Efficacy, Acceptability, and Tolerability of Antipsychotics in Treatment-Resistant Schizophrenia: A Network Meta-analysis.

Importance In treatment-resistant schizophrenia, clozapine is considered the standard treatment. However, clozapine use has restrictions owing to its many adverse effects. Moreover, an increasing number of randomized clinical trials (RCTs) of other antipsychotics have been published. Objective To integrate all the randomized evidence from the available antipsychotics used for treatment-resistant schizophrenia by performing a network meta-analysis. Data Sources MEDLINE, EMBASE, Biosis, PsycINFO, PubMed, Cochrane Central Register of Controlled Trials, World Health Organization International Trial Registry, and clinicaltrials.gov were searched up to June 30, 2014. Study Selection At least 2 independent reviewers selected published and unpublished single- and double-blind RCTs in treatment-resistant schizophrenia (any study-defined criterion) that compared any antipsychotic (at any dose and in any form of administration) with another antipsychotic or placebo. Data Extraction and Synthesis At least 2 independent reviewers extracted all data into standard forms and assessed the quality of all included trials with the Cochrane Collaboration's risk-of-bias tool. Data were pooled using a random-effects model in a Bayesian setting. Main Outcomes and Measures The primary outcome was efficacy as measured by overall change in symptoms of schizophrenia. Secondary outcomes included change in positive and negative symptoms of schizophrenia, categorical response to treatment, dropouts for any reason and for inefficacy of treatment, and important adverse events. Results Forty blinded RCTs with 5172 unique participants (71.5% men; mean [SD] age, 38.8 [3.7] years) were included in the analysis. Few significant differences were found in all outcomes. In the primary outcome (reported as standardized mean difference; 95% credible interval), olanzapine was more effective than quetiapine (-0.29; -0.56 to -0.02), haloperidol (-0. 29; -0.44 to -0.13), and sertindole (-0.46; -0.80 to -0.06); clozapine was more effective than haloperidol (-0.22; -0.38 to -0.07) and sertindole (-0.40; -0.74 to -0.04); and risperidone was more effective than sertindole (-0.32; -0.63 to -0.01). A pattern of superiority for olanzapine, clozapine, and risperidone was seen in other efficacy outcomes, but results were not consistent and effect sizes were usually small. In addition, relatively few RCTs were available for antipsychotics other than clozapine, haloperidol, olanzapine, and risperidone. The most surprising finding was that clozapine was not significantly better than most other drugs. Conclusions and Relevance Insufficient evidence exists on which antipsychotic is more efficacious for patients with treatment-resistant schizophrenia, and blinded RCTs-in contrast to unblinded, randomized effectiveness studies-provide little evidence of the superiority of clozapine compared with other second-generation antipsychotics. Future clozapine studies with high doses and patients with extremely treatment-refractory schizophrenia might be most promising to change the current evidence.

Thyroid function within the normal range and risk of coronary heart disease: an individual participant data analysis of 14 cohorts

IMPORTANCE Some experts suggest that serum thyrotropin levels in the upper part of the current reference range should be considered abnormal, an approach that would reclassify many individuals as having mild hypothyroidism. Health hazards associated with such thyrotropin levels are poorly documented, but conflicting evidence suggests that thyrotropin levels in the upper part of the reference range may be associated with an increased risk of coronary heart disease (CHD). OBJECTIVE To assess the association between differences in thyroid function within the reference range and CHD risk. DESIGN, SETTING, AND PARTICIPANTS Individual participant data analysis of 14 cohorts with baseline examinations between July 1972 and April 2002 and with median follow-up ranging from 3.3 to 20.0 years. Participants included 55,412 individuals with serum thyrotropin levels of 0.45 to 4.49 mIU/L and no previously known thyroid or cardiovascular disease at baseline. EXPOSURES Thyroid function as expressed by serum thyrotropin levels at baseline. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) of CHD mortality and CHD events according to thyrotropin levels after adjustment for age, sex, and smoking status. RESULTS Among 55,412 individuals, 1813 people (3.3%) died of CHD during 643,183 person-years of follow-up. In 10 cohorts with information on both nonfatal and fatal CHD events, 4666 of 48,875 individuals (9.5%) experienced a first-time CHD event during 533,408 person-years of follow-up. For each 1-mIU/L higher thyrotropin level, the HR was 0.97 (95% CI, 0.90-1.04) for CHD mortality and 1.00 (95% CI, 0.97-1.03) for a first-time CHD event. Similarly, in analyses by categories of thyrotropin, the HRs of CHD mortality (0.94 [95% CI, 0.74-1.20]) and CHD events (0.97 [95% CI, 0.83-1.13]) were similar among participants with the highest (3.50-4.49 mIU/L) compared with the lowest (0.45-1.49 mIU/L) thyrotropin levels. Subgroup analyses by sex and age group yielded similar results. CONCLUSIONS AND RELEVANCE Thyrotropin levels within the reference range are not associated with risk of CHD events or CHD mortality. This finding suggests that differences in thyroid function within the population reference range do not influence the risk of CHD. Increased CHD risk does not appear to be a reason for lowering the upper thyrotropin reference limit.

Placental plasticity in monochorionic twins: Impact on birth weight and placental weight

INTRODUCTION The knowledge about adaptive mechanisms of monochorionic placentas to fulfill the demands of two instead of one fetus is largely speculative. The aim of our study was to investigate the impact of chorionicity on birth weight and placental weight in twin pregnancies. METHODS Forty Monochorionic (MC) and 43 dichorionic (DC) twin pregnancies were included in this retrospective study. Individual and total (sum of both twins) birth weights, placental weights ratios between placental and birth weights and observed-to-expected (O/E)-ratios were calculated and analyzed. Additionally, we investigated whether in twin pregnancies placental and birth weights follow the law of allometric metabolic scaling. RESULTS MC pregnancies showed higher placental O/E-ratios than DC ones (2.25 ± 0.85 versus 1.66 ± 0.61; p < 0.05), whereas the total neonatal birth weight O/E-ratios were not different. In DC twins total placental weights correlated significantly with gestational age (r = 0.74, p < 0.001), but not in MC twins. Analysis of deliveries ≤32 weeks revealed that the placenta to birth weight ratio in MC twins was higher than in matched DC twins (0.49 ± 0.3 versus 0.24 ± 0.03; p = 0.03). Allometric metabolic scaling revealed that dichorionic twin placentas scale with birth weight, while the monochorionic ones do not. DISCUSSION The weight of MC placentas compared to that of DC is not gestational age dependent in the third trimester. Therefore an early accelerated placental growth pattern has to be postulated which leads to an excess placental mass particularly below 32 weeks of gestation. The monochorionic twins do not follow allometric metabolic scaling principle making them more vulnerable to placental compromise.

The Gut Microbiome and Cirrhosis: Basic Aspects

In this chapter the basic aspects helping to understand the microbiome in terms of quantity, diversity, complexity, function, and interaction with the host are discussed. First the nomenclature, definitions of taxa, and measures of diversity as well as methods to unravel this kingdom are outlined. A brief summary on its physiological relevance for general health and the functions exerted specifically by the microbiome is presented. Differences in the composition of the microbiome along the gastrointestinal tract and across the gut wall and its interindividual variations, enterotypes, and stability are highlighted. The reader will be familiarized with all different modulators impacting on the microbiome, namely, intrinsic and extrinsic factors. Intrinsic factors include gastrointestinal secretions (gastric acid, bile, pancreatic juice, mucus), antimicrobial peptides, motility, enteric nervous system, and host genotype. Extrinsic factors are mainly dietary choices, hygiene, stress, alcohol consumption, exercise, and medications. The second part of the chapter focuses on quantitative and qualitative changes in microbiome in liver cirrhosis. The mechanisms contributing to dysbiosis, small intestinal bacterial overgrowth, and bacterial translocation are delineated underscoring their role for the liver-gut axis.

Phonological Translation in Bilingual and Monolingual Children

Bilingual children face a variety of challenges that their monolingual peers do not. For instance, switching between languages requires the phonological translation of proper names, a skill that requires mapping the phonemic units of one language onto the phonemic units of the other. Proficiency of phonological awareness has been linked to reading success, but little information is available about phonological awareness across multiple phonologies. Furthermore, the relationship between this kind of phonological awareness and reading has never been addressed. The current study investigated phonological translation using a task designed to measure children's ability to map one phonological system onto another. A total of 425 kindergarten and second grade monolingual and bilingual students were evaluated. The results suggest that monolinguals generally performed poorly. Bilinguals translated real names more accurately than fictitious names, in both directions. Correlations between phonological translation and measures of reading ability were moderate, but reliable. Phonological translation is proposed as a tool with which to evaluate phonological awareness through the perspective of children who live with two languages and two attendant phonemic systems.

DRUG METABOLISM IN LIVER TUMORS: PURIFICATION AND CHARACTERIZATION OF NADPH-CYTOCHROME-P450 REDUCTASE AND THE RESOLUTION OF MULTIPLE FORMS OF CYTOCHROME P-450

The hydroxylation of N- and O-methyl drugs and a polycyclic hydrocarbon has been demonstrated in microsomes prepared from two transplantable Morris hepatomas (i.e., 7288C. t.c. and 5123 t.c.(H). The hydroxylation rates of the drug benzphetamine and the polycyclic hydrocarbon benzo {(alpha)} pyrene by tumor microsomes were inducible 2 to 3-fold and 2-fold, respectively by pretreatment of rats with phenobarbital/hydrocortisone. Hepatoma 5123t.c.(h) microsomal hydroxylation activities were more inducible after these pretreatments than hepatoma 7288C.t.c. Two chemotherapeutic drugs (cyclophosphamide and isophosphamide) were shown to be mutagenic after activation by the tumor hemogenate with the TA100 strain of Salmonella typhimurium bacteria. NADPH-cytochrome P-450 was purified from phenobarbital/hydrocortisone treated rat hepatoma 5123t.c.(H) microsomes 353-fold with a specific activity 63.6 nmol of cytochrome c reduced per min per mg of protein. The purified enzyme, has an apparent molecular weight of 79,500 daltons, and contained an equal molar ratio of FMN and FAD, with a total flavin content of 16.4 nmol per mg of protein. The purified enzyme also catalyzed electron transfer to artificial electron acceptors with the K(,m) values of the hepatoma reductase similar to those of purified liver reductase. The K(,m) value of the hepatoma reductase (13 uM) for NADPH was similar to that of purified liver reductase (5.0 uM). In addition the purified hepatoma reductase was immunochemically similar to the liver reductase.^ Hepatoma cytochrome P-450, the hemeprotein component of the hepatoma microsomes of rats pretreated with phenobarbital/hydrocortisone. The resolution of the six forms was achieved by the DE-53 ion-exchange chromatography, and further purified by hydroxyapatite. The six different fractions that contained P-450 activity, had specific contents from 0.47 to 1.75 nmol of cytochrome P-450 per mg of protein, and indicated a 2 to 9-fold purification as compared to the original microsomes. In addition, difference spectra, molecular weights and immunological results suggest there are at least six different forms of cytochrome P-450 in hepatoma 5123 t.c.(H). ^

The association of area socioeconomic status and cancer screening: A systematic review and multilevel study

Background. The gap between actual and ideal rates of routine cancer screening in the U.S., particularly for colorectal cancer screening (CRCS) (1;2), is responsible for an unnecessary burden of morbidity and mortality, particularly for disadvantaged groups. Knowledge about the effects of individual and area influences is being advanced by a growing body of research that has examined the association of area socioeconomic status (SES) and cancer screening after controlling for individual SES. The findings from this emerging and heterogeneous research in the cancer screening literature have been mixed. Moreover, multilevel studies in this area have not yet adequately explored the possibility of differential associations by population subgroup, despite some evidence suggesting gender-specific effects. ^ Objectives and methods. This dissertation reports on a systematic review of studies on the association of area SES and cancer screening and a multilevel study of the association between area SES and CRCS. The specific aims of the systematic review are to: (1) describe the study designs, constructs, methods, and measures; (2) describe the association of area SES and cancer screening; and (3) identify neglected areas of research. ^ The empiric study linked a pooled sample of respondents aged ≥50 years without a personal history of colorectal cancer from the 2003 and 2005 California Health Interview Surveys with a comprehensive set of census-tract level area SES measures from the 2000 U.S. Census. Two-level random intercept models were used to test 2 hypotheses: (1) area SES will be associated with adherence to two modalities of CRCS after controlling for individual SES; and (2) gender will moderate the relationship between area socioeconomic status and adherence to both modalities of CRCS. ^ Results. The systematic review identified 19 eligible studies that demonstrated variability in study designs, methods, constructs, and measures. The majority of tested associations were either not statistically significant or significant and in the positive direction, indicating that as area SES increased, the odds of CRCS increased. The multilevel study demonstrated that while multiple aspects of area SES were associated with CRCS after controlling for individual SES, associations differed by screening modality and in the case of endoscopy, they also differed by gender. ^ Conclusions. Conceptual and methodologic heterogeneity and weaknesses in the literature to date limit definitive conclusions about the underlying relationships between area SES and cancer screening. The multilevel study provided partial support for both hypotheses. Future research should continue to explore the role of gender as a moderating influence with the aim of identifying the mechanisms linking area SES and cancer prevention behaviors. ^

2005 ACIP recommendations effect on newborn hepatitis B vaccination rates and the factors affecting the successful implementation of the recommendations in the US

Background. Hepatitis B virus infection is one of major causes of acute and chronic hepatitis, cirrhosis of the liver, and primary hepatocellular carcinoma. Hepatitis B and its long term consequences are major health problems in the United States. Hepatitis B virus can be vertically transmitted from mother to infant during birth. Hepatitis B vaccination at birth is the most effective measure to prevent the newborn from HBV infection and its consequences, and is part of any robust perinatal hepatitis B prevention program following ACIP recommendations. Universal vaccination of the new born will prevent HBV infection during early childhood and, assuming that children receive the three dosages of the vaccine, it will also prevent adolescent and adult infections. Hepatitis B vaccination is now recommended as part of a comprehensive strategy to eliminate HBV transmission in the United States. ^ Objective. (1)To assess if the hepatitis B vaccination rates of newborn babies have improved after the 2005 ACIP recommendations. (2) To identify factors that affects the implementation of ACIP recommendation for hepatitis B vaccination in newborn babies. These factors will encourage ongoing improvement by identifying successful efforts and pinpointing areas that fall short and need attention. Additional focus areas may be identified to accelerate progress in eliminating perinatal HBV transmission.^ Methods. This review includes information from all pertinent articles, reviews, National immunization survey (NIS) surveys, reports, peer reviewed literature and web sources that were published after 1991.The key words to be used for selecting the articles are: "Perinatal Hepatitis B Prevention program", "Universal Hepatitis B vaccination of newborn babies", "ACIP Recommendations." The data gathered will be supplemented with an analysis of vaccination rates using the National Immunization Survey (NIS) birth dose coverage data.^ Results. The data collected in the NIS of 2009 reveals that the national coverage for birth dose of HepB increased to 60.8% from 50.1% in 2006. The largest increase observed for the birth dose in the past 5 years is from 2008 which increased from 55.3 % to 60.8% in 2009. By state, coverage ranged from 22.8% in Vermont to 80.7% in Michigan. %. Overall, in 2009 the estimated vaccination rates are in higher ranges for most states compared to the estimated vaccination rates in 2006. States vary widely in hepatitis B vaccination rates and in their compliance with the 2005 ACIP recommendation. There are many factors at various stages that might affect the successful implementation of the new ACIP recommendation as revealed in literature review. ^ Conclusions. HBV perinatal transmission can be eliminated, but it requires identifying the gaps and measures taken to increase the current vaccination coverage, ensuring timely administration of post exposure immunoprophylaxis and continued evaluations of the impact of immunization recommendations.^

(Table 1) Concentration of organohalogenated compounds in clean and contaminated hair of polar bears (Ursus maritimus) from East Greenland

In this pilot study, we report on levels of persistent organohalogenated contaminants (OHCs) in hair of polar bears (Ursus maritimus) from East Greenland sampled between 1999 and 2001. To our knowledge, this is the first study on the validation of polar bear hair as a non-invasive matrix representative of concentrations and profiles in internal organs and blood plasma. Because of low sample weights (13-140 mg), only major bioaccumulative OHCs were detected above the limit of quantification: five polychlorinated biphenyl (PCB) congeners (CB 99, 138, 153, 170 and 180), one polybrominated diphenyl ether (PBDE) congener (BDE 47), oxychlordane, trans-nonachlor and ß-hexachlorocyclohexane. The PCB profile in hair was similar to that of internal tissues (i.e. adipose, liver, brain and blood), with CB 153 and 180 as the major congeners in all matrices. A gender difference was found for concentrations in hair relative to concentrations in internal tissues. Females (n = 6) were found to display negative correlations, while males (n = 5) showed positive correlations, although p-values were not found significant. These negative correlations in females may reflect seasonal OHC mobilisation from periphery adipose tissue due to, for example, lactation and fasting. The lack of significance in most correlations may be due to small sample sizes and seasonal variability of concentrations in soft tissues. Further research with larger sample weights and sizes is therefore necessary to draw more definitive conclusions on the usefulness of hair for biomonitoring OHCs in polar bears and other fur mammals.

Decision evaluation in complex risk network systems (DecernsSDSS) demo and Black River case study

The selection of metrics for ecosystem restoration programs is critical for improving the quality of monitoring programs and characterizing project success. Moreover it is oftentimes very difficult to balance the importance of multiple ecological, social, and economical metrics. Metric selection process is a complex and must simultaneously take into account monitoring data, environmental models, socio-economic considerations, and stakeholder interests. We propose multicriteria decision analysis (MCDA) methods, broadly defined, for the selection of optimal sets of metrics to enhance evaluation of ecosystem restoration alternatives. Two MCDA methods, a multiattribute utility analysis (MAUT), and a probabilistic multicriteria acceptability analysis (ProMAA), are applied and compared for a hypothetical case study of a river restoration involving multiple stakeholders. Overall, the MCDA results in a systematic, unbiased, and transparent solution, informing restoration alternatives evaluation. The two methods provide comparable results in terms of selected metrics. However, because ProMAA can consider probability distributions for weights and utility values of metrics for each criteria, it is suggested as the best option if data uncertainty is high. Despite the increase in complexity in the metric selection process, MCDA improves upon the current ad-hoc decision practice based on the consultations with stakeholders and experts, and encourages transparent and quantitative aggregation of data and judgement, increasing the transparency of decision making in restoration projects. We believe that MCDA can enhance the overall sustainability of ecosystem by enhancing both ecological and societal needs.

Adverse aerodynamics effects of a high speed train under the influence of cross winds, analysis and optimization of wind fence

The research work that here is summarized, it is classed on the area of dynamics and measures of railway safety, specifically in the study of the influence of the cross wind on the high-speed trains as well as the study of new mitigation measures like wind breaking structures or wind fences, with optimized shapes. The work has been developed in the Research Center in Rail Technology (CITEF), and supported by the Universidad Politécnica de Madrid, Spain.

The Extended Water Footprint and illegal groundwater use in the Upper Guadiana Basin (Spain)

Tablas de Daimiel National Park is located in the Upper Guadiana Basin and represents one of the largest and most important wetlands in Europe. The long term ecological integrity of this wetland is inherently associated with the maintenance of a shallow groundwater table, namely the Western Mancha aquifer (WMA) or Aquifer 23. The intensive use of groundwater, mainly for irrigation, has led over the last decades to deep socio‐economic changes. Such intensive use has also lowered the water table of Aquifer 23, drastically reducing the flooded area of the wetland and threatening its ecological integrity. A number of plans and measures have been developed and implemented since the declaration of overexploitation of Aquifer 23 in the year 1987. The most recent one is the Special Plan for the Upper Guadiana (SPUG), approved in 2008. This Plan is the main measure to comply with achieving the objective of good quantitative and qualitative status required under the Water Framework Directive (2000). This paper offers a new type of integrated analysis which allows assessing under a common lens the physical, economic and social dimensions of groundwater use in the area. The first objective is to calculate the groundwater footprint of agricultural production in the Upper Guadiana basin and its evolution during 2000‐2008. For this purpose, we have applied the Extended Water Footprint (EWF) methodology ‐a novel approach based on the classical Water Footprint (WF) approach‐ that includes an assessment of the water productivity from an economic and social perspective. Compared to the classical WF, the EWF allows for a more complete overview of the sector, providing new insights for policy decisions (e.g. to define options and possibilities on water re‐allocation in order to achieve both better ecosystem conservation and social equity). The second objective is to use the EWF to compare the existing authorized and non‐authorized or illegal use of water. This allows us to discuss current initiatives by public authorities in relation to the existing frame of water rights

A new dominance intensity method to deal with ordinal information about a DM's preferences within MAVT

Dominance measuring methods are a new approach to deal with complex decision-making problems with imprecise information. These methods are based on the computation of pairwise dominance values and exploit the information in the dominance matrix in dirent ways to derive measures of dominance intensity and rank the alternatives under consideration. In this paper we propose a new dominance measuring method to deal with ordinal information about decision-maker preferences in both weights and component utilities. It takes advantage of the centroid of the polytope delimited by ordinal information and builds triangular fuzzy numbers whose distances to the crisp value 0 constitute the basis for the de?nition of a dominance intensity measure. Monte Carlo simulation techniques have been used to compare the performance of this method with other existing approaches.

Bringing South Caucasus Closer to Europe: Achievements and Challenges in ENP Implantation. Natolin Research Paper 03/March 2011

While the initial Commission Communication on Wider Europe (March 2003) did not include Armenia, Georgia and Azerbaijan in the forthcoming policy for the EU’s new neighbourhood, the Southern Caucasus region has now gained considerable attention in the framework of the ENP and beyond, not least because of security considerations. The ENP undoubtedly represents a step forward in the EU’s policy towards Armenia, Azerbaijan and Georgia, yet its implementation highlights major differences between the three countries and important weaknesses in all three of them. The Eastern Partnership addresses some of these weaknesses and it also significantly strengthens the EU’s offer to South Caucasus countries, which is now fully in line with the perspectives proposed to the Western NIS. The paper highlights five main conclusions and recommendations: • Political, economic, social and diplomatic developments in the South Caucasus in the 2000's highlight both diverging trends and the persistence of tensions between the three countries. They also have different aspirations vis-à-vis the EU and different records in ENP implementation. The EU should therefore mainly rely upon an individual approach towards each country. • While bilateral relations should form the basis of the EU's approach, most of the challenges faced by Georgia, Armenia and Azerbaijan are not confined to national borders and require regional solutions. This applies primarily, but not exclusively, to the unresolved conflicts. The EU should promote targeted regional cooperation including, inter alia, confidence-building measures to address indirectly the protracted conflicts and measures supporting drivers of change, which play a critical role in the confidence-building process; • Under the ENP, especially since the opening of negotiations for association agreements and with the perspective of DCFTA, trade-related issues, market and regulatory reform have become prominent in the EU's relations with all three Caucasus countries. At the same time, the priorities identified when the ENP was launched, i.e. good governance and the rule of law, still correspond to major challenges in the South Caucasus. The EU should more clearly prioritise good governance and the rule of law as the basis of both the ENP and successful reforms; • In all partner countries (but even more so in the South Caucasus), ENP implementation has been adversely affected by poor administrative capacities and weak institutional coordination. The EU should increasingly focus on institutional reform/capacity building in its support to partner countries and ensure that the link between the ENP and domestic reform processes is strengthened; • In the South Caucasus the EU has recently concentrated on a few assistance tools such as budget support, Twinning and TAIEX. While these instruments undoubtedly bring an added value, they should be better combined with tools allowing for greater flexibility and targeting non-governmental actors, e.g. EIDHR/NSA.

Economic and climate change pressures on biodiversity in southern Mediterranean coastal areas. MEDPRO Technical Report No. 24/February 2013

This paper establishes and measures key biodiversity and ecosystem health indicators and the number of world heritage sites in coastal areas at global level. It then estimates – econometrically – the indicators’ influence on the provision of tourism values through the marine ecosystem function as a harbour of biodiversity, and as a provider of amenity values and marine cultural identity. The report then focuses on the MEDPRO region, providing some estimates of the potential impact of climate change on these services for a given temperature increase scenario. Finally, the effect on ecosystemrelated tourism is computed for the four MEDPRO social economic scenarios. The analysis is enriched by some quantification of the potential costs of adaptation.