1. Homogeneity of expectations and planning consistency. Given the reality that information is distributed asymmetrically, how should the individual state of information be taken into account when determining (subjective) decision values? And how should capital cost be kept consistent with the risks that are explicitly or implicitly taken into account when revenues (cash flows) are being planned? 2. Diversification. How should non-diversified (idiosyncratic) risks in capital cost and valuation be taken into account when the evaluator does not have a perfectly diversified portfolio (and also cannot obtain one)? 3. Risk measures. When determining cost of capital and company value, what are the consequences of applying measures of risk other than the beta factor and standard deviations of the CAPM because in an imperfect capital market (a) creditors are subject to financing restrictions and/or (b) the evaluator is applying a safety first approach and thus wants to limit the extent of downside risks such as the probability of insolvency?This paper deals with all of these aspects, whereby, for the sake of simplicity, only a 1-periodmodel (without taxes) is examined. Chapter II shows how the expected values of returns and the risk measure are derived consistent to planning from the company's (i.e. the evaluator's) information regarding the uncertain returns to be evaluated. Chapter III then shows how a replication model can be used to take imperfect diversification into account. The equity capital cost rate is calculated for an arbitrary degree of diversification and it is shown how a company's capital cost can be derived from the probability distribution of its uncertain returns (earnings), rather than from its returns expressed as a relative change in value. It is then shown how this approach can be generalised by utilizing risk measures other than standard deviations and the beta factor based on them. Such risk measures are helpful with non-normal distributions of returns.


Identifying the causal effect of monetary policy on inflation remains a challenge. Researchers frequently find evidence of a 'price puzzle': increases in the policy rate are followed by higher rather than lower inflation. This can be explained by the forward-looking behaviour of the central bank. Inflation does not rise in response to an increase in the policy rate but, instead, the central bank raises its policy rate when it expects inflation to increase in the future. To identify the true causal effects of monetary policy on inflation, it is hence necessary to control for this systematic policy response to expected inflation. For Australia, however, the price puzzle has been found even when controlling for the cash rate's systematic response to the Reserve Bank's own inflation forecasts. I argue that this is due to an additional but omitted systematic response of the cash rate to credit market shocks. Easier credit market conditions lead to an economic expansion and higher inflation. Therefore, the Bank raises the cash rate – its policy rate – when credit spreads decline. However, the Bank's inflation forecasts do not fully capture the inflationary effect of easier credit conditions. As a result, cash rate changes are positively correlated with future inflation even when purging them of the cash rate's response to the Bank's inflation forecasts. Accordingly, I show that accounting for the cash rate's additional response to credit market conditions resolves the price puzzle. As expected, a higher cash rate reduces inflation and output growth, and raises the unemployment rate.


We study the entrance in a retail market of consumers who are less elastic because of hurriedness and lack of information. Theory predicts that firms react by increasing prices to expand surplus extraction, but this effect weakens as market competition increases. High frequency data from Italian pharmacies confirm these predictions. Monthly variation in the number of newborns at the city level generates exogenous changes in the number of less elastic buyers (the parents) who consume a basket of hygiene products demanded by more experienced and elastic consumers as well. We estimate that the number of newborns has a positive effect on the equilibrium price even if marginal costs are decreasing. We exploit exogenous variation in market competition generated by the Italian legislation concerning how many pharmacies should operate in a city as a function of the existing population. Using a Regression Discontinuity design we find that an increase in competition has a significant and negative effect on the capacity of sellers to extract surplus from less elastic buyers.


A generic template for clinical trials simulations that are typically required by statisticians is developed. Realistic clinical trials data sets are created using a unifying model that allows general correlation structures for endpoint*timepoint data and nonnormal distributions (including time-to-event), and computationally efficient algorithms are presented. The model allows for patient dropout and noncompliance. A grid-enabled SAS-based system has been developed to implement this model; details are presented summarizing the system development. An example illustrating use of the system is given.


Optimal time for choosing Aortic Valve Replacement in Aortic Stenosis patients is based on understanding the natural history of the disease and prognostic variables, such as age, symptom status and co-morbid factors. In patients with advanced congestive heart failure, the valvular area and transvalvular gradients, determined by echocardiography and cardiac catheterization studies, have limitations for preoperative evaluation; before surgery the reversibility of this myocardial depression must be identified. At present, there is widespread agreement that valve replacement is indicated for symptomatic severe aortic stenosis regardless of age; however, cardiac surgery remains controversial in asymptomatic patients but with abnormal response to exercise, ventricular tachycardia, valve area lesser than 0.6 cm2, and marked or excessive left ventricular hypertrophy. The presence of moderate or severe valvular calcification, together with a rapid increase in aortic-jet velocity, identifies patients with a very poor prognosis and these patients should be considered for surgery. Finally, the decision to operate a patient must be considered on individual factors and whether quality of life is improved, and not just on operative mortality and morbidity.


© 2019 American Physical Society. In electromagnetic scattering, the so-called T matrix encompasses the optical response of a scatterer for any incident excitation and is most commonly defined using the basis of multipolar fields. It can therefore be viewed as a generalization of the concept of polarizability of the scatterer. We calculate here the series expansion of the T matrix for a spheroidal particle in the small-size, long-wavelength limit, up to third lowest order with respect to the size parameter, X, which we will define rigorously for a nonspherical particle. T is calculated from the standard extended boundary condition method with a linear system involving two infinite matrices P and Q, whose matrix elements are integrals on the particle surface. We show that the limiting form of the P and Q matrices, which is different in the special case of spheroid, ensures that this Taylor expansion can be obtained by considering only multipoles of order 3 or less (i.e., dipoles, quadrupoles, and octupoles). This allows us to obtain self-contained expressions for the Taylor expansion of T(X). The lowest order is O(X3) and equivalent to the quasistatic limit or Rayleigh approximation. Expressions to order O(X5) are obtained by Taylor expansion of the integrals in P and Q followed by matrix inversion. We then apply a radiative correction scheme, which makes the resulting expressions valid up to order O(X6). Orientation-averaged extinction, scattering, and absorption cross sections are then derived. All results are compared to the exact T-matrix predictions to confirm the validity of our expressions and assess their range of applicability. For a wavelength of 400 nm, the new approximation remains valid (within 1% error) up to particle dimensions of the order of 100-200 nm depending on the exact parameters (aspect ratio and material). These results provide a relatively simple and computationally friendly alternative to the standard T-matrix method for spheroidal particles smaller than the wavelength, in a size range much larger than for the commonly used Rayleigh approximation.


This paper is devoted to the findings of a bibliometric analysis of 52 syllabi on economic sociology provided by the members of the American Sociological Association section "Economic Sociology" and scholars from the UK, France, Germany, and Russia. In addition, the initial collection was expanded to course syllabi submitted from outside of sociology, including management departments, policy programs and anthropology. The analysis aims at measuring to what extent economic sociologists are consensual and have an agreement upon a set of core texts. Two indicators of the reference canonicity that might appear on a syllabus are developed. The first counts the number of times a reference is observed in the collected syllabi. The second indicator is based on a Kleinberg's HITS algorithm applied for search ranking, which better captures the relational aspect of consensus formation in economic sociology as a scientific discipline. The research findings demonstrate that rather small group of articles, largely rooted in a relational-network perspective and a cultural/political approach, form the canon of economic sociology. The Granovetter's paper on social embeddedness (published in 1985) still emerges as the most popularly listed reference on the observed 39 syllabi. Additionally, the author highlights role of "broker", references that bridge different territories of economic sociology. The article Bazaar Economy by Clifford Geertz published in"American Economic Review" (1978) is one example of such references


Studies the problem of assigning a collection of operating frequencies to a collection of radio transmitters under various constraints including co-channel constraints, adjacent-channel constraints and co-site constraints using graph-colouring methods. Traditionally, these methods have been applied only to the co-channel constraint problem. The authors show how they can be generalised to apply to all cases. They also give two new graph colouring algorithms that can be applied to the problem which are modifications of the smallest-last algorithm.<<ETX>>


Fixing software bugs has always been an important and time-consuming process in software development. Fixing concurrency bugs has become especially critical in the multicore era. However, fixing concurrency bugs is challenging, in part due to non-deterministic failures and tricky parallel reasoning. Beyond correctly fixing the original problem in the software, a good patch should also avoid introducing new bugs, degrading performance unnecessarily, or damaging software readability. Existing tools cannot automate the whole fixing process and provide good-quality patches.
 We present AFix, a tool that automates the whole process of fixing one common type of concurrency bug: single-variable atomicity violations. AFix starts from the bug reports of existing bug-detection tools. It augments these with static analysis to construct a suitable patch for each bug report. It further tries to combine the patches of multiple bugs for better performance and code readability. Finally, AFix's run-time component provides testing customized for each patch. Our evaluation shows that patches automatically generated by AFix correctly eliminate six out of eight real-world bugs and significantly decrease the failure probability in the other two cases. AFix patches never introduce new bugs and usually have similar performance to manually-designed patches.


Carboxylic acids adsorption on
anatase TiO2 is a key process in circular economy and
sustainability. Yet, in spite of several decades of investigations, its
intimate working mechanisms still remain elusive. In particular, the behavior
of the acid proton and its localization – either on the molecule or on the
surface – are still open issues. By modeling the adsorption of formic acid on
top of regular (101) anatase TiO2 surfaces, we found that, in the 0
K limit, the acid proton is shared between a carboxylic oxygen and a surface oxygen.
In this regime, the proton behavior is mainly governed by quantum
delocalization effects in a single potential well. Nonetheless, as temperature
is raised to room conditions, simulations evidenced a rapid "classical"
shuttling of the proton due to the onset of a two-wells free energy profile
separated by a free energy barrier of the order of kT. This picture, supported by the agreement between simulated and
experimental IR spectra, shows that the titania surface acts like a protecting
group for the carboxylic acid functionality. Such a conceptual insight might
help rationalize the chemical processes of carboxylic species on TiO2
surfaces.


In recent years, the treatment process of patients and disabled people who need rehabilitation and physical medicine has become more effective with the use of new devices and developing technology. The rehabilitation robot is one of the most important developments in new technology. The right therapeutic exercises and the objectivity of the evaluation of the range of motion (ROM; generated torque and muscular activation measurement of the patient) are extremely important factors during treatment. In this study, a lower limb rehabilitation robot was modified and controlled for upper limbs. The retrofitted robot system is able to do passive, active, and active-assistive therapeutic exercises. On the other hand, it performs active-assistive exercises using muscular activation. A web-based human machine interface, which can support home-care service, was developed to control the robotic system. This interface includes a performance evaluation unit, which is able to use not only ROM and torque, but also muscular activation of patients for the assessment of therapy results. Thanks to this system, assessment and physical therapy can be realized by a single robotic system for both upper and lower limbs using physical parameters such as ROM, generated torque, and muscular activation of the limbs. Satisfactory performance of the system is observed in the tests performed with a healthy subject.


Understanding of a research projects' impact is crucial due to increasing importance of this element in a research application's evaluation. This is especially valid regarding projects granted from Horizon 2020. This paper aims at drawing attention of a Polish applicant to the notion of impact and explaining why its description is an important part of each research project application. Moreover, the paper comprises practical guidelines on analysis and demonstrating impact. The author interprets also the notions related to impact like: lead user, end user, value chain and technology readiness level.


Abstract Intense competition in retailing sector requires searching for new and more effective tools of competing with rivals. One of the possible ways seems to go through applying positioning concept in retailing. Positioning in retailing refers to strategy for development of a desirable image, which would help to differentiate a retail company and move away from direct price competition. Besides that, image management provides possibilities for increasing customer perceived value and/or increasing prices. The paper presents methodology for establishing multiple retailers' positions. This methodology is based on evaluation of image attributes' importance for customers. Factor analysis allows revealing more general latent factors that are used to evaluate retailers' positions in a perceptual space. This allows drawing conclusions on how much Lithuanian multiple retailers are similar or differentiated from the standpoint of their customers.


Methane (CH4) emissions via emergent aquatic macrophytes can contribute substantially to the global CH4 balance. We addressed temporal variability in CH4 flux by using the static chamber approach to quantify fluxes from plots dominated by two species considered to differ in flux transport mechanisms (Phragmites australis, Carex rostrata). Temporal variability in daily mean emissions from early June to early October was substantial. The variable that best explained this variation was air temperature. Regular and consistent diel changes were absent and therefore less relevant to include when estimating or modelling CH4 emissions. Methane emissions per m 2 from nearby plots were similar for Phragmites australis and Carex rostrata indicating that CH4 production in the system influenced emissions more than the species identity. This study indicates that previously observed diel patterns and specieseffects on emissions require further evaluation to support improved local and regional CH4 flux assessments.


John Rae's inter-temporal choices explained the statistical nature of human behavior in 1834. However, despite the subject's insight in the objectiveness of behavior, inter-temporal choices remains a peripheral science. This paper takes a sequential approach to question how inter-temporal choices could be behind human behavior, behavioral anomalies and even market anomalies. If these inter-temporal anomalies were consistent, unarbitrageable and explain asset returns better than the Fama and French Factor model, this could further our understanding of asset pricing models by establishing a new duration factor which could subsume both size and value factors.


Extremely low-frequency pulsed electromagnetic field (ELF-PEMF) devices have been used in the clinic for the treatment of bone disorders over the past 30 years. However, the underlying mechanism of which ELF-PEMFs exert an effect on tissues at a cellular level is not well understood. Hence, in this study, we explored the potential of different ELF-PEMF signals in modulating human adipose-derived mesenchymal stromal cells' (hAMSC) osteogenic capability. The cell proliferation rate was assessed using carboxyfluorescein succinimidyl ester (CFSE) method. The osteogenesis potential of cells was determined by alkaline phosphatase (ALP) activity, Alizarin-Red S staining, and RT-qPCR. Finally, the intracellular signaling pathway of a selected ELF-PEMF signal was examined using the PathScan Intracellular Signaling Array. Among the tested ELF-PEMF signals, program 20 (26 Hz) showed activation of the Akt and MAPK/ERK signaling cascade and significant upregulations of collagen I, alkaline phosphatase, and osteocalcin when compared to nonstimulated cells. This study demonstrates the potential of certain ELF-PEMF signal parameters to induce osteogenic differentiation of hAMSC and provides important clues in terms of the molecular mechanisms for the stimulation of osteogenic effects by ELF-PEMF on hAMSC.


Objective Abnormal expression of micro-ribonucleic acid (miRNA [miR])-128 has been observed in various human cancer types, and its validated target genes are implicated in cancer-related cellular processes, such as cell proliferation, differentiation, and apoptosis. Especially, it has been demonstrated that miR-128 may play an important role in the proliferation of human osteosarcoma cells in vitro by directly inhibiting PTEN, which functions as a tumor suppressor in this malignancy. In the current study, we investigated the involvement of miR-128 and its target gene PTEN in tumor progression and prognosis in patients with primary osteosarcoma. Materials and methods Expression levels of miR-128 and PTEN messenger RNA in osteosarcoma and noncancerous bone tissues obtained from 100 patients with primary osteosarcoma were detected by quantitative real-time polymerase chain reaction. Results Expression levels of miR-128 and PTEN messenger RNA in osteosarcoma tissues were significantly higher and lower, respectively, than those in noncancerous bone tissues (both P<0.001). In addition, high miR-128 expression and low PTEN expression, alone (miR-128-high or PTEN-low) or combined (miR-128-high/PTEN-low), were all dramatically associated with poor response to chemotherapy and positive metastasis. More importantly, the associations of miR-128-high/PTEN-low expression with these clinicopathological parameters were more significant than miR-128-high or PTEN-low alone. Finally, miR-128 expression, PTEN expression, miR-128/PTEN expression, the response to chemotherapy and the metastatic status were all identified as independent prognostic factors for overall survival and disease-free survival. Conclusion These findings indicate for the first time that the deregulation of miR-128 and its target gene PTEN may be involved in the aggressive progression of human osteosarcoma. Notably, the upregulation of miR-128 cooperating with the downregulation of PTEN may confer an unfavorable prognosis in patients with this malignancy.


To determine how accurately elderly subjects recall recent falls, we studied 304 ambulatory men and women over the age of 60 years who completed a 12‐month prospective study of risk factors for falling. We developed a system of weekly follow‐up and home visits to record and confirm all falls. During the study, 179 participants suffered at least one fall that was confirmed by home visit. At the end of the study, all subjects were interviewed by telephone about whether they had suffered a fall during the preceding 3, 6, or 12 months. Depending on the time period of recall, 13% to 32% of those with confirmed falls did not recall falling during the specific period of time. Recall was better for the preceding 12 months than for 3 or 6 months. There were only weak correlations (r = 0.28 to 0.59) between the number of falls that were documented and the number that the subjects recalled during each of these periods. Those with lower scores on the Mini‐Mental State Examination were more likely to forget falls. We conclude that elderly subjects often do not recall falls that occurred during specific periods of time over the preceding 3 to 12 months. Researchers and clinicians should consider using methods besides long‐term recall for ascertaining and counting falls over specific periods of time.


This thesis describes the general functions of the New Zealand news media system and the structure, organisation and control of both the daily press and broadcasting and television services in New Zealand. In order to analyse the performance of daily newspapers in detail, a methodology is laid down for the quantitative description of the subject content of newspapers. A sample of the wire copy transmitted to daily newspapers in New Zealand by the New Zealand Press Association is analysed and a study is made of the news selection and display practices observed by 16 daily newspapers in their handling of this material. Further samples of the content of the same 16 daily papers are then analysed in order to obtain characteristic subject content descriptions and to provide material for a generalised discussion of the way in which the newspapers appear to be exercising their functions. This leads to a treatment of the problems facing the New Zealand daily press and a brief outline of the role of the New Zealand Press Association in the New Zealand news media system, as well as a discussion of the possibilities that exist for the improved education and training of journalists. The work then concludes with a set of appendices in which the full texts of various documents are reproduced, as well as a bibliography of literature relevant to the general field of research on the New Zealand mass media.


The protection of the environment from the effects of mining activities, though cardinal, has been a daunting task in Zambia. A polluted environment affects the rights of those who depend on a clean one for their survival. In remedying the pollution caused by mining activities, numerous legislative and policy frameworks have been put in place and institutions responsible for ensuring compliance operationalised. Notwithstanding such interventions, the problem of pollution emanating from mining activities has persisted. This has led individuals and spirited non-governmental organisations to bring legal actions firstly against erring mining companies for their failure to comply with environmental regulations, and secondly against the government for its failure to ensure compliance by the mining companies. The courts before whom such matters have been brought have seemingly prioritised the supposed development brought by investment in the mining sector over the environmental rights of those whose livelihood is anchored in a clean environment. The article underscores the mandate of the courts in safeguarding the environmental rights of persons whose survival is dependent on a clean environment. In doing so the article critically examines the cases which have come before the courts and how these cases have been dealt with in relation to the protection of the environment and ultimately an individual's environmental rights.


This paper review of the chromatic dispersion compensation in optical fiber communication system. In optical communication system to compensate dispersion Fiber Bragg grating (FBG) is one amongst the applicable and necessary components. During this the appliance of chirped FBG was studied as a dispersion compensator in optical communication systems. This paper studied the various types of simulation in optical fiber communication system. The reviews of the analysis based on the chromatic dispersion are studied in the paper.


In recent years the technology on embankments dams has developed sensibly due to the advances in soil mechanic, and in all related sciences. Nevertheless their vulnerability to overtopping is still an open theme of discussion. Such an extreme phenomenon can lead to catastrophic consequences with loss of stability and failure of the entire structure. In spite of that, the consequences of an overtopping are still difficult to analyze and to prevent optimally. The possibility to define a numerical instrument to provide support for analyzing the failure of a dam is an important step ahead for organizing the intervention measures and for optimizing the economic plan. This is the principal reason why the Spanish ministry of Science and Innovation is funding the XPRES project,
between the Polytechnic University of Madrid (UPM), the Centre for Hydrographical Studies of CEDEX and the International Centre for Numerical Methods in Engineering (CIMNE).
The characterization of the failure process is dealt with by combining new numerical models, developed by CIMNE, with experimental tests on physical models of different sizes and scales carried out by UPM and CEDEX. In the present paper the work carried out by CIMNE is presented. The numerical model is based on combination
of Lagrangian Particle Finite Element Method (PFEM) and Eulerian level set techniques in order to optimize the coupling between the dynamic effect of water inside and outside the dam, with the structural deformation and
collapse induced on the down stream shoulder. The breaching formation and the consequent beginning of the failure are analyzed with particular interest. The specific features of the adopted method make it appropriate to treat the rockfill material and its large deformations and shape changes. A variable viscosity law and an energetic erosion criterion are used to take into account mass sliding and erosion acting in combined or alternative way.


The GEANT4 code offers an extensive set of hadronic models for various projectiles and energy ranges. These models include theoretical, parameterized and, for low energy neutrons, data driven models. Theoretical or semi-empirical models sometimes cannot reproduce experimental data at low energies(<100MeV), especially for low Z elements, and therefore recent GEANT4 developments included a new particle\hp package which uses evaluated nuclear databases for proton interactions below 200 MeV. These recent developments have been used to study target designs for low energy proton accelerators, as replacements of research reactors, for medical applications. Presented in this paper are results of benchmarking of these new models for a range of targets, from lithium neutron production targets to molybdenum isotope production targets, with experimental data. Also included is a discussion of the most promising target designs that have currently been studied.


PURPOSE
13 cis Retinoic acid (isotretinoin) is a retinoid with preclinical evidence of anti-prostate cancer activity. This phase II, cross-over, randomized study of advanced, predominantly androgen-dependent prostate cancer patients was designed to assess primarily the effect on prostate-specific antigen (PSA) decline and toxicity of adding isotretinoin to hormonal therapy and, secondarily, the potential antitumor activity of the combination.

PATIENTS AND METHODS
Thirty-seven D0 to D2 patients were randomized soon after initiating luteinizing hormone-releasing hormone agonist with antiandrogen treatment to add (arm 1) or not (arm 2) isotretinoin from weeks 1 to 12. After cross-over on week 13, patients in arm 1 discontinued while patients in arm 2 added isotretinoin from weeks 14 to 25. Observation on hormonal therapy alone continued until week 49.

RESULTS
Baseline and randomization median PSA for 30 assessable patients were, respectively, 34 and 18.2 ng/mL for arm 1 and 31 and 13.4 ng/mL for arm 2. Median PSA at week 13 was 0.5 ng/mL (range, < 0.05 to 136 ng/mL) for arm 1 and 0.7 ng/mL (range, < 0.05 to 4.4 ng/mL) for arm 2; at week 25, 0.1 ng/mL (range, < 0.05 to 121 ng/mL) and 0.4 ng/mL (range, < 0.05 to 3.1 ng/mL), respectively. At week 49, arm 1 had median PSA of 0.1 ng/mL (range, < 0.05 to 345 ng/mL) and arm 2, 0.3 ng/mL (range, < 0.05 to 8.8 ng/mL); seven of 15 and three of 15 patients, respectively, had undetectable PSA levels (P =.12). Frequent isotretinoin-related toxicity included grade 1 cheilitis (76%), skin dryness (43%), and elevated triglycerides (50%).

CONCLUSION
Isotretinoin does not impair PSA decline or add significant toxicity to hormonal therapy. An adequately powered, randomized study would be required to determine whether the combination is superior to standard hormonal treatment.