Discovering biomarkers for antidepressant response: protocol from the Canadian biomarker integration network in depression (CAN-BIND) and clinical characteristics of the first patient cohort

Background Major Depressive Disorder (MDD) is among the most prevalent and disabling medical conditions worldwide. Identification of clinical and biological markers (“biomarkers”) of treatment response could personalize clinical decisions and lead to better outcomes. This paper describes the aims, design, and methods of a discovery study of biomarkers in antidepressant treatment response, conducted by the Canadian Biomarker Integration Network in Depression (CAN-BIND). The CAN-BIND research program investigates and identifies biomarkers that help to predict outcomes in patients with MDD treated with antidepressant medication. The primary objective of this initial study (known as CAN-BIND-1) is to identify individual and integrated neuroimaging, electrophysiological, molecular, and clinical predictors of response to sequential antidepressant monotherapy and adjunctive therapy in MDD. Methods CAN-BIND-1 is a multisite initiative involving 6 academic health centres working collaboratively with other universities and research centres. In the 16-week protocol, patients with MDD are treated with a first-line antidepressant (escitalopram 10–20 mg/d) that, if clinically warranted after eight weeks, is augmented with an evidence-based, add-on medication (aripiprazole 2–10 mg/d). Comprehensive datasets are obtained using clinical rating scales; behavioural, dimensional, and functioning/quality of life measures; neurocognitive testing; genomic, genetic, and proteomic profiling from blood samples; combined structural and functional magnetic resonance imaging; and electroencephalography. De-identified data from all sites are aggregated within a secure neuroinformatics platform for data integration, management, storage, and analyses. Statistical analyses will include multivariate and machine-learning techniques to identify predictors, moderators, and mediators of treatment response. Discussion From June 2013 to February 2015, a cohort of 134 participants (85 outpatients with MDD and 49 healthy participants) has been evaluated at baseline. The clinical characteristics of this cohort are similar to other studies of MDD. Recruitment at all sites is ongoing to a target sample of 290 participants. CAN-BIND will identify biomarkers of treatment response in MDD through extensive clinical, molecular, and imaging assessments, in order to improve treatment practice and clinical outcomes. It will also create an innovative, robust platform and database for future research.

Seismic activity triggered by water wells in the Parana Basin, Brazil

Triggered seismicity is commonly associated with deep water reservoirs or injection wells where water is injected at high pressure into the reservoir rock. However, earth tremors related solely to the opening of groundwater wells are extremely rare. Here we present a clear case of seismicity induced by pore-pressure changes following the drilling of water wells that exploit a confined aquifer in the intracratonic Parana Basin of southeastern Brazil. Since 2004, shallow seismic activity, with magnitudes up to 2.9 and intensities V MM, has been observed near deep wells (120-200 m) that were drilled in early 2003 near the town of Bebedouro. The wells were drilled for irrigation purposes, cross a sandstone layer about 60-80 m thick and extract water from a confined aquifer in fractured zones between basalt flow layers. Seismic activity, mainly event swarms, has occurred yearly since 2004, mostly during the rainy season when the wells are not pumped. During the dry season when the wells are pumped almost continuously, the activity is very low. A seismographic network, installed in March 2005, has located more than 2000 microearthquakes. The events are less than 1 km deep (mostly within the 0.5 km thick basalt layer) and cover an area roughly 1.5 km x 5 km across. The seismicity generally starts in a small area and expands to larger distances with an equivalent hydraulic diffusivity ranging from 0.06 to 0.6 m(2)/s. Geophysical and geothermal logging of several wells in the area showed that water from the shallow sandstone aquifer enters the well at the top and usually forms waterfalls. The waterfalls flow down the sides of the wells and feed the confined, fractured aquifer in the basalt layer at the bottom. Two seismic areas are observed: the main area surrounds several wells that are pumped continuously during the dry season, and a second area near another well (about 10 km from the first area) that is not used for irrigation and not pumped regularly. The main area displays cyclic annual activity, but the second area does not. We explain the earthquake swarms as being triggered by pore pressure diffusion in the fractured basalt layer due to additional pressure from the newly connected surface aquifer. This reaches critically prestressed areas up to a few kilometers away from the wells. During periods of continuous pumping, the reduction of pore pressure in the confined aquifer stops the seismic activity. Our study suggests that this kind of activity may be more common than previously thought and implies that many other cases of small tremors associated with the drilling of water wells may have gone unnoticed.

Are tortoises important seed dispersers in Amazonian forests?

According to most studies on seed dispersal in tropical forests, mammals and birds are considered the main dispersal agents and the role played by other animal groups remains poorly explored. We investigate qualitative and quantitative components of the role played by the tortoise Chelonoidis denticulata in seed dispersal in southeastern Amazon, and the influence of seasonal variation in tortoise movement patterns on resulting seed shadows. Seed shadows produced by this tortoise were estimated by combining information on seed passage times through their digestive tract, which varied from 3 to 17 days, with a robust dataset on movements obtained from 18 adult C. denticulata monitored with radio transmitters and spoon-and-line tracking devices. A total of 4,206 seeds were found in 94 collected feces, belonging to 50 seed morphotypes of, at least, 25 plant genera. Very low rates of damage to the external structure of the ingested seeds were observed. Additionally, results of germination trials suggested that passage of seeds through C. denticulata`s digestive tract does not seem to negatively affect seed germination. The estimated seed shadows are likely to contribute significantly to the dispersal of seeds away from parent plants. During the dry season seeds were dispersed, on average, 174.1 m away from the location of fruit ingestion; during the rainy season, this mean dispersal distance increased to 276.7 m. Our results suggest that C. denticulata plays an important role in seed dispersal in Amazonian forests and highlight the influence of seasonal changes in movements on the resulting seed shadows.

The Evolution of Modularity in the Mammalian Skull II: Evolutionary Consequences

Changes in patterns and magnitudes of integration may influence the ability of a species to respond to selection. Consequently, modularity has often been linked to the concept of evolvability, but their relationship has rarely been tested empirically. One possible explanation is the lack of analytical tools to compare patterns and magnitudes of integration among diverse groups that explicitly relate these aspects to the quantitative genetics framework. We apply such framework here using the multivariate response to selection equation to simulate the evolutionary behavior of several mammalian orders in terms of their flexibility, evolvability and constraints in the skull. We interpreted these simulation results in light of the integration patterns and magnitudes of the same mammalian groups, described in a companion paper. We found that larger magnitudes of integration were associated with a blur of the modules in the skull and to larger portions of the total variation explained by size variation, which in turn can exert a strong evolutionary constraint, thus decreasing the evolutionary flexibility. Conversely, lower overall magnitudes of integration were associated with distinct modules in the skull, to smaller fraction of the total variation associated with size and, consequently, to weaker constraints and more evolutionary flexibility. Flexibility and constraints are, therefore, two sides of the same coin and we found them to be quite variable among mammals. Neither the overall magnitude of morphological integration, the modularity itself, nor its consequences in terms of constraints and flexibility, were associated with absolute size of the organisms, but were strongly associated with the proportion of the total variation in skull morphology captured by size. Therefore, the history of the mammalian skull is marked by a trade-off between modularity and evolvability. Our data provide evidence that, despite the stasis in integration patterns, the plasticity in the magnitude of integration in the skull had important consequences in terms of evolutionary flexibility of the mammalian lineages.

Chromosome polymorphism in Astyanax fasciatus (Teleostei, Characidae). 2-Chromosomal location of a satellite DNA

Studies about composition of repetitive sequences and their chromosomal location have been helpful to evolutionary studies in many distinct organisms. In order to keep on assessing the possible relationships among different cytotypes of Astyanax fasciatus (Teleostei, Characiformes) in the Mogi-Guacu River (Sao Paulo State, Brazil), C-banding, chromomycin A 3 staining, and fluorescent in situ hybridization with a repetitive DNA sequence (As51) isolated from Astyanax scabripinnis were performed in the present work. The constitutive heterochromatin was distributed in terminal regions on long arms of submetacentric, subtelocentric, and acrocentric chromosomes and in the terminal region on short arms of a pair of submetacentric chromosomes in both standard cytotypes. This latter heterochromatic site was also GC-rich, as revealed by chromomycin A(3) staining, corresponding to the nucleolar organizer region (NOR), as shown by previous studies. The sites of the satellite As51 DNA were located in terminal regions on long arms of several chromosomes. Some variant karyotypic forms, which diverge from the two standard cytotypes, also presented distinctive chromosomes carrying As51 satellite DNA. It is possible that the standard 2n = 46 cytotype represents an invader population in the Mogi-Guacu River able to interbreed with the resident standard 2n = 48 cytotype. Therefore, the variant karyotypes would be related to a possible viable offspring, where complementary chromosomal rearrangements could favor new locations of the satellite DNA analyzed. Copyright (C) 2008 S. Karger AG, Basel

Long-Term Culture of Mouse Embryonic Stem Cell-Derived Adherent Neurospheres and Functional Neurons

Innumerous protocols, using the mouse embryonic stem (ES) cells as model for in vitro study of neurons functional properties and features, have been developed. Most of these protocols are short lasting, which, therefore, does not allow a careful analysis of the neurons maturation, aging, and death processes. We describe here a novel and efficient long-lasting protocol for in vitro ES cells differentiation into neuronal cells. It consists of obtaining embryoid bodies, followed by induction of neuronal differentiation with retinoic acid of nonadherent embryoid bodies (three-dimensional model), which further allows their adherence and formation of adherent neurospheres (AN, bi-dimensional model). The AN can be maintained for at least 12 weeks in culture under repetitive mechanical splitting, providing a constant microenvironment (in vitro niche) for the neuronal progenitor cells avoiding mechanical dissociation of AN. The expression of neuron-specific proteins, such as nestin, sox1, beta III-tubulin, microtubule-associated protein 2, neurofilament medium protein, Tau, neuronal nuclei marker, gamma-aminobutyric acid, and 5-hydroxytryptamine, were confirmed in these cells maintained during 3 months under several splitting. Additionally, expression pattern of microtubule-associated proteins, such as lissencephaly (Lis1) and nuclear distribution element-like (Ndel1), which were shown to be essential for differentiation and migration of neurons during embryogenesis, was also studied. As expected, both proteins were expressed in undifferentiated ES cells, AN, and nonrosette neurons, although presenting different spatial distribution in AN. In contrast to previous studies, using cultured neuronal cells derived from embryonic and adult tissues, only Ndel1 expression was observed in the centrosome region of early neuroblasts from AN. Mature neurons, obtained from ES cells in this work, display ionic channels and oscillations of membrane electrical potential typical of electrically excitable cells, which is a characteristic feature of the functional central nervous system (CNS) neurons. Taken together, our study demonstrated that AN are a long-term culture of neuronal cells that can be used to analyze the process of neuronal differentiation dynamics. Thus, the protocol described here provides a new experimental model for studying neurological diseases associated with neuronal differentiation during early development, as well as it represents a novel source of functional cells that can be used as tools for testing the effects of toxins and/or drugs on neuronal cells.

Innate immune response in the sea urchin Echinometra lucunter (Echinodermata)

Echinometra lucunter, (Pinda) is a sea urchin encountered in the Brazilian coast and exposed to high and low temperatures related to low and high tides. Despite their great distribution and importance, few studies have been done on the biological function of their coelomocytes. Thus, Echinometra lucunter perivisceral coelomocytes were characterized under optical and transmission electron microscopy. Phagocytic amoebocytes in the perivisceral coelom were labelled by injecting ferritin, and ferritin labelled phagocytic amoebocytes were found in the peristomial connective tissue after injecting India ink into the tissue, indicating the amoebocytes ability to respond to an inflammatory stimulus. Results showed that the phagocytic amoebocytes were the main inflammatory cells found in the innate immune response of E lucunter. While other works have recorded these phenomena in sea urchins found in moderate and constant temperature, this study reports on these same phenomena in a tropical sea urchin under great variation of temperature, thus providing new data to inflammatory studies in invertebrate pathology. (C) 2007 Elsevier Inc. All rights reserved.

The potential for first-generation ethanol production from sugarcane

Ethanol production from sugarcane, mainly in Brazil, on the basis of first-generation technology (22.5 billion liters, in 2007/2008 season, in 3.4 million hectares) replaces 1% of the gasoline used in the world today and is highly competitive in economic terms with ethanol produced from other crops in the USA and Europe. In this paper we discuss the potential for sugarcane ethanol expansion from two angles: (1) productivity gains which would allow greater production in the same area and (2) geographical expansion to larger areas. The potential of first-generation technology for the production of ethanol from sugarcane is far from being exhausted. There are gains in productivity of approximately a factor of two from genetically modified varieties and a geographical expansion by a factor of ten of the present level of production in many sugar-producing countries. The replacement of 10% of the gasoline used in the world by ethanol from sugarcane seems possible before second-generation technology reaches technological maturity and possibly economic competitiveness. (C) 2009 Society of Chemical Industry and John Wiley & Sons, Ltd

Persuading the Public : A Linguistic Analysis of Barack Obama’s Speech on “Super Tuesday” 2008

This essay examines the persuasive side of language in a speech given by Senator Barack Obama on Super Tuesday in February 2008. It studies how Senator Obama utilizes language to convince and persuade his audience. This is done from an Aristotelian point of view, meaning that the study focuses foremost on how the senator’s word choices relate to Aristotle’s three means of persuasion, ethos, pathos and logos. Those basic guiding principles are relevant to use since Aristotle’s work on the subject of rhetoric is still today one of the most relevant works in that field. The analysis is basically performed through personal observations guided by previous studies, within the frame of Aristotelian rhetoric. The results show how Senator Obama enforces the three means of persuasion through language and how it can be considered persuasive. The study might add to rhetoric studies from a linguistic perspective since it reaches a better understanding of language used in the field of politics, where rhetoric is a prominent component.

Det är värre att inte börja studera än att hoppa av: En fenomenologisk studie om hur icke traditionella studenter upplever studieavhopp från högskoleutbildning

In Sweden we have the highest rate of nontraditional students among Europe. Coincidently, we also have the highest rates of drop outs among OECD. In this particular field, drop out from higher education, there is a need fore more qualitative studies that can support the "statistics". Studies about experiences of drop outs are significant for society, university and individual. The aim of this study is to describe and understand how nontraditional student experiences drop out from higher education. What do they tell regarding their meeting with the university? How is the drop out visible before the decision to quit? How can the way forward to the drop out be described? What does the university mean for them? The theoretical point of departure is the concept lifeworld and the method is phenomenological hermeneutic with narrative interviews with 5 students. The result points out that the meeting with the university implies a meeting with other individuals, and also a "meeting" within the student himself, by inner questioning and reflection. The students’ relationship to the studies is characterized by the experience of understanding. The dropouts are visible through different events. The decision per se has increased over time and the students have also grown personally by the decision. To understand or not understand is crucial for the experience of learning. The drop out can also be seen as a transition and a turning point. The drop out is an effort and takes place without professional staff, therefore needs to be discussed in public.

Road Design for Future Maintenance : Life-cycle Cost Analyses for Road Barriers

The cost of a road construction over its service life is a function of design, quality of construction as well as maintenance strategies and operations. An optimal life-cycle cost for a road requires evaluations of the above mentioned components. Unfortunately, road designers often neglect a very important aspect, namely, the possibility to perform future maintenance activities. Focus is mainly directed towards other aspects such as investment costs, traffic safety, aesthetic appearance, regional development and environmental effects. This doctoral thesis presents the results of a research project aimed to increase consideration of road maintenance aspects in the planning and design process. The following subgoals were established: Identify the obstacles that prevent adequate consideration of future maintenance during the road planning and design process; and Examine optimisation of life-cycle costs as an approach towards increased efficiency during the road planning and design process. The research project started with a literature review aimed at evaluating the extent to which maintenance aspects are considered during road planning and design as an improvement potential for maintenance efficiency. Efforts made by road authorities to increase efficiency, especially maintenance efficiency, were evaluated. The results indicated that all the evaluated efforts had one thing in common, namely ignorance of the interrelationship between geometrical road design and maintenance as an effective tool to increase maintenance efficiency. Focus has mainly been on improving operating practises and maintenance procedures. This fact might also explain why some efforts to increase maintenance efficiency have been less successful. An investigation was conducted to identify the problems and difficulties, which obstruct due consideration of maintainability during the road planning and design process. A method called “Change Analysis” was used to analyse data collected during interviews with experts in road design and maintenance. The study indicated a complex combination of problems which result in inadequate consideration of maintenance aspects when planning and designing roads. The identified problems were classified into six categories: insufficient consulting, insufficient knowledge, regulations and specifications without consideration of maintenance aspects, insufficient planning and design activities, inadequate organisation and demands from other authorities. Several urgent needs for changes to eliminate these problems were identified. One of the problems identified in the above mentioned study as an obstacle for due consideration of maintenance aspects during road design was the absence of a model for calculating life-cycle costs for roads. Because of this lack of knowledge, the research project focused on implementing a new approach for calculating and analysing life-cycle costs for roads with emphasis on the relationship between road design and road maintainability. Road barriers were chosen as an example. The ambition is to develop this approach to cover other road components at a later stage. A study was conducted to quantify repair rates for barriers and associated repair costs as one of the major maintenance costs for road barriers. A method called “Case Study Research Method” was used to analyse the effect of several factors on barrier repairs costs, such as barrier type, road type, posted speed and seasonal effect. The analyses were based on documented data associated with 1625 repairs conducted in four different geographical regions in Sweden during 2006. A model for calculation of average repair costs per vehicle kilometres was created. Significant differences in the barrier repair costs were found between the studied barrier types. In another study, the injuries associated with road barrier collisions and the corresponding influencing factors were analysed. The analyses in this study were based on documented data from actual barrier collisions between 2005 and 2008 in Sweden. The result was used to calculate the cost for injuries associated with barrier collisions as a part of the socio-economic cost for road barriers. The results showed significant differences in the number of injuries associated with collisions with different barrier types. To calculate and analyse life-cycle costs for road barriers a new approach was developed based on a method called “Activity-based Life-cycle Costing”. By modelling uncertainties, the presented approach gives a possibility to identify and analyse factors crucial for optimising life-cycle costs. The study showed a great potential to increase road maintenance efficiency through road design. It also showed that road components with low investment costs might not be the best choice when including maintenance and socio-economic aspects. The difficulties and problems faced during the collection of data for calculating life-cycle costs for road barriers indicated a great need for improving current data collecting and archiving procedures. The research focused on Swedish road planning and design. However, the conclusions can be applied to other Nordic countries, where weather conditions and road design practices are similar. The general methodological approaches used in this research project may be applied also to other studies.

Evaluation of a Micro PV-Diesel Hybrid System in Tanzania

In April 2011 a monitoring system was installed to enable studies of the performance and the usage of a micro PV-Diesel Hybrid system at the Ihushi Development Center (IDC) near Mwanza in Tanzania. Estimations of the load have been obtained by a survey of installed appliances and interviews with users of installed equipment. The load profile obtained by measurements has been analyzed and compared to estimations of the energy use. Further, the system size and performance were studied.

Inte bara jämställdhet : Beslutet om föräldraledighet, moderskaps- och faderskapsidealoch idéer om barns bästa

More than gender equality. Decisions on parental leave and ideals around motherhood, fatherhood and the best interest of the child On the basis of 40 semi-structured interviews, this study discusses decision making processes regarding parental leave among nascent first-time middle-class parents in Sweden. We analyze motives and ideas behind the couples’ plans and decisions and how decisions on parental leave were made. We furthermore show how the decision making processes can be discussed in relation to the institutional context. The results show that ideals and norms of gender equality are accompanied by gendered divisions of work and care and a partially traditional view on motherhood and fatherhood. Contrary to previous studies, we do not find a clear link between gender equal ideals and explicit negotiations. An equal division of parental leave is, in some couples, taken for granted to such an extent that the decision on how to divide the leave is taken implicitly rather than explicitly. Decisions on division of parental leave are not isolated processes. Rather, ideals and norms around motherhood, fatherhood, gender equality and not least what is ‘in the best interest of the child’ constitute part of the context in which these decision making processes take place.

Perspektiv på ålder i vardagslivets interaktioner

Perspective on age in everyday interactions The aim of the article is to discuss how ethnomethodology and (symbolic) interactionism may contribute to sociological studies on age in everyday interactions. A theoretical framework on age, ‘age-as-accomplished’, inspired by ethnomethodology and symbolic interactionist approach has been proposed by Laz (1998; 2003). Our comparison of these approaches show, that the perspectives are incompatible, for example with regard to the definitions of culture, interaction and meaning. As such issues are not discussed by Laz, the theoretical framework is lacking in transparency and clarity. Ultimately the definition of ‘age as accomplished’ is not congruent with the notions of meaning and interpretation as used by Laz. In some respects the perspectives may though be complementary and valuable in age studies, for example the detailed study of situated norms in ethnomethodology, as well as some new developments within (symbolic) interactionist perspectives focusing on social status, and issues of subordination and superordination as relational processes.

Emergency department triage scales and their components : a systematic review of the scientific evidence

Emergency department (ED) triage is used to identify patients' level of urgency and treat them based on their triage level. The global advancement of triage scales in the past two decades has generated considerable research on the validity and reliability of these scales. This systematic review aims to investigate the scientific evidence for published ED triage scales. The following questions are addressed: 1. Does assessment of individual vital signs or chief complaints affect mortality during the hospital stay or within 30 days after arrival at the ED? 2. What is the level of agreement between clinicians' triage decisions compared to each other or to a gold standard for each scale (reliability)? 3. How valid is each triage scale in predicting hospitalization and hospital mortality? A systematic search of the international literature published from 1966 through March 31, 2009 explored the British Nursing Index, Business Source Premier, CINAHL, Cochrane Library, EMBASE, and PubMed. Inclusion was limited to controlled studies of adult patients (≥15 years) visiting EDs for somatic reasons. Outcome variables were death in ED or hospital and need for hospitalization (validity). Methodological quality and clinical relevance of each study were rated as high, medium, or low. The results from the studies that met the inclusion criteria and quality standards were synthesized applying the internationally developed GRADE system. Each conclusion was then assessed as having strong, moderately strong, limited, or insufficient scientific evidence. If studies were not available, this was also noted. We found ED triage scales to be supported, at best, by limited and often insufficient evidence. The ability of the individual vital signs included in the different scales to predict outcome is seldom, if at all, studied in the ED setting. The scientific evidence to assess interrater agreement (reliability) was limited for one triage scale and insufficient or lacking for all other scales. Two of the scales yielded limited scientific evidence, and one scale yielded insufficient evidence, on which to assess the risk of early death or hospitalization in patients assigned to the two lowest triage levels on a 5-level scale (validity).