Study protocol of cost-effectiveness and cost-utility of a biopsychosocial multidisciplinary intervention in the evolution of non-specific sub-acute low back pain in the working population: cluster randomised trial.

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.Background: Low back pain (LBP), with high incidence and prevalence rate, is one of the most common reasons to consult the health system and is responsible for a significant amount of sick leave, leading to high health and social costs. The objective of the study is to assess the cost-effectiveness and cost-utility analysis of a multidisciplinary biopsychosocial educational group intervention (MBEGI) of non-specific sub-acute LBP in comparison with the usual care in the working population recruited in primary healthcare centres. Methods/design: The study design is a cost-effectiveness and cost-utility analysis of a MBEGI in comparison with the usual care of non-specific sub-acute LBP.Measures on effectiveness and costs of both interventions will be obtained from a cluster randomised controlled clinical trial carried out in 38 Catalan primary health care centres, enrolling 932 patients between 18 and 65 years old with a diagnosis of non-specific sub-acute LBP. Effectiveness measures are: pharmaceutical treatments, work sick leave (% and duration in days), Roland Morris disability, McGill pain intensity, Fear Avoidance Beliefs (FAB) and Golberg Questionnaires. Utility measures will be calculated from the SF-12. The analysis will be performed from a social perspective. The temporal horizon is at 3 months (change to chronic LBP) and 12 months (evaluate the outcomes at long term. Assessment of outcomes will be blinded and will follow the intention-to-treat principle. Discussion: We hope to demonstrate the cost-effectiveness and cost-utility of MBEGI, see an improvement in the patients' quality of life, achieve a reduction in the duration of episodes and the chronicity of non-specific low back pain, and be able to report a decrease in the social costs. If the intervention is cost-effectiveness and cost-utility, it could be applied to Primary Health Care Centres. Trial registration: ISRCTN: ISRCTN5871969

A Global View of Cancer-Specific Transcript Variants by Subtractive Transcriptome-Wide Analysis

BACKGROUND: Alternative pre-mRNA splicing (AS) plays a central role in generating complex proteomes and influences development and disease. However, the regulation and etiology of AS in human tumorigenesis is not well understood. METHODOLOGY/PRINCIPAL FINDINGS: A Basic Local Alignment Search Tool database was constructed for the expressed sequence tags (ESTs) from all available databases of human cancer and normal tissues. An insertion or deletion in the alignment of EST/EST was used to identify alternatively spliced transcripts. Alignment of the ESTs with the genomic sequence was further used to confirm AS. Alternatively spliced transcripts in each tissue were then subtractively cross-screened to obtain tissue-specific variants. We systematically identified and characterized cancer/tissue-specific and alternatively spliced variants in the human genome based on a global view. We identified 15,093 cancer-specific variants of 9,989 genes from 27 types of human cancers and 14,376 normal tissue-specific variants of 7,240 genes from 35 normal tissues, which cover the main types of human tumors and normal tissues. Approximately 70% of these transcripts are novel. These data were integrated into a database HCSAS (http://202.114.72.39/database/human.html, pass:68756253). Moreover, we observed that the cancer-specific AS of both oncogenes and tumor suppressor genes are associated with specific cancer types. Cancer shows a preference in the selection of alternative splice-sites and utilization of alternative splicing types. CONCLUSIONS/SIGNIFICANCE: These features of human cancer, together with the discovery of huge numbers of novel splice forms for cancer-associated genes, suggest an important and global role of cancer-specific AS during human tumorigenesis. We advise the use of cancer-specific alternative splicing as a potential source of new diagnostic, prognostic, predictive, and therapeutic tools for human cancer. The global view of cancer-specific AS is not only useful for exploring the complexity of the cancer transcriptome but also widens the eyeshot of clinical research

Differential Inhibitor Sensitivity between Human Kinases VRK1 and VRK2

Human vaccinia-related kinases (VRK1 and VRK2) are atypical active Ser-Thr kinases implicated in control of cell cycle entry, apoptosis and autophagy, and affect signalling by mitogen activated protein kinases (MAPK). The specific structural differences in VRK catalytic sites make them suitable candidates for development of specific inhibitors. In this work we have determined the sensitivity of VRK1 and VRK2 to kinase inhibitors, currently used in biological assays or in preclinical studies, in order to discriminate between the two proteins as well as with respect to the vaccinia virus B1R kinase. Both VRK proteins and vaccinia B1R are poorly inhibited by inhibitors of different types targeting Src, MEK1, B-Raf, JNK, p38, CK1, ATM, CHK1/2 and DNA-PK, and most of them have no effect even at 100 µM. Despite their low sensitivity, some of these inhibitors in the low micromolar range are able to discriminate between VRK1, VRK2 and B1R. VRK1 is more sensitive to staurosporine, RO-31-8220 and TDZD8. VRK2 is more sensitive to roscovitine, RO 31–8220, Cdk1 inhibitor, AZD7762, and IC261. Vaccinia virus B1R is more sensitive to staurosporine, KU55933, and RO 31–8220, but not to IC261. Thus, the three kinases present a different pattern of sensitivity to kinase inhibitors. This differential response to known inhibitors can provide a structural framework for VRK1 or VRK2 specific inhibitors with low or no cross-inhibition. The development of highly specific VRK1 inhibitors might be of potential clinical use in those cancers where these kinases identify a clinical subtype with a poorer prognosis, as is the case of VRK1 in breast cancer

Effectiveness of a cognitive behavioral intervention in patients with medically unexplained symptoms: cluster randomized trial

BACKGROUND: Medically unexplained symptoms are an important mental health problem in primary care and generate a high cost in health services.Cognitive behavioral therapy and psychodynamic therapy have proven effective in these patients. However, there are few studies on the effectiveness of psychosocial interventions by primary health care. The project aims to determine whether a cognitive-behavioral group intervention in patients with medically unexplained symptoms, is more effective than routine clinical practice to improve the quality of life measured by the SF-12 questionary at 12 month. METHODS/DESIGN: This study involves a community based cluster randomized trial in primary healthcare centres in Madrid (Spain). The number of patients required is 242 (121 in each arm), all between 18 and 65 of age with medically unexplained symptoms that had seeked medical attention in primary care at least 10 times during the previous year. The main outcome variable is the quality of life measured by the SF-12 questionnaire on Mental Healthcare. Secondary outcome variables include number of consultations, number of drug (prescriptions) and number of days of sick leave together with other prognosis and descriptive variables. Main effectiveness will be analyzed by comparing the percentage of patients that improve at least 4 points on the SF-12 questionnaire between intervention and control groups at 12 months. All statistical tests will be performed with intention to treat. Logistic regression with random effects will be used to adjust for prognostic factors. Confounding factors or factors that might alter the effect recorded will be taken into account in this analysis. DISCUSSION: This study aims to provide more insight to address medically unexplained symptoms, highly prevalent in primary care, from a quantitative methodology. It involves intervention group conducted by previously trained nursing staff to diminish the progression to the chronicity of the symptoms, improve quality of life, and reduce frequency of medical consultations. TRIAL REGISTRATION: The trial was registered with ClinicalTrials.gov, number NCT01484223 [http://ClinicalTrials.gov].S

A functional alternative splicing mutation in human tryptophan hydroxylase-2

The brain serotonergic system has an essential role in the physiological functions of the central nervous system and dysregulation of serotonin (5-HT) homeostasis has been implicated in many neuropsychiatric disorders. The tryptophan hydroxylase-2 (TPH2) gene is the rate-limiting enzyme in brain 5-HT synthesis, and thus is an ideal candidate gene for understanding the role of dysregulation of brain serotonergic homeostasis. Here, we characterized a common, but functional single-nucleotide polymorphism (SNP rs1386493) in the TPH2 gene, which decreases efficiency of normal RNA splicing, resulting in a truncated TPH2 protein (TPH2-TR) by alternative splicing. TPH2-TR, which lacks TPH2 enzyme activity, dominant-negatively affects full-length TPH2 function, causing reduced 5-HT production. The predicted mRNA for TPH2-TR is present in postmortem brain of rs1386493 carriers. The rs13864923 variant does not appear to be overrepresented in either global or multiplex depression cohorts. However, in combination with other gene variants linked to 5-HT homeostasis, this variant may exhibit important epistatic influences

Looking to the future of zebrafish as a model to understand the genetic basis of eye disease

In this brief commentary, we provide some of our thoughts and opinions on the current and future use of zebrafish to model human eye disease, dissect pathological progression and advance in our understanding of the genetic bases of microphthalmia, andophthalmia and coloboma (MAC) in humans. We provide some background on eye formation in fish and conservation and divergence across vertebrates in this process, discuss different approaches for manipulating gene function and speculate on future research areas where we think research using fish may prove to be particularly effective

Effective Rheology of Bubbles Moving in a Capillary Tube

We calculate the average volumetric flux versus pressure drop of bubbles moving in a single capillary tube with varying diameter, finding a square-root relation from mapping the flow equations onto that of a driven overdamped pendulum. The calculation is based on a derivation of the equation of motion of a bubble train from considering the capillary forces and the entropy production associated with the viscous flow. We also calculate the configurational probability of the positions of the bubbles.Comment: 4 pages, 1 figur

TRY plant trait database - enhanced coverage and open access

Plant traits-the morphological, anatomical, physiological, biochemical and phenological characteristics of plants-determine how plants respond to environmental factors, affect other trophic levels, and influence ecosystem properties and their benefits and detriments to people. Plant trait data thus represent the basis for a vast area of research spanning from evolutionary biology, community and functional ecology, to biodiversity conservation, ecosystem and landscape management, restoration, biogeography and earth system modelling. Since its foundation in 2007, the TRY database of plant traits has grown continuously. It now provides unprecedented data coverage under an open access data policy and is the main plant trait database used by the research community worldwide. Increasingly, the TRY database also supports new frontiers of trait-based plant research, including the identification of data gaps and the subsequent mobilization or measurement of new data. To support this development, in this article we evaluate the extent of the trait data compiled in TRY and analyse emerging patterns of data coverage and representativeness. Best species coverage is achieved for categorical traits-almost complete coverage for 'plant growth form'. However, most traits relevant for ecology and vegetation modelling are characterized by continuous intraspecific variation and trait-environmental relationships. These traits have to be measured on individual plants in their respective environment. Despite unprecedented data coverage, we observe a humbling lack of completeness and representativeness of these continuous traits in many aspects. We, therefore, conclude that reducing data gaps and biases in the TRY database remains a key challenge and requires a coordinated approach to data mobilization and trait measurements. This can only be achieved in collaboration with other initiatives

Centrality dependence of charged particle production at large transverse momentum in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm{NN}}} = 2.76 TeV

The inclusive transverse momentum ($p_{\rm T}$) distributions of primary charged particles are measured in the pseudo-rapidity range $|\eta|<0.8$ as a function of event centrality in Pb-Pb collisions at $\sqrt{s_{\rm{NN}}}=2.76$ TeV with ALICE at the LHC. The data are presented in the $p_{\rm T}$ range $0.15<p_{\rm T}<50$ GeV/$c$ for nine centrality intervals from 70-80% to 0-5%. The Pb-Pb spectra are presented in terms of the nuclear modification factor $R_{\rm{AA}}$ using a pp reference spectrum measured at the same collision energy. We observe that the suppression of high-$p_{\rm T}$ particles strongly depends on event centrality. In central collisions (0-5%) the yield is most suppressed with $R_{\rm{AA}}\approx0.13$ at $p_{\rm T}=6$-7 GeV/$c$. Above $p_{\rm T}=7$ GeV/$c$, there is a significant rise in the nuclear modification factor, which reaches $R_{\rm{AA}} \approx0.4$ for $p_{\rm T}>30$ GeV/$c$. In peripheral collisions (70-80%), the suppression is weaker with $R_{\rm{AA}} \approx 0.7$ almost independently of $p_{\rm T}$. The measured nuclear modification factors are compared to other measurements and model calculations.Comment: 17 pages, 4 captioned figures, 2 tables, authors from page 12, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/284

Charge separation relative to the reaction plane in Pb-Pb collisions at sNN=2.76\sqrt{s_{\rm NN}}= 2.76 TeV

Measurements of charge dependent azimuthal correlations with the ALICE detector at the LHC are reported for Pb-Pb collisions at $\sqrt{s_{\rm NN}} = 2.76$ TeV. Two- and three-particle charge-dependent azimuthal correlations in the pseudo-rapidity range $|\eta| < 0.8$ are presented as a function of the collision centrality, particle separation in pseudo-rapidity, and transverse momentum. A clear signal compatible with a charge-dependent separation relative to the reaction plane is observed, which shows little or no collision energy dependence when compared to measurements at RHIC energies. This provides a new insight for understanding the nature of the charge dependent azimuthal correlations observed at RHIC and LHC energies.Comment: 12 pages, 3 captioned figures, authors from page 2 to 6, published version, figures at http://aliceinfo.cern.ch/ArtSubmission/node/286