13,113 research outputs found

    Degeneration of the intervertebral disc with new approaches for treating low back pain.

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    This review paper discusses the process of disc degeneration and the current understanding of cellular degradation in patients who present with low back pain. The role of surgical treatment for low back pain is analysed with emphasis on the proven value of spinal fusion. The interesting and novel developments of stem cell research in the treatment of low back pain are presented with special emphasis on the importance of the cartilaginous end plate and the role of IL-1 in future treatment modalities

    Modeling reactivity to biological macromolecules with a deep multitask network

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    Most small-molecule drug candidates fail before entering the market, frequently because of unexpected toxicity. Often, toxicity is detected only late in drug development, because many types of toxicities, especially idiosyncratic adverse drug reactions (IADRs), are particularly hard to predict and detect. Moreover, drug-induced liver injury (DILI) is the most frequent reason drugs are withdrawn from the market and causes 50% of acute liver failure cases in the United States. A common mechanism often underlies many types of drug toxicities, including both DILI and IADRs. Drugs are bioactivated by drug-metabolizing enzymes into reactive metabolites, which then conjugate to sites in proteins or DNA to form adducts. DNA adducts are often mutagenic and may alter the reading and copying of genes and their regulatory elements, causing gene dysregulation and even triggering cancer. Similarly, protein adducts can disrupt their normal biological functions and induce harmful immune responses. Unfortunately, reactive metabolites are not reliably detected by experiments, and it is also expensive to test drug candidates for potential to form DNA or protein adducts during the early stages of drug development. In contrast, computational methods have the potential to quickly screen for covalent binding potential, thereby flagging problematic molecules and reducing the total number of necessary experiments. Here, we train a deep convolution neural networkthe XenoSite reactivity modelusing literature data to accurately predict both sites and probability of reactivity for molecules with glutathione, cyanide, protein, and DNA. On the site level, cross-validated predictions had area under the curve (AUC) performances of 89.8% for DNA and 94.4% for protein. Furthermore, the model separated molecules electrophilically reactive with DNA and protein from nonreactive molecules with cross-validated AUC performances of 78.7% and 79.8%, respectively. On both the site- and molecule-level, the model’s performances significantly outperformed reactivity indices derived from quantum simulations that are reported in the literature. Moreover, we developed and applied a selectivity score to assess preferential reactions with the macromolecules as opposed to the common screening traps. For the entire data set of 2803 molecules, this approach yielded totals of 257 (9.2%) and 227 (8.1%) molecules predicted to be reactive only with DNA and protein, respectively, and hence those that would be missed by standard reactivity screening experiments. Site of reactivity data is an underutilized resource that can be used to not only predict if molecules are reactive, but also show where they might be modified to reduce toxicity while retaining efficacy. The XenoSite reactivity model is available at http://swami.wustl.edu/xenosite/p/reactivity

    Effect of hole-shape irregularities on photonic crystal waveguides

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    The effect of irregular hole shape on the spectrum and radiation losses of a photonic crystal waveguide is studied using Bloch-mode expansion. Deviations from a perfectly circular hole are characterized by a radius fluctuation amplitude and correlation angle. It is found that the parameter which determines the magnitude of the effect of disorder is the standard deviation of the hole areas. Hence, for a fixed amplitude of the radius fluctuation around the hole, those effects are strongly dependent on the correlation angle of the irregular shape. This result suggests routes to potentially improve the quality of photonic crystal structures.Comment: 3 pages, 3 figure

    Diagnosis and treatment of chlamydia and gonorrhoea in general practice in England 2000–2011: a population-based study using data from the UK Clinical Practice Research Datalink

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    Objectives: To determine the relative contribution of general practices (GPs) to the diagnosis of chlamydia and gonorrhoea in England and whether treatment complied with national guidelines. Design: Analysis of longitudinal electronic health records in the Clinical Practice Research Datalink (CPRD) and national sexually transmitted infection (STI) surveillance databases, England, 2000–2011. Setting: GPs, and community and specialist STI services. Participants: Patients diagnosed with chlamydia (n=1 386 169) and gonorrhoea (n=232 720) at CPRD GPs, and community and specialist STI Services from 2000–2011. Main outcome measures: Numbers and rates of chlamydia and gonorrhoea diagnoses; percentages of patients diagnosed by GPs relative to other services; percentage of GP patients treated and antimicrobials used; percentage of GP patients referred. Results: The diagnosis rate (95% CI) per 100 000 population of chlamydia in GP increased from 22.8 (22.4–23.2) in 2000 to 29.3 (28.8–29.7) in 2011 (p<0.001), while the proportion treated increased from 59.5% to 78.4% (p=0.001). Over 90% were prescribed a recommended antimicrobial. Over the same period, the diagnosis rate (95% CI) per 100 000 population of gonorrhoea in GP ranged between 3.2 (3–3.3) and 2.4 (2.2–2.5; p=0.607), and the proportion treated ranged between 32.7% and 53.6% (p=0.262). Despite being discontinued as a recommended therapy for gonorrhoea in 2005, ciprofloxacin accounted for 42% of prescriptions in 2007 and 20% in 2011. Over the study period, GPs diagnosed between 9% and 16% of chlamydia cases and between 6% and 9% of gonorrhoea cases in England. Conclusions: GP makes an important contribution to the diagnosis and treatment of bacterial STIs in England. While most patients diagnosed with chlamydia were managed appropriately, many of those treated for gonorrhoea received antimicrobials no longer recommended for use. Given the global threat of antimicrobial resistance, GPs should remain abreast of national treatment guidelines and alert to treatment failure in their patients

    The Marketing–Sales Interface at the Interface: Creating Market-Based Capabilities through Organizational Synergy

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    The firm’s quest to create customer value is dependent on the synergistic coordination of many parts of the organization, wherein internal resources and capabilities are effectively harnessed to create a competitive advantage. The often suboptimal relationship between marketing and sales acts as an inhibitor to success in this regard and has been the subject of much attention in both the academic literature and popular press. The authors offer new insights into this issue by examining how the marketing–sales interface affects, and is affected by, other functional areas in the development of key organizational capabilities. They introduce a holistic framework that identifies key levers that must be integrated through cross-functional coordination and cooperation to achieve superior market-based capabilities that in turn enable the firm to create lasting customer value. Propositions linking the levers to market-based capabilities are offered to shape new research opportunities in the domain of the marketing and sales interface

    On Galilean invariance and nonlinearity in electrodynamics and quantum mechanics

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    Recent experimental results on slow light heighten interest in nonlinear Maxwell theories. We obtain Galilei covariant equations for electromagnetism by allowing special nonlinearities in the constitutive equations only, keeping Maxwell's equations unchanged. Combining these with linear or nonlinear Schroedinger equations, e.g. as proposed by Doebner and Goldin, yields a Galilean quantum electrodynamics.Comment: 12 pages, added e-mail addresses of the authors, and corrected a misprint in formula (2.10
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