Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism (MUSIASEM): an outline of rationale and theory

This paper presents an outline of rationale and theory of the MuSIASEM scheme (Multi-Scale Integrated Analysis of Societal and Ecosystem Metabolism). First, three points of the rationale behind our MuSIASEM scheme are discussed: (i) endosomatic and exosomatic metabolism in relation to Georgescu-Roegen’s flow-fund scheme; (2) the bioeconomic analogy of hypercycle and dissipative parts in ecosystems; (3) the dramatic reallocation of human time and land use patterns in various sectors of modern economy. Next, a flow-fund representation of the MUSIASEM scheme on three levels (the whole national level, the paid work sectors level, and the agricultural sector level) is illustrated to look at the structure of the human economy in relation to two primary factors: (i) human time - a fund; and (ii) exosomatic energy - a flow. The three levels representation uses extensive and intensive variables simultaneously. Key conceptual tools of the MuSIASEM scheme - mosaic effects and impredicative loop analysis - are explained using the three level flow-fund representation. Finally, we claim that the MuSIASEM scheme can be seen as a multi-purpose grammar useful to deal with sustainability issues.

Leniency programs, antitrust enforcement and multimarket contact : three essays in industrial organization

The Layout of My Thesis This thesis contains three chapters in Industrial Organization that build on the work outlined above. The first two chapters combine leniency programs with multimarket contact and provide a thorough analysis of the potential effects of Amnesty Plus and Penalty Plus. The third chapter puts the whole discussion on leniency programs into perspective by examining other enforcement tools available to an antitrust authority. The main argument in that last chapter is that a specific instrument can only be as effective as the policy in which it is embedded. It is therefore important for an antitrust authority to know how it best accompanies the introduction or modification of a policy instrument that helps deterrence. INTRODUCTION Chapter 1 examines the efféct of Amnesty Plus and Penalty Plus on the incentives of firms to report cartel activities. The main question is whether the inclusion of these policies in a leniency program undermine the effectiveness of the latter by discouraging the firms to apply for amnesty. The model is static and focus on the ex post incentives of firms to desist from collusion. The results suggest that, because Amnesty Plus and Penalty Plus encourage the reporting of a second cartel after a first detection, a firm, anticipating this, may be reluctant to seek leniency and to report in the first place. However, the effect may also go in the opposite direction, and Amnesty Plus and Penalty Plus may encourage the simultaneous reporting of two cartels. Chapter 2 takes this idea further to the stage of cartel formation. This chapter provides a complete characterization of the potential anticompetitive and procompetitive effects of Amnesty Plus in a infinitely repeated game framework when the firms use their multimarket contact to harshen punishment. I suggest a clear-cut policy rule that prevents potential adverse effects and thereby show that, if policy makers follow this rule, a leniency program with Amnesty Plus performs better than one without. Chapter 3 characterizes the socially optimal enforcement effort of an antitrust authority and shows how this effort changes with the introduction or modification of specific policy instruments. The intuition is that the policy instrument may increase the marginal benefit of conducting investigations. If this effect is strong enough, a more rigorous detection policy becomes socially desirable.

Impact of genetic SLC28 transporter and ITPA variants on ribavirin 21 serum level, hemoglobin drop and therapeutic response in patients with HCV infection

Background: T reatment o f chronic hepatitis C i s evolving, a nd direct acting antivirals ( DAAs) are now a dded to p egylated interferon-α ( Peg- INF-α) and ribavirin (RBV) for the treatment o f hepatitis C v irus ( HCV) genotype 1 infection. DAAs c ause d ifferent side effects and can even worsen RBV induced hemolytic anemia. T herefore, identifying host genetic d eterminants of R BV bioavailability and therapeutic e fficacy will remain crucial for individualized treatment. Recent d ata showed associations between R BV induced h emolytic anemia and genetic polymorphisms o f concentrative nucleoside transporters s uch as C NT3 (SLC28A3) and i nosine t riphosphatase (ITPA). T o analyze t he association of genetic variants of SLC28 transporters and ITPA with RBV induced hemolytic anemia and treatment o utcome. Methods: I n our study, 173 patients f rom t he S wiss Hepatitis C C ohort Study and 2 2 patients from Swiss Association for the Study of the Liver study 24 (61% HCV g enotype 1, 3 9% genotypes 2 o r 3) were analyzed for SLC28A2 single nucleotide p olymorphism (SNP) rs11854484, SLC28A3 rs56350726 and SLC28A3 rs10868138 as well as ITPA SNPs rs1127354 and rs7270101. RBV serum levels during treatment were measured in 49 patients. Results: SLC28A2 r s11854484 genotype TT was associated with significantly higher dosage- and body weight-adjusted RBV levels as compared to genotypes TC and CC (p=0.04 and p=0.02 at weeks 4 and 8, respectively). ITPA SNPs rs1127354 and rs7270101 were associated with h emolytic a nemia both in genotype as w ell as i n allelic a nalyses. SLC28A3 rs56350726 genotype TT (vs. AT/AA, RR=2.1; 95% CI 1.1-4.1) as well as the T allele (vs. A; RR=1.8, 95% CI 1.1-3.2) were associated with increased SVR rates. The combined analysis of overall ITPA activity and SLC28 v ariants together revealed n o significant a dditive effects on either treatment-related anemia or SVR. Conclusions: T he newly identified association between RBV serum levels a nd SLC28A2 rs11854484 genotype as well as the replicated association of ITPA and SLC28A3 g enetic p olymorphisms w ith RBV induced hemolytic anemia and treatment r esponse underpin the need for further studies on host genetic d eterminants of R BV bioavailability and therapeutic e fficacy f or individualized treatment of chronic hepatitis C.

Correlation of wear in vivo and six laboratory wear methods.

OBJECTIVE: We examined the correlation between clinical wear rates of restorative materials and enamel (TRAC Research Foundation, Provo, USA) and the results of six laboratory test methods (ACTA, Alabama (generalized, localized), Ivoclar (vertical, volumetric), Munich, OHSU (abrasion, attrition), Zurich). METHODS: Individual clinical wear data were available from clinical trials that were conducted by TRAC Research Foundation (formerly CRA) together with general practitioners. For each of the n=28 materials (21 composite resins for intra-coronal restorations [20 direct and 1 indirect], 5 resin materials for crowns, 1 amalgam, enamel) a minimum of 30 restorations had been placed in posterior teeth, mainly molars. The recall intervals were up to 5 years with the majority of materials (n=27) being monitored, however, only for up to 2 years. For the laboratory data, the databases MEDLINE and IADR abstracts were searched for wear data on materials which were also clinically tested by TRAC Research Foundation. Only those data for which the same test parameters (e.g. number of cycles, loading force, type of antagonist) had been published were included in the study. A different quantity of data was available for each laboratory method: Ivoclar (n=22), Zurich (n=20), Alabama (n=17), OHSU and ACTA (n=12), Munich (n=7). The clinical results were summed up in an index and a linear mixed model was fitted to the log wear measurements including the following factors: material, time (0.5, 1, 2 and 3 years), tooth (premolar/molar) and gender (male/female) as fixed effects, and patient as random effect. Relative ranks were created for each material and method; the same was performed with the clinical results. RESULTS: The mean age of the subjects was 40 (±12) years. The materials had been mostly applied in molars (81%) and 95% of the intracoronal restorations were Class II restorations. The mean number of individual wear data per material was 25 (range 14-42). The mean coefficient of variation of clinical wear data was 53%. The only significant correlation was reached by OHSU (abrasion) with a Spearman r of 0.86 (p=0.001). Zurich, ACTA, Alabama generalized wear and Ivoclar (volume) had correlation coefficients between 0.3 and 0.4. For Zurich, Alabama generalized wear and Munich, the correlation coefficient improved if only composites for direct use were taken into consideration. The combination of different laboratory methods did not significantly improve the correlation. SIGNIFICANCE: The clinical wear of composite resins is mainly dependent on differences between patients and less on the differences between materials. Laboratory methods to test conventional resins for wear are therefore less important, especially since most of them do not reflect the clinical wear.

Phosphodiesterase-5 inhibition mimics intermittent reoxygenation and improves cardioprotection in the hypoxic myocardium.

Although chronic hypoxia is a claimed myocardial risk factor reducing tolerance to ischemia/reperfusion (I/R), intermittent reoxygenation has beneficial effects and enhances heart tolerance to I/R. AIM OF THE STUDY: To test the hypothesis that, by mimicking intermittent reoxygenation, selective inhibition of phosphodiesterase-5 activity improves ischemia tolerance during hypoxia. Adult male Sprague-Dawley rats were exposed to hypoxia for 15 days (10% O₂) and treated with placebo, sildenafil (1.4 mg/kg/day, i. p.), intermittent reoxygenation (1 h/day exposure to room air) or both. Controls were normoxic hearts. To assess tolerance to I/R all hearts were subjected to 30-min regional ischemia by left anterior descending coronary artery ligation followed by 3 h-reperfusion. Whereas hypoxia depressed tolerance to I/R, both sildenafil and intermittent reoxygenation reduced the infarct size without exhibiting cumulative effects. The changes in myocardial cGMP, apoptosis (DNA fragmentation), caspase-3 activity (alternative marker for cardiomyocyte apoptosis), eNOS phosphorylation and Akt activity paralleled the changes in cardioprotection. However, the level of plasma nitrates and nitrites was higher in the sildenafil+intermittent reoxygenation than sildenafil and intermittent reoxygenation groups, whereas total eNOS and Akt proteins were unchanged throughout. CONCLUSIONS: Sildenafil administration has the potential to mimic the cardioprotective effects led by intermittent reoxygenation, thereby opening the possibility to treat patients unable to be reoxygenated through a pharmacological modulation of NO-dependent mechanisms.

Menarche, menopause, and breast cancer risk: individual participant meta-analysis, including 118 964 women with breast cancer from 117 epidemiological studies.

BACKGROUND: Menarche and menopause mark the onset and cessation, respectively, of ovarian activity associated with reproduction, and affect breast cancer risk. Our aim was to assess the strengths of their effects and determine whether they depend on characteristics of the tumours or the affected women. METHODS: Individual data from 117 epidemiological studies, including 118 964 women with invasive breast cancer and 306 091 without the disease, none of whom had used menopausal hormone therapy, were included in the analyses. We calculated adjusted relative risks (RRs) associated with menarche and menopause for breast cancer overall, and by tumour histology and by oestrogen receptor expression. FINDINGS: Breast cancer risk increased by a factor of 1·050 (95% CI 1·044-1·057; p<0·0001) for every year younger at menarche, and independently by a smaller amount (1·029, 1·025-1·032; p<0·0001), for every year older at menopause. Premenopausal women had a greater risk of breast cancer than postmenopausal women of an identical age (RR at age 45-54 years 1·43, 1·33-1·52, p<0·001). All three of these associations were attenuated by increasing adiposity among postmenopausal women, but did not vary materially by women's year of birth, ethnic origin, childbearing history, smoking, alcohol consumption, or hormonal contraceptive use. All three associations were stronger for lobular than for ductal tumours (p<0·006 for each comparison). The effect of menopause in women of an identical age and trends by age at menopause were stronger for oestrogen receptor-positive disease than for oestrogen receptor-negative disease (p<0·01 for both comparisons). INTERPRETATION: The effects of menarche and menopause on breast cancer risk might not be acting merely by lengthening women's total number of reproductive years. Endogenous ovarian hormones are more relevant for oestrogen receptor-positive disease than for oestrogen receptor-negative disease and for lobular than for ductal tumours. FUNDING: Cancer Research UK.

Multilevel Modelling with Spatial Effects

In multilevel modelling, interest in modeling the nested structure of hierarchical data has been accompanied by increasing attention to different forms of spatial interactions across different levels of the hierarchy. Neglecting such interactions is likely to create problems of inference, which typically assumes independence. In this paper we review approaches to multilevel modelling with spatial effects, and attempt to connect the two literatures, discussing the advantages and limitations of various approaches.

Anatomy of contaminated aquifers of an industrial site: insights from the stable isotope compositions of waters and dissolved inorganic carbon

The hydrogen and oxygen isotopes of water and the carbon isotope composition of dissolved inorganic carbon (DIC) from different aquifers at an industrial site, highly contaminated by organic pollutants representing residues of the former gas production, have been used as natural tracers to characterize the hydrologic system. On the basis of their stable isotope compositions as well as the seasonal variations, different groups of waters (precipitation, surface waters, groundwaters and mineral waters) as well as seasonably variable processes of mixing between these waters can clearly be distinguished. In addition, reservoir effects and infiltration rates can be estimated. In the northern part of the site an influence of uprising mineral waters within the Quaternary aquifers, presumably along a fault zone, can be recognized. Marginal infiltration from the Neckar River in the cast and surface water infiltration adjacent to a steep hill on the western edge of the site with an infiltration rate of about one month can also be resolved through the seasonal variation. Quaternary aquifers closer to the centre of the site show no seasonal variations, except for one borehole close to a former mill channel and another borehole adjacent to a rain water channel. Distinct carbon isotope compositions and concentrations of DIC for these different groups of waters reflect variable influence of different components of the natural carbon cycle: dissolution of marine carbonates in the mineral waters, biogenic, soil-derived CO2 in ground- and surface waters, as well as additional influence of atmospheric CO2 for the surface waters. Many Quaternary aquifer waters have, however, distinctly lower delta(13)C(DIC) values and higher DIC concentrations compared to those expected for natural waters. Given the location of contaminated groundwaters at this site but also in the industrially well-developed valley outside of this site, the most likely source for the low C-13(DIC) values is a biodegradation of anthropogenic organic substances, in particular the tar oils at the site.

Testing the Tunnel Effect: Comparison, Age and Happiness in UK and German Panels

In contrast to previous results combining all ages we find positive effects of comparison income on happiness for the under 45s, and negative effects for those over 45. In the BHPS these coefficients are several times the magnitude of own income effects. In GSOEP they cancel to give no effect of effect of comparison income on life satisfaction in the whole sample, when controlling for fixed effects, and time-in-panel, and with flexible, age-group dummies. The residual age-happiness relationship is hump-shaped in all three countries. Results are consistent with a simple life cycle model of relative income under uncertainty.

Development and Democratization

Current studies, mainly focused on the postwar period, are split on the impact of development on democracy. Examining panel data that runs from early nineteenth century (a time where hardly any democracy was in place) to the end of the twentieth century, I show income matters positively for democratization – both after controlling for country and time effects and instrumenting for income. Since the effect of time partly varies over time, with some historical periods that are more favorable to democracy than others, I investigate the domestic variables (a decreasing marginal effect of growth in already developed economies) and international factors (the strategies of great powers toward small countries) generating that result. I finally probe the underlying processes through which income shapes political institutions, showing that development produces key changes in the distribution and nature of wealth that, in turn, make democracy a stable political outcome.

School composition effects in Spain

Drawing on PISA data of 2006, this study examines the impact of socio-economic school composition on science test score achievement for Spanish students in compulsory secondary schools. We define school composition in terms of the average parental human capital of students in the same school. These contextual peer effects are estimated using a semi-parametric methodology, which enables the spillovers to affect all the parameters of the educational production function. We also deal with the potential problem of self-selection of student into schools, using an artificial sorting that we argue to be independent from unobserved student’s abilities. The results indicate that the association between socio-economic school composition and test score results is clearly positive and significantly higher when computed with the semi-parametric approach. However, we find that the endogenous sorting of students into schools plays a fundamental role, given that the spillovers are significantly reduced when this selection process is ruled out from our measure of school composition effects. Specifically, the estimations suggest that the contextual peer effects are moderately positive only in those schools where the socio-economic composition is considerably elevated. In addition, we find some evidence of asymmetry of how the external effects and the sorting process actually operate, which seem affect in a different way males and females as well as high and low performance students.

Industrial Location and Space: New Insights

This paper tries to resolve some of the main shortcomings in the empirical literature of location decisions for new plants, i.e. spatial effects and overdispersion. Spatial effects are omnipresent, being a source of overdispersion in the data as well as a factor shaping the functional relationship between the variables that explain a firm’s location decisions. Using Count Data models, empirical researchers have dealt with overdispersion and excess zeros by developments of the Poisson regression model. This study aims to take this a step further, by adopting Bayesian methods and models in order to tackle the excess of zeros, spatial and non-spatial overdispersion and spatial dependence simultaneously. Data for Catalonia is used and location determinants are analysed to that end. The results show that spatial effects are determinant. Additionally, overdispersion is descomposed into an unstructured iid effect and a spatially structured effect. Keywords: Bayesian Analysis, Spatial Models, Firm Location. JEL Classification: C11, C21, R30.

Consensus summary statement of the International Multidisciplinary Consensus Conference on Multimodality Monitoring in Neurocritical Care : A statement for healthcare professionals from the Neurocritical Care Society and the European Society of Intensive Care Medicine.

Neurocritical care depends, in part, on careful patient monitoring but as yet there are little data on what processes are the most important to monitor, how these should be monitored, and whether monitoring these processes is cost-effective and impacts outcome. At the same time, bioinformatics is a rapidly emerging field in critical care but as yet there is little agreement or standardization on what information is important and how it should be displayed and analyzed. The Neurocritical Care Society in collaboration with the European Society of Intensive Care Medicine, the Society for Critical Care Medicine, and the Latin America Brain Injury Consortium organized an international, multidisciplinary consensus conference to begin to address these needs. International experts from neurosurgery, neurocritical care, neurology, critical care, neuroanesthesiology, nursing, pharmacy, and informatics were recruited on the basis of their research, publication record, and expertise. They undertook a systematic literature review to develop recommendations about specific topics on physiologic processes important to the care of patients with disorders that require neurocritical care. This review does not make recommendations about treatment, imaging, and intraoperative monitoring. A multidisciplinary jury, selected for their expertise in clinical investigation and development of practice guidelines, guided this process. The GRADE system was used to develop recommendations based on literature review, discussion, integrating the literature with the participants' collective experience, and critical review by an impartial jury. Emphasis was placed on the principle that recommendations should be based on both data quality and on trade-offs and translation into clinical practice. Strong consideration was given to providing pragmatic guidance and recommendations for bedside neuromonitoring, even in the absence of high quality data.

Comparative study and identification of potent eukaryotic transcriptional repressors in gene switch systems.

In mammalian cells, proper gene regulation is achieved by the complex interplay of transcription factors that activate or repress gene expression by binding to the regulatory regions of target promoters. While transcriptional activators have been extensively characterised and classified into functional groups, relatively little is known about the comparative strength and cell type-specificity of transcriptional repressors. Here, we have compared the ability of a series of eukaryotic repression domains to silence basal and activated transcription. A series of the most potent repression domains was further tested in the context of a gene therapy gene-switch system in various cell types. The results indicate that the analysed repression domains exert varying silencing activities in different promoter contexts. Furthermore, their potential for gene silencing varies also depending on the cellular context. When multimerised within one chimeric repressor protein, particular combinations of repressor domains were found to display synergistic repressing effects and efficient repression in a panel of cell lines. This approach thus allowed the identification of transcriptional repressors that are both potent and versatile in terms of cellular specificity as a basis for gene switch systems.

Mental health and growing up factsheet. Drugs and alcohol - what parents need to know.

Information about drugs and alcohol - what parents need to know: information for parents, carers and anyone who works with young people. About this leaflet This is one in a series of leaflets for parents, teachers and young people entitled Mental Health and Growing Up. These leaflets aim to provide practical, up-to-date information about mental health problems (emotional, behavioural and psychiatric disorders) that can affect children and young people. This leaflet offers practical advice for parents, teachers and carers who are worried that a young person is misusing drugs or alcohol. Why do I need to know about a young person using drugs or alcohol? Many young people smoke, drink alcohol and may try drugs. It is important you are aware of this and do not ignore it as a time when they are just having fun or experimenting. It doesnââ,‰"¢t take much for the young people to soon lose control and to need help to recover from this problem. How common is it? By the age of 16, up to half of young people have tried an illegal drug. Young people are trying drugs earlier and more are drinking alcohol. What are the different types of drugs which cause problems? The most commonly used, readily available and strongly addictive drugs are tobacco and alcohol. There are numerous others that can be addictive. Alcohol and cannabis are sometimes seen as ââ,¬Ëogatewayââ,‰"¢ drugs that lead to the world of other drugs like cocaine and heroin. Drugs are also classed as ââ,¬Ëolegalââ,‰"¢ andââ,¬Ëoillegalââ,‰"¢. The obviously illegal drugs include cannabis (hash), speed (amphetamines), ecstasy (E), cocaine and heroin. Using ââ,¬Ëolegalââ,‰"¢ drugs (like cigarettes, alcohol, petrol, glue) does not mean they are safe or allowed to be misused. It just means they may be bought or sold for specific purposes and are limited to use by specific age groups. There are clear laws regarding alcohol and young people. For more detailed information on various drugs, their side-effects and the law, see ââ,¬ËoFurther Informationââ,‰"¢ at the end of the factsheet. Why do young people use drugs or alcohol? Young people may try or use drugs or alcohol for various reasons. They may do it for fun, because they are curious, or to be like their friends. Some are experimenting with the feeling of intoxication. Sometimes they use it to cope with difficult situations or feelings of worry and low mood. A young person is more likely to try or use drugs or alcohol if they hang out or stay with friends or family who use them. What can be the problems related to using drugs or alcohol? Drugs and alcohol can have different effects on different people. In young people especially the effects can be unpredictable and potentially dangerous. Even medications for sleep or painkillers can be addictive and harmful if not used the way they are prescribed by a doctor. Drugs and alcohol can damage health. Sharing needles or equipment can cause serious infections, such as HIV and hepatitis. Accidents, arguments and fights are more likely after drinking and drug use. Young people are more likely to engage in unprotected sex when using drugs. Using drugs can lead to serious mental illnesses, such as psychosis and depression. When does it become addiction or problem? It is very difficult to know when exactly using drugs or alcohol is more than just ââ,¬Ëocasualââ,‰"¢. Addiction becomes more obvious when the young person spends most of their time thinking about, looking for or using drugs. Drugs or alcohol then become the focus of the young personââ,‰"¢s life. They ignore their usual work, such as not doing their schoolwork, or stop doing their usual hobbies/sports such as dancing or football. How do I know if there is a problem or addiction? Occasional use can be very difficult to detect. If the young person is using on a regular basis, their behaviour often changes. Look for signs such as: ïâ?s§ unexplained moodiness ïâ?s§ behaviour that is ââ,¬Ëoout of character' ïâ?s§ loss of interest in school or friends ïâ?s§ unexplained loss of clothes or money ïâ?s§ unusual smells and items like silver foil, needle covers. Remember, the above changes can also mean other problems, such as depression, rather than using drugs. What do I do if I am worried? If you suspect young person is using drugs, remember some general rules. ïâ?s§ Pay attention to what the child is doing, including schoolwork, friends and leisure time. ïâ?s§ Learn about the effects of alcohol and drugs (see websites listed below). ïâ?s§ Listen to what the child says about alcohol and drugs, and talk about it with them. ïâ?s§ Encourage the young person to be informed and responsible about drugs and alcohol. ïâ?s§ Talk to other parents, friends or teachers about drugs - the facts and your fears and seek help. If someone in the family or close friend is using drugs or alcohol, it is important that they seek help too. It may be hard to expect the young person to give up, especially if a parent or carer is using it too. My child is abusing drugs. What do I do? ïâ?s§ If your child is using drugs or alcohol, seek help. ïâ?s§ Do stay calm and make sure of facts. ïâ?s§ Don't give up on them, get into long debates or arguments when they are drunk, stoned or high. ïâ?s§ Donââ,‰"¢t be angry or blame themââ,‰?othey need your help and trust to make journey of recovery. Where can I get help? You can talk in confidence to a professional like your GP or practice nurse, a local drug project or your local child and adolescent mental health. They can refer your child to relevant services and they will be able to offer you advice and support. You may also be able to seek help through a school nurse, teacher or social worker. You can find this information from your local area telephone book or council website, or ask for the address from your health centre. [For the full factsheet, click on the link above]This resource was contributed by The National Documentation Centre on Drug Use.