180 research outputs found

    The Translation Evidence Mechanism. The Compact between Researcher and Clinician.

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    Currently, best evidence is a concentrated effort by researchers. Researchers produce information and expect that clinicians will implement their advances in improving patient care. However, difficulties exist in maximizing cooperation and coordination between the producers, facilitators, and users (patients) of best evidence outcomes. The Translational Evidence Mechanism is introduced to overcome these difficulties by forming a compact between researcher, clinician and patient. With this compact, best evidence may become an integral part of private practice when uncertainties arise in patient health status, treatments, and therapies. The mechanism is composed of an organization, central database, and decision algorithm. Communication between the translational evidence organization, clinicians and patients is through the electronic chart. Through the chart, clinical inquiries are made, patient data from provider assessments and practice cost schedules are collected and encrypted (HIPAA standards), then inputted into the central database. Outputs are made within a timeframe suitable to private practice and patient flow. The output consists of a clinical practice guideline that responds to the clinical inquiry with decision, utility and cost data (based on the "average patient") for shared decision-making within informed consent. This shared decision-making allows for patients to "game" treatment scenarios using personal choice inputs. Accompanying the clinical practice guideline is a decision analysis that explains the optimized clinical decision. The resultant clinical decision is returned to the central database using the clinical practice guideline. The result is subsequently used to update current best evidence, indicate the need for new evidence, and analyze the changes made in best evidence implementation. When updates in knowledge occur, these are transmitted to the provider as alerts or flags through patient charts and other communication modalities

    Probability-Utility Model for Managing Evidence-based Central Database

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    The Probability-Utility Model is dependent on the clinical practice guideline for its function. The Model functions to provide decision analyses that demonstrate to clinicians and patients how personal preferences change the character of best evidence. Initially, patients are provided a clinical practice guideline based on “average patient” best evidence. The Model works to demonstrate how decision, utility, and cost best evidence impact on decisions. It offers to patients an explanation of these impacts. Thus, patients may become more informed about the choices that go into making optimal clinical decisions for their own personal health care. The model also provides for visual images to be used in discussing their personal choices when considering different treatment options and clinical scenarios. The calculations accomplished through the Model provide trade-off analyses by which discussions may be facilitated between provider and patient in reaching informed consent and optimal clinical decisions in formulating treatment plans

    Transforming scientific evidence into better consumer choices

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    Translational research using evidence-based and comparative effectiveness research continues to evolve, becoming a useful tool in improving informed consent and decision-making in the clinical setting. While in development, emerging technologies, including cellular and molecular biology, are leading to establishing evidence-based dental practices. One emerging technology, which conjoins bench proteomic findings to clinical decision-making for treatment intervention, is the Translational Evidence Mechanism. This mechanism was developed to be a foundation for a compact between researcher, translational researcher, clinician, and patient. The output of such a mechanism is the clinical practice guideline (CPG), an interactive tool for dentists and patients to game evidence in reaching optimum clinical decisions that correspond to individual patient preferences and values. As such, the clinical practice guideline requires the vesting of decision, utility, and cost best evidence. Evidence-based research provides decision data, a first attempt at supporting decision-making by providing best outcome data. Since then comparative effectiveness research has emerged, using systematic review analysis to compare similar treatments or procedures in maximizing the choice of the most effective cost/benefit option within the context of best evidence. With innovation in the clinical practice guideline for optimizing efficacy and comparative effectiveness research, evidence-based practices will shape a new approach to health-based systems that adhere to shared decision-making between bench scientists, healthcare providers and patients

    The Repertoire of Heterotrimeric G Proteins and RGS Proteins in Ciona intestinalis

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    BACKGROUND:Heterotrimeric G proteins and regulators of G protein signaling (RGS) proteins are key downstream interacting partners in the G protein coupled receptor (GPCR) signaling pathway. The highly versatile GPCR transmembrane signaling system is a consequence of the coupling of a diverse set of receptors to downstream partners that include multiple subforms of G proteins and regulatory proteins including RGS proteins, among others. While the GPCR repertoire of Ciona intestinalis, representing the basal chordate is known, the repertoire of the heterotrimeric G proteins and RGS proteins is unknown. METHODOLOGY/PRINCIPAL FINDINGS:In the present study, we performed an in-silico genome-wide search of C. intestinalis for its complement of G proteins and RGS proteins. The identification of several one-to-one orthologs of human G proteins at the levels of families, subfamilies and types and of homologs of the human RGS proteins suggests an evolutionarily conserved structure function relationship of the GPCR signaling mechanism in the chordates. CONCLUSIONS:The C. intestinalis genome encodes a highly conserved, albeit, limited repertoire of the heterotrimeric G protein complexes with the size of subunit types comparable with that in lower eukaryotes

    Automatic Filtering and Substantiation of Drug Safety Signals

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    Drug safety issues pose serious health threats to the population and constitute a major cause of mortality worldwide. Due to the prominent implications to both public health and the pharmaceutical industry, it is of great importance to unravel the molecular mechanisms by which an adverse drug reaction can be potentially elicited. These mechanisms can be investigated by placing the pharmaco-epidemiologically detected adverse drug reaction in an information-rich context and by exploiting all currently available biomedical knowledge to substantiate it. We present a computational framework for the biological annotation of potential adverse drug reactions. First, the proposed framework investigates previous evidences on the drug-event association in the context of biomedical literature (signal filtering). Then, it seeks to provide a biological explanation (signal substantiation) by exploring mechanistic connections that might explain why a drug produces a specific adverse reaction. The mechanistic connections include the activity of the drug, related compounds and drug metabolites on protein targets, the association of protein targets to clinical events, and the annotation of proteins (both protein targets and proteins associated with clinical events) to biological pathways. Hence, the workflows for signal filtering and substantiation integrate modules for literature and database mining, in silico drug-target profiling, and analyses based on gene-disease networks and biological pathways. Application examples of these workflows carried out on selected cases of drug safety signals are discussed. The methodology and workflows presented offer a novel approach to explore the molecular mechanisms underlying adverse drug reactions

    The impact of cyclin-dependent kinase 5 depletion on poly(ADP-ribose) polymerase activity and responses to radiation

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    Cyclin-dependent kinase 5 (Cdk5) has been identified as a determinant of sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors. Here, the consequences of its depletion on cell survival, PARP activity, the recruitment of base excision repair (BER) proteins to DNA damage sites, and overall DNA single-strand break (SSB) repair were investigated using isogenic HeLa stably depleted (KD) and Control cell lines. Synthetic lethality achieved by disrupting PARP activity in Cdk5-deficient cells was confirmed, and the Cdk5KD cells were also found to be sensitive to the killing effects of ionizing radiation (IR) but not methyl methanesulfonate or neocarzinostatin. The recruitment profiles of GFP-PARP-1 and XRCC1-YFP to sites of micro-irradiated Cdk5KD cells were slower and reached lower maximum values, while the profile of GFP-PCNA recruitment was faster and attained higher maximum values compared to Control cells. Higher basal, IR, and hydrogen peroxide-induced polymer levels were observed in Cdk5KD compared to Control cells. Recruitment of GFP-PARP-1 in which serines 782, 785, and 786, potential Cdk5 phosphorylation targets, were mutated to alanines in micro-irradiated Control cells was also reduced. We hypothesize that Cdk5-dependent PARP-1 phosphorylation on one or more of these serines results in an attenuation of its ribosylating activity facilitating persistence at DNA damage sites. Despite these deficiencies, Cdk5KD cells are able to effectively repair SSBs probably via the long patch BER pathway, suggesting that the enhanced radiation sensitivity of Cdk5KD cells is due to a role of Cdk5 in other pathways or the altered polymer levels

    Caveolae-dependent and -independent uptake of albumin in cultured rodent pulmonary endothelial cells

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    Although a critical role for caveolae-mediated albumin transcytosis in pulmonary endothelium is well established, considerably less is known about caveolae-independent pathways. In this current study, we confirmed that cultured rat pulmonary microvascular (RPMEC) and pulmonary artery (RPAEC) endothelium endocytosed Alexa488-labeled albumin in a saturable, temperature-sensitive mode and internalization resulted in co-localization by fluorescence microscopy with cholera B toxin and caveolin-1. Although siRNA to caveolin-1 (cav-1) in RPAEC significantly inhibited albumin uptake, a remnant portion of albumin uptake was cav-1-independent, suggesting alternative pathways for albumin uptake. Thus, we isolated and cultured mouse lung endothelial cells (MLEC) from wild type and cav-1-/- mice and noted that ∼ 65% of albumin uptake, as determined by confocal imaging or live cell total internal reflectance fluorescence microscopy (TIRF), persisted in total absence of cav-1. Uptake of colloidal gold labeled albumin was evaluated by electron microscopy and demonstrated that albumin uptake in MLEC from cav-1-/- mice was through caveolae-independent pathway(s) including clathrin-coated pits that resulted in endosomal accumulation of albumin. Finally, we noted that albumin uptake in RPMEC was in part sensitive to pharmacological agents (amiloride [sodium transport inhibitor], Gö6976 [protein kinase C inhibitor], and cytochalasin D [inhibitor of actin polymerization]) consistent with a macropinocytosis-like process. The amiloride sensitivity accounting for macropinocytosis also exists in albumin uptake by both wild type and cav-1 -/- MLEC. We conclude from these studies that in addition to the well described caveolar-dependent pulmonary endothelial cell endocytosis of albumin, a portion of overall uptake in pulmonary endothelial cells is cav-1 insensitive and appears to involve clathrin-mediated endocytosis and macropinocytosis-like process. © 2013 Li et al

    Elective surgery cancellations due to the COVID-19 pandemic: global predictive modelling to inform surgical recovery plans.

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    BACKGROUND: The COVID-19 pandemic has disrupted routine hospital services globally. This study estimated the total number of adult elective operations that would be cancelled worldwide during the 12 weeks of peak disruption due to COVID-19. METHODS: A global expert response study was conducted to elicit projections for the proportion of elective surgery that would be cancelled or postponed during the 12 weeks of peak disruption. A Bayesian β-regression model was used to estimate 12-week cancellation rates for 190 countries. Elective surgical case-mix data, stratified by specialty and indication (surgery for cancer versus benign disease), were determined. This case mix was applied to country-level surgical volumes. The 12-week cancellation rates were then applied to these figures to calculate the total number of cancelled operations. RESULTS: The best estimate was that 28 404 603 operations would be cancelled or postponed during the peak 12 weeks of disruption due to COVID-19 (2 367 050 operations per week). Most would be operations for benign disease (90·2 per cent, 25 638 922 of 28 404 603). The overall 12-week cancellation rate would be 72·3 per cent. Globally, 81·7 per cent of operations for benign conditions (25 638 922 of 31 378 062), 37·7 per cent of cancer operations (2 324 070 of 6 162 311) and 25·4 per cent of elective caesarean sections (441 611 of 1 735 483) would be cancelled or postponed. If countries increased their normal surgical volume by 20 per cent after the pandemic, it would take a median of 45 weeks to clear the backlog of operations resulting from COVID-19 disruption. CONCLUSION: A very large number of operations will be cancelled or postponed owing to disruption caused by COVID-19. Governments should mitigate against this major burden on patients by developing recovery plans and implementing strategies to restore surgical activity safely

    Stress, ageing and their influence on functional, cellular and molecular aspects of the immune system

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    The immune response is essential for keeping an organism healthy and for defending it from different types of pathogens. It is a complex system that consists of a large number of components performing different functions. The adequate and controlled interaction between these components is necessary for a robust and strong immune response. There are, however, many factors that interfere with the way the immune response functions. Stress and ageing now consistently appear in the literature as factors that act upon the immune system in the way that is often damaging. This review focuses on the role of stress and ageing in altering the robustness of the immune response first separately, and then simultaneously, discussing the effects that emerge from their interplay. The special focus is on the psychological stress and the impact that it has at different levels, from the whole system to the individual molecules, resulting in consequences for physical health

    Photography-based taxonomy is inadequate, unnecessary, and potentially harmful for biological sciences

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    The question whether taxonomic descriptions naming new animal species without type specimen(s) deposited in collections should be accepted for publication by scientific journals and allowed by the Code has already been discussed in Zootaxa (Dubois & Nemésio 2007; Donegan 2008, 2009; Nemésio 2009a–b; Dubois 2009; Gentile & Snell 2009; Minelli 2009; Cianferoni & Bartolozzi 2016; Amorim et al. 2016). This question was again raised in a letter supported by 35 signatories published in the journal Nature (Pape et al. 2016) on 15 September 2016. On 25 September 2016, the following rebuttal (strictly limited to 300 words as per the editorial rules of Nature) was submitted to Nature, which on 18 October 2016 refused to publish it. As we think this problem is a very important one for zoological taxonomy, this text is published here exactly as submitted to Nature, followed by the list of the 493 taxonomists and collection-based researchers who signed it in the short time span from 20 September to 6 October 2016
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