Evidence synthesis as the key to more coherent and efficient research

<p>Abstract</p> <p>Background</p> <p>Systematic review and meta-analysis currently underpin much of evidence-based medicine. Such methodologies bring order to <it>previous </it>research, but <it>future </it>research planning remains relatively incoherent and inefficient.</p> <p>Methods</p> <p>To outline a framework for evaluation of health interventions, aimed at increasing coherence and efficiency through i) making better use of information contained within the existing evidence-base when designing future studies; and ii) maximising the information available and thus potentially reducing the need for future studies.</p> <p>Results</p> <p>The framework presented insists that an up-to-date meta-analysis of existing randomised controlled trials (RCTs) should always be considered before future trials are conducted. Such a meta-analysis should inform critical design issues such as sample size determination. The contexts in which the use of individual patient data meta-analysis and mixed treatment comparisons modelling may be beneficial before further RCTs are conducted are considered. Consideration should also be given to how any newly planned RCTs would contribute to the totality of evidence through its incorporation into an updated meta-analysis. We illustrate how new RCTs can have very low power to change inferences of an existing meta-analysis, particularly when between study heterogeneity is taken into consideration.</p> <p>Conclusion</p> <p>While the collation of existing evidence as the basis for clinical practice is now routine, a more coherent and efficient approach to planning future RCTs to strengthen the evidence base needs to be developed. The framework presented is a proposal for how this situation can be improved.</p

Multi-dimensionality and variability in folk classification of stingless bees (Apidae: Meliponini)

Background: Not long ago Eugene Hunn suggested using a combination of cognitive, linguistic, ecological and evolutionary theories in order to account for the dynamic character of ethnoecology in the study of folk classification systems. In this way he intended to question certain homogeneity in folk classifications models and deepen in the analysis and interpretation of variability in folk classifications. This paper studies how a rural culturally mixed population of the Atlantic Forest of Misiones (Argentina) classified honey-producing stingless bees according to the linguistic, cognitive and ecological dimensions of folk classification. We also analyze the socio-ecological meaning of binomialization in naming and the meaning of general local variability in the appointment of stingless bees. Methods: We used three different approaches: the classical approach developed by Brent Berlin which relies heavily on linguistic criteria, the approach developed by Eleonor Rosch which relies on psychological (cognitive) principles of categorization and finally we have captured the ecological dimension of folk classification in local narratives. For the second approximation, we developed ways of measuring the degree of prototypicality based on a total of 107 comparisons of the type "X is similar to Y" identified in personal narratives. Results: Various logical and grouping strategies coexist and were identified as: graded of lateral linkage, hierarchical and functional. Similarity judgments among folk taxa resulted in an implicit logic of classification graded according to taxa's prototypicality. While there is a high agreement on naming stingless bees with monomial names, a considerable number of underrepresented binomial names and lack of names were observed. Two possible explanations about reported local naming variability are presented. Conclusions: We support the multidimensionality of folk classification systems. This confirms the specificity of local classification systems but also reflects the use of grouping strategies and mechanisms commonly observed in other cultural groups, such as the use of similarity judgments between more or less prototypical organisms. Also we support the idea that alternative naming results from a process of fragmentation of knowledge or incomplete transmission of knowledge. These processes lean on the facts that culturally based knowledge, on the one hand, and biologic knowledge of nature on the other, can be acquired through different learning pathways.Fil: Zamudio, Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Córdoba. Instituto Multidisciplinario de Biología Vegetal (p); ArgentinaFil: Hilgert, Norma Ines. Consejo Nacional de Investigaciones Cientiâ­ficas y Tecnicas. Centro Cientifico Tecnologico Nordeste. Instituto de Biologia Subtropical. Instituto de Biologia Subtropical - Nodo Puerto Iguazu; Argentin

Exceptional river gorge formation from unexceptional floods

An understanding of rates and mechanisms of incision and knickpoint retreat in bedrock rivers is fundamental to perceptions of landscape response to external drivers, yet only sparse field data are available. Here we present eye witness accounts and quantitative surveys of rapid, amphitheatre-headed gorge formation in unweathered granite from the overtopping of a rock-cut dam spillway by small-moderate floods (~100–1,500 m3 s−1). The amount of erosion demonstrates no relationship with flood magnitude or bedload availability. Instead, structural pattern of the bedrock through faults and joints appears to be the primary control on landscape change. These discontinuities facilitate rapid erosion (>270 m headward retreat; ~100 m incision; and ~160 m widening over 6 years) principally through fluvial plucking and block topple. The example demonstrates the potential for extremely rapid transient bedrock erosion even when rocks are mechanically strong and flood discharges are moderate. These observations are relevant to perceived models of gorge formation and knickpoint retreat

Leisure-time physical activity, cardiorespiratory fitness and feelings of hopelessness in men

<p>Abstract</p> <p>Background</p> <p>Leisure-time physical activity (LTPA) and cardiorespiratory fitness contribute to mental health. Hopelessness has been linked to impaired mental health, cardiovascular events and mortality. Previous studies have focused on physical exercise and depression. We examined the associations of LTPA and cardiorespiratory fitness with feelings of hopelessness.</p> <p>Methods</p> <p>In this cross-sectional study leisure-time physical activity, maximal oxygen uptake (VO_2max), hopelessness and cardiovascular risk factors were assessed in a population-based cohort of 2428 men aged 42 – 60 years old at baseline.</p> <p>Results</p> <p>Men feeling more hopeless about their future and reaching goals were less physically active, less fit and had a higher prevalence of many cardiovascular risk factors than men with lower levels of hopelessness. In a logistic regression model adjusted for age, smoking, alcohol consumption, cardiovascular disease and socioeconomic status, men engaging in less than 60 min/week of moderate-to-vigorous LTPA were 37% (95% CI 11 – 67%) more likely to feel hopeless than those engaging in at least 2.5 h/wk of LTPA. After further adjusting for elevated depressive symptoms the association of LTPA and hopelessness remained significant. VO_2maxwas also associated with hopelessness, but not after adjustment for depressive symptoms.</p> <p>Conclusion</p> <p>Moderate and vigorous LTPA and cardiorespiratory fitness were inversely associated with hopelessness in these middle-aged men. These findings suggest that physical inactivity and poor cardiorespiratory fitness is an important associate of hopelessness, a distinct element of low subjective well-being.</p

Informatics Technology Mimics Ecology: Dense, Mutualistic Collaboration Networks Are Associated with Higher Publication Rates

Information technology (IT) adoption enables biomedical research. Publications are an accepted measure of research output, and network models can describe the collaborative nature of publication. In particular, ecological networks can serve as analogies for publication and technology adoption. We constructed network models of adoption of bioinformatics programming languages and health IT (HIT) from the literature

Disease concepts and treatment by tribal healers of an Amazonian forest culture

<p>Abstract</p> <p>Background</p> <p>The extensive medicinal plant knowledge of Amazonian tribal peoples is widely recognized in the scientific literature and celebrated in popular lore. Despite this broad interest, the ethnomedical systems and knowledge of disease which guide indigenous utilization of botanical diversity for healing remain poorly characterized and understood. No study, to our knowledge, has attempted to directly examine patterns of actual disease recognition and treatment by healers of an Amazonian indigenous culture.</p> <p>Methods</p> <p>The establishment of traditional medicine clinics, operated and directed by elder tribal shamans in two remote Trio villages of the Suriname rainforest, presented a unique investigational opportunity. Quantitative analysis of clinic records from both villages permitted examination of diseases treated over a continuous period of four years. Cross-cultural comparative translations were articulated of recorded disease conditions through ethnographic interviews of elder Trio shamans and a comprehensive atlas of indigenous anatomical nomenclature was developed.</p> <p>Results</p> <p>20,337 patient visits within the period 2000 to 2004 were analyzed. 75 disease conditions and 127 anatomical terms are presented. Trio concepts of disease and medical practices are broadly examined within the present and historical state of their culture.</p> <p>Conclusion</p> <p>The findings of this investigation support the presence of a comprehensive and highly formalized ethnomedical institution within Trio culture with attendant health policy and conservation implications.</p

A Switching Mechanism in Doxorubicin Bioactivation Can Be Exploited to Control Doxorubicin Toxicity

Although doxorubicin toxicity in cancer cells is multifactorial, the enzymatic bioactivation of the drug can significantly contribute to its cytotoxicity. Previous research has identified most of the components that comprise the doxorubicin bioactivation network; however, adaptation of the network to changes in doxorubicin treatment or to patient-specific changes in network components is much less understood. To investigate the properties of the coupled reduction/oxidation reactions of the doxorubicin bioactivation network, we analyzed metabolic differences between two patient-derived acute lymphoblastic leukemia (ALL) cell lines exhibiting varied doxorubicin sensitivities. We developed computational models that accurately predicted doxorubicin bioactivation in both ALL cell lines at high and low doxorubicin concentrations. Oxygen-dependent redox cycling promoted superoxide accumulation while NADPH-dependent reductive conversion promoted semiquinone doxorubicin. This fundamental switch in control is observed between doxorubicin sensitive and insensitive ALL cells and between high and low doxorubicin concentrations. We demonstrate that pharmacological intervention strategies can be employed to either enhance or impede doxorubicin cytotoxicity in ALL cells due to the switching that occurs between oxygen-dependent superoxide generation and NADPH-dependent doxorubicin semiquinone formation

The Colocalization Potential of HIV-Specific CD8+ and CD4+ T-Cells is Mediated by Integrin β7 but Not CCR6 and Regulated by Retinoic Acid

CD4+ T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8+ and CD4+ T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a “signature” for HIV-specific but not CMV-specific CD4+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4+ versus CD8+ T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8+ T-cells may colocalize in excess with CD4+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6+CD4+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8+ T-cells to migrate in the vicinity of CCR6+CD4+ T-cells may facilitate HIV replication and dissemination at mucosal sites

Evaluation of Continuous Tumor-Size-Based End Points as Surrogates for Overall Survival in Randomized Clinical Trials in Metastatic Colorectal Cancer

IMPORTANCE: Tumor measurements can be used to estimate time to nadir and depth of nadir as potential surrogates for overall survival (OS). OBJECTIVE: To assess time to nadir and depth of nadir as surrogates for OS in metastatic colorectal cancer. DESIGN, SETTING, AND PARTICIPANTS: Pooled analysis of 20 randomized clinical trials within the Aide et Recherche en Cancerologie Digestive database, which contains academic and industry-sponsored trials, was conducted. Three sets of comparisons were performed: chemotherapy alone, antiangiogenic agents, and anti–epidermal growth factor receptor agents in first-line treatment for patients with metastatic colorectal cancer. MAIN OUTCOMES AND MEASURES: Surrogacy of time to nadir and depth of nadir was assessed at the trial level based on joint modeling of relative tumor-size change vs baseline and OS. Treatment effects on time to nadir and on depth of nadir were defined in terms of between-arm differences in time to nadir and in depth of nadir, and both were assessed in linear regressions for their correlation with treatment effects (hazard ratios) on OS within each set. The strengths of association were quantified using sample-size–weighted coefficients of determination (R2), with values closer to 1.00 indicating stronger association. At the patient level, the correlation was assessed between modeled relative tumor-size change and OS. RESULTS: For 14 chemotherapy comparisons in 4289 patients, the R2 value was 0.63 (95% CI, 0.30-0.96) for the association between treatment effects on time to nadir and OS and 0.08 (95% CI, 0-0.37) for depth of nadir and OS. For 11 antiangiogenic agent comparisons (4854 patients), corresponding values of R2 were 0.25 (95% CI, 0-0.72) and 0.06 (95% CI, 0-0.35). For 8 anti–epidermal growth factor receptor comparisons (2684 patients), corresponding values of R2 were 0.24 (95% CI, 0-0.83) and 0.21 (95% CI, 0-0.78). CONCLUSIONS AND RELEVANCE: In contrast with early reports favoring depth of response as a surrogate, these results suggest that neither time to nadir nor depth of nadir is an acceptable surrogate for OS in the first-line treatment of metastatic colorectal cancer

Resolving the neural circuits of anxiety

Although anxiety disorders represent a major societal problem demanding new therapeutic targets, these efforts have languished in the absence of a mechanistic understanding of this subjective emotional state. While it is impossible to know with certainty the subjective experience of a rodent, rodent models hold promise in dissecting well-conserved limbic circuits. The application of modern approaches in neuroscience has already begun to unmask the neural circuit intricacies underlying anxiety by allowing direct examination of hypotheses drawn from existing psychological concepts. This information points toward an updated conceptual model for what neural circuit perturbations could give rise to pathological anxiety and thereby provides a roadmap for future therapeutic development.National Institute of Diabetes and Digestive and Kidney Diseases (U.S.) (NIH Director’s New Innovator Award DP2-DK-102256-01)National Institute of Mental Health (U.S.) (NIH) R01-MH102441-01)JPB Foundatio