Monotone Constrained Tensor-product B-spline with application to screening studies

When different markers are responsive to different aspects of a disease, combination of multiple markers could provide a better screening test for early detection. It is also resonable to assume that the risk of disease changes smoothly as the biomarker values change and the change in risk is monotone with respect to each biomarker. In this paper, we propose a boundary constrained tensor-product B-spline method to estimate the risk of disease by maximizing a penalized likelihood. To choose the optimal amount of smoothing, two scores are proposed which are extensions of the GCV score (O'Sullivan et al. (1986)) and the GACV score (Ziang and Wahba (1996)) to incorporate linear constraints. Simulation studies are carried out to investigate the performance of the proposed estimator and the selection scores. In addidtion, sensitivities and specificities based ona pproximate leave-one-out estimates are proposed to generate more realisitc ROC curves. Data from a pancreatic cancer study is used for illustration.

The Getting-Out-of-Bed (GoB) scale: a measure of motivation and life outlook in older adults with cancer

OBJECTIVE: To develop and evaluate the psychometric properties of a measure of motivation and life outlook (Getting-Out-of-Bed [GoB]). DESIGN: Secondary analysis of baseline and 6-month data from a longitudinal follow-up study of older breast cancer survivors. PARTICIPANTS: Women (N = 660) diagnosed with primary breast cancer stage I-IIIA disease, age >or=65 years, and permission to contact from an attending physician in four geographic regions in the United States (city-based Los Angeles, California; statewide in Minnesota, North Carolina, and Rhode Island). MEASUREMENT: Data were collected over 6-months of follow-up from consenting patients' medical records and telephone interviews with patients. Data collected included the 4-item GoB, health-related quality of life (HRQoL), breast cancer, sociodemographic, and health-related characteristics. RESULTS: Factor analysis produced, as hypothesized, one principal component with eigen values of 2.74(baseline) and 2.91(6-months) which explained 68.6%(baseline) and 72.7%(6-months) of total variance. In further psychometric analyses, GoB exhibited good construct validity (divergent: low nonstatistically significant correlations with unrelated constructs; convergent: moderate statistically significant correlations with related constructs; discriminant: distinguished high HRQoL groups with a high level of significance), excellent internal reliability (Cronbach's alpha 0.84(baseline), 0.87(6-months)), and produced stable measurements over 6-months. Women with GoB scores >or=50 at baseline were more likely at 6-months to have good HRQoL, good self-perceived health, and report regular exercise, indicating good predictive ability. CONCLUSION: GoB demonstrated overall good psychometric properties in this sample of older breast cancer survivors, suggestive of a promising tool for assessing motivation and life outlook in older adults. Nevertheless, because it was developed and initially evaluated in a select sample, using measures with similar but not exact content overlap further evaluation is needed before it can be recommended for widespread use.

The “Out of Africa Tribe” (II): Paleolithic warriors with big canoes and protective weapons

It is generally difficult to establish a timeline for the appearance of different technologies and tools during human cultural evolution. Here I use stochastic character mapping of discrete traits using human mtDNA phylogenies rooted to the Reconstructed Sapiens Reference Sequence (RSRS) as a model to address this question. The analysis reveals that the ancestral state of Homo sapiens was hunting, using material innovations that included bows and arrows, stone axes and spears. However, around 80,000 y before present, a transition occurred, from this ancestral hunting tradition, toward the invention of protective weapons such as shields, the appearance of ritual fighting as a socially accepted behavior and the construction of war canoes for the fast transport of large numbers of warriors. This model suggests a major cultural change, during the Palaeolithic, from hunters to warriors. Moreover, in the light of the recent Out of Africa Theory, it suggests that the “Out of Africa Tribe” was a tribe of warriors that had developed protective weapons such as shields and used big war canoes to travel the sea coast and big rivers in raiding expeditions.

Impacts of out-migration on land management in mountain areas

INTRODUCTION Out-migration from mountain areas is leaving behind half families and elderly to deal with managing the land alongside daily life challenges. A potential reduction of labour force as well as expertise on cropping practices, maintenance of terraces and irrigation canals, slope stabilization, grazing, forest and other land management practices are further challenged by changing climate conditions and increased environmental threats. An understanding of the resilience of managed land resources in order to enhance adaptation to environmental and socio-economic variability, and evidence of the impact of Sustainable Land Management (SLM) on the mitigation of environmental threats have so far not sufficiently been tackled. The study presented here aims to find out how land management in mountains is being affected by migration in the context of natural hazards and climate change in two study sites, namely Quillacollo District of Bolivia and Panchase area of Western Nepal, and which measures are needed to increase resilience of livelihoods and land management practices. The presentation includes draft results from first field work periods in both sites. A context of high vulnerability According to UNISDR, vulnerability is defined as “the characteristics and circumstances of a community, system or asset that make it susceptible to the damaging effects of a hazard”.Hazards are another threat affecting people’s livelihood in mountainous area. They can be either natural or human induced. Landslides, debris flow and flood are affecting peopleGood land management can significantly reduce occurrence of hazards. In the opposite bad land management or land abandonment can lead to negative consequences on the land, and thus again increase vulnerability of people’s livelihoods. METHODS The study integrates bio-physical and socio-economic data through a case study as well as a mapping approach. From the social sciences, well-tested participatory qualitative methodologies, typically used in Vulnerability and Capacity Analyses, such as semi-structured interviews with so-called ‘key informants’, transect walks, participatory risk and social resource mapping are applied. The bio-physical analysis of the current environmental conditions determining hazards and structural vulnerability are obtained from remote sensing analysis, field work studies, and GIS analysis The assessment of the consequences of migration in the area of origin is linked with a mapping and appraisal of land management practices (www.wocat.net, Schwilch et al., 2011). The WOCAT mapping tool (WOCAT/LADA/DESIRE 2008) allows capturing the major land management practices / technologies, their spread, effectiveness and impact within a selected area. Data drawn from a variety of sources are compiled and harmonised by a team of experts, consisting of land degradation and conservation specialists working in consultation with land users from various backgrounds. The specialists’ and land users’ knowledge is combined with existing datasets and documents (maps, GIS layers, high-resolution satellite images, etc.) in workshops that are designed to build consensus regarding the variables used to assess land degradation and SLM. This process is also referred to as participatory expert assessment or consensus mapping. The WOCAT mapping and SLM documentation methodologies are used together with participatory mapping and other socio-economic data collection (interviews, questionnaires, focus group discussions, expert consultation) to combine information about migration types and land management issues. GIS and other spatial visualization tools (e.g. Google maps) will help to represent and understand these links. FIRST RESULTS Nepal In Nepal, migration is a common strategy to improve the livelihoods. Migrants are mostly men and they migrate to other Asian countries, first to India and then to the Gulf countries. Only a few women are migrating abroad. Women migrate essentially to main Nepali cities when they can afford it. Remittances are used primarily for food and education; however they are hardly used for agricultural purposes. Besides traditional agriculture being maintained, only few new practices are emerging, such as vegetable farming or agroforestry. The land abandonment is a growing consequence of outmigration, resulting in the spreading of invasive species. However, most impacts of migration on land management are not yet clear. Moreover, education is a major concern for the respondents; they want their children having a better education and get better opportunities. Linked to this, unemployment is another major concern of the respondents, which in turn is “solved” through outmigration. Bolivia Migration is a common livelihood strategy in Bolivia. In the area of study, whole families are migrating downward to the cities of the valleys or to other departments of Bolivia, especially to Chapare (tropics) for the coca production and to Santa Cruz. Some young people are migrating abroad, mostly to Argentina. There are few remittances and if those are sent to the families in the mountain areas, then they are mainly used for agriculture purpose. The impacts of migration on land management practices are not clear although there are some important aspects to be underlined. The people who move downward are still using their land and coming back during part of the week to work on it. As a consequence of this multi-residency, there is a tendency to reduce land management work or to change the way the land is used. As in Nepal, education is a very important issue in this area. There is no secondary school, and only one community has a primary school. After the 6th grade students have therefore to go down into the valley towns to study. The lack of basic education is pushing more and more people to move down and to leave the mountains. CONCLUSIONS This study is on-going, more data have to be collected to clearly assess the impacts of out-migration on land management in mountain areas. The first results of the study allow us to present a few interesting findings. The two case studies are very different, however in both areas, young people are not staying anymore in the mountains and leave behind half families and elderly to manage the land. Additionally in both cases education is a major reason for moving out, even though the causes are not always the same. More specifically, in the case of Nepal, the use of remittances underlines the fact that investment in agriculture is not the first choice of a family. In the case of Bolivia, some interesting findings showed that people continue to work on their lands even if they move downward. The further steps of the study will help to explore these interesting issues in more detail. REFERENCES Schwilch G., Bestelmeyer B., Bunning S., Critchley W., Herrick J., Kellner K., Liniger H.P., Nachtergaele F., Ritsema C.J., Schuster B., Tabo R., van Lynden G., Winslow M. 2011. Experiences in Monitoring and Assessment of Sustainable Land Management. Land Degradation & Development 22 (2), 214-225. Doi 10.1002/ldr.1040 WOCAT/LADA/DESIRE 2008. A Questionnaire for Mapping Land Degradation and Sustainable Land Management. Liniger H.P., van Lynden G., Nachtergaele F., Schwilch G. (eds), Centre for Development and Environment, Institute of Geography, University of Berne, Berne

Search for long-lived stopped R-hadrons decaying out-of-time with pp collisions using the ATLAS detector

An updated search is performed for gluino, top squark, or bottom squark R-hadrons that have come to rest within the ATLAS calorimeter, and decay at some later time to hadronic jets and a neutralino, using 5.0 and 22.9 fb(-1) of pp collisions at 7 and 8 TeV, respectively. Candidate decay events are triggered in selected empty bunch crossings of the LHC in order to remove pp collision backgrounds. Selections based on jet shape and muon system activity are applied to discriminate signal events from cosmic ray and beam-halo muon backgrounds. In the absence of an excess of events, improved limits are set on gluino, stop, and sbottom masses for different decays, lifetimes, and neutralino masses. With a neutralino of mass 100 GeV, the analysis excludes gluinos with mass below 832 GeV (with an expected lower limit of 731 GeV), for a gluino lifetime between 10 mu s and 1000 s in the generic R-hadron model with equal branching ratios for decays to q (q) over bar(chi) over tilde (0) and g (chi) over tilde (0). Under the same assumptions for the neutralino mass and squark lifetime, top squarks and bottom squarks in the Regge R-hadron model are excluded with masses below 379 and 344 GeV, respectively.

Territorial Cohesion through Spatial Policies: An Analysis with Cultural Theory and Clumsy Solutions

The European Territorial Cohesion Policy has been the subject of numerous debates in recent years. Most contributions focus on understanding the term itself and figuring out what is behind it, or arguing for or against a stronger formal competence of the European Union in this field. This article will leave out these aspects and pay attention to (undefined and legally non-binding) conceptual elements of territorial cohesion, focusing on the challenge of linking it within spatial policies and organising the relations. Therefore, the theoretical approach of Cultural Theory and its concept of clumsy solution are applied to overcome the dilemma of typical dichotomies by adding a third and a fourth (but not a fifth) perspective. In doing so, normative contradictions between different rational approaches can be revealed, explained and approached with the concept of ‘clumsy solutions’. This contribution aims at discussing how this theoretical approach helps us explain and frame a coalition between the Territorial Cohesion Policy and spatial policies. This approach contributes to finding the best way of linking and organising policies, although the solution might be clumsy according to the different rationalities involved.

Prognostic significance of foveal capillary drop-out and previous panretinal photocoagulation for diabetic macular oedema treated with ranibizumab

AIMS To investigate the prognostic significance of macular capillary drop-out and previous panretinal laser photocoagulation in diabetic macular oedema treated with intravitreal ranibizumab. METHODS Retrospective observational case series. Treatment-naive patients with diabetic macular oedema that had been treated with intravitreal ranibizumab as per the RESTORE study protocol for at least 12 months were included. Some patients (n=15) had previous panretinal laser photocoagulation. Best-corrected visual acuity and central retina thickness were recorded monthly. The foveal avascular zone and the perifoveal capillaries were quantitatively and qualitatively assessed on fluorescein angiography on two occasions during the observational period. RESULTS From the 46 eyes (46 patients) in this study, 13 (28%) had evidence of perifoveal capillary drop-out. Central retinal thickness was significantly thinner at baseline (p=0.02) and throughout the study period in these eyes compared with those with normal perifoveal capillaries. Both groups responded with a significant gain of best-corrected visual acuity to ranibizumab treatment (7.6±3.3 and 6.3±1.3 ETDRS letters, respectively). Eyes with previous panretinal laser photocoagulation displayed a comparable final outcome regarding function and morphology, requiring a similar intensity of intravitreal injections. CONCLUSIONS Perifoveal capillary drop-out did not limit the gain of visual acuity from intravitreal ranibizumab treatment. The reduction of central retina thickness was similar to that seen in eyes with normal perifoveal capillaries. Central retinal thickness in eyes with perifoveal capillary drop-out was generally reduced. However, this did not affect their benefit from treatment. Ranibizumab did not increase the amount of perifoveal capillary loss.

Out-of-Body Experiences and Other Complex Dissociation Experiences in a Patient with Unilateral Peripheral Vestibular Damage and Deficient Multisensory Integration

Out-of-body experiences (OBEs) are illusory perceptions of one's body from an elevated disembodied perspective. Recent theories postulate a double disintegration process in the personal (visual, proprioceptive and tactile disintegration) and extrapersonal (visual and vestibular disintegration) space as the basis of OBEs. Here we describe a case which corroborates and extends this hypothesis. The patient suffered from peripheral vestibular damage and presented with OBEs and lucid dreams. Analysis of the patient's behaviour revealed a failure of visuo-vestibular integration and abnormal sensitivity to visuo-tactile conflicts that have previously been shown to experimentally induce out-of-body illusions (in healthy subjects). In light of these experimental findings and the patient's symptomatology we extend an earlier model of the role of vestibular signals in OBEs. Our results advocate the involvement of subcortical bodily mechanisms in the occurrence of OBEs.

Idiopathic multifocal choroiditis/punctate inner choroidopathy with acute photoreceptor loss or dysfunction out of proportion to clinically visible lesions.

PURPOSE To report acute/subacute vision loss and paracentral scotomata in patients with idiopathic multifocal choroiditis/punctate inner choroidopathy due to large zones of acute photoreceptor attenuation surrounding the chorioretinal lesions. METHODS Multimodal imaging case series. RESULTS Six women and 2 men were included (mean age, 31.5 ± 5.8 years). Vision ranged from 20/20-1 to hand motion (mean, 20/364). Spectral domain optical coherence tomography demonstrated extensive attenuation of the external limiting membrane, ellipsoid and interdigitation zones, adjacent to the visible multifocal choroiditis/punctate inner choroidopathy lesions. The corresponding areas were hyperautofluorescent on fundus autofluorescence and were associated with corresponding visual field defects. Full-field electroretinogram (available in three cases) showed markedly decreased cone/rod response, and multifocal electroretinogram revealed reduced amplitudes and increased implicit times in two cases. Three patients received no treatment, the remaining were treated with oral corticosteroids (n = 4), oral acyclovir/valacyclovir (n = 2), intravitreal/posterior subtenon triamcinolone acetate (n = 3), and anti-vascular endothelial growth factor (n = 2). Visual recovery occurred in only three cases of whom two were treated. Varying morphological recovery was found in six cases, associated with decrease in hyperautofluorescence on fundus autofluorescence. CONCLUSION Multifocal choroiditis/punctate inner choroidopathy can present with transient or permanent central photoreceptor attenuation/loss. This presentation is likely a variant of multifocal choroiditis/punctate inner choroidopathy with chorioretinal atrophy. Associated changes are best evaluated using multimodal imaging.

Riding out of the storm: How to deal with the complexity of grid and cloud management

Over the last decade, Grid computing paved the way for a new level of large scale distributed systems. This infrastructure made it possible to securely and reliably take advantage of widely separated computational resources that are part of several different organizations. Resources can be incorporated to the Grid, building a theoretical virtual supercomputer. In time, cloud computing emerged as a new type of large scale distributed system, inheriting and expanding the expertise and knowledge that have been obtained so far. Some of the main characteristics of Grids naturally evolved into clouds, others were modified and adapted and others were simply discarded or postponed. Regardless of these technical specifics, both Grids and clouds together can be considered as one of the most important advances in large scale distributed computing of the past ten years; however, this step in distributed computing has came along with a completely new level of complexity. Grid and cloud management mechanisms play a key role, and correct analysis and understanding of the system behavior are needed. Large scale distributed systems must be able to self-manage, incorporating autonomic features capable of controlling and optimizing all resources and services. Traditional distributed computing management mechanisms analyze each resource separately and adjust specific parameters of each one of them. When trying to adapt the same procedures to Grid and cloud computing, the vast complexity of these systems can make this task extremely complicated. But large scale distributed systems complexity could only be a matter of perspective. It could be possible to understand the Grid or cloud behavior as a single entity, instead of a set of resources. This abstraction could provide a different understanding of the system, describing large scale behavior and global events that probably would not be detected analyzing each resource separately. In this work we define a theoretical framework that combines both ideas, multiple resources and single entity, to develop large scale distributed systems management techniques aimed at system performance optimization, increased dependability and Quality of Service (QoS). The resulting synergy could be the key 350 J. Montes et al. to address the most important difficulties of Grid and cloud management.

Interference with gene regulation in living sea urchin embryos: Transcription factor Knock Out (TKO), a genetically controlled vector for blockade of specific transcription factors

“TKO” is an expression vector that knocks out the activity of a transcription factor in vivo under genetic control. We describe a successful test of this concept that used a sea urchin transcription factor of known function, P3A2, as the target. The TKO cassette employs modular cis-regulatory elements to express an encoded single-chain antibody that prevents the P3A2 protein from binding DNA in vivo. In normal development, one of the functions of the P3A2 transcription factor is to repress directly the expression of the CyIIIa cytoskeletal actin gene outside the aboral ectoderm of the embryo. Ectopic expression in oral ectoderm occurs if P3A2 sites are deleted from CyIIIa expression constructs, and we show here that introduction of an αP3A2⋅TKO expression cassette causes exactly the same ectopic oral expression of a coinjected wild-type CyIIIa construct. Furthermore, the αP3A2⋅TKO cassette derepresses the endogenous CyIIIa gene in the oral ectoderm and in the endoderm. αP3A2⋅TKO thus abrogates the function of the endogenous SpP3A2 transcription factor with respect to spatial repression of the CyIIIa gene. Widespread expression of αP3A2⋅TKO in the endoderm has the additional lethal effect of disrupting morphogenesis of the archenteron, revealing a previously unsuspected function of SpP3A2 in endoderm development. In principle, TKO technology could be utilized for spatially and temporally controlled blockade of any transcription factor in any biological system amenable to gene transfer.

Antigenic peptides containing large PEG loops designed to extend out of the HLA-A2 binding site form stable complexes with class I major histocompatibility complex molecules.

Recognition of peptides bound to class I major histocompatibility complex (MHC) molecules by specific receptors on T cells regulates the development and activity of the cellular immune system. We have designed and synthesized de novo cyclic peptides that incorporate PEG in the ring structure for binding to class I MHC molecules. The large PEG loops are positioned to extend out of the peptide binding site, thus creating steric effects aimed at preventing the recognition of class I MHC complexes by T-cell receptors. Peptides were synthesized and cyclized on polymer support using high molecular weight symmetrical PEG dicarboxylic acids to link the side chains of lysine residues substituted at positions 4 and 8 in the sequence of the HLA-A2-restricted human T-lymphotrophic virus type I Tax peptide. Cyclic peptides promoted the in vitro folding and assembly of HLA-A2 complexes. Thermal denaturation studies using circular dichroism spectroscopy showed that these complexes are as stable as complexes formed with antigenic peptides.