Non-Gaussian Discriminative Factor Models via the Max-Margin Rank-Likelihood

We consider the problem of discriminative factor analysis for data that are in general non-Gaussian. A Bayesian model based on the ranks of the data is proposed. We first introduce a new {\em max-margin} version of the rank-likelihood. A discriminative factor model is then developed, integrating the max-margin rank-likelihood and (linear) Bayesian support vector machines, which are also built on the max-margin principle. The discriminative factor model is further extended to the {\em nonlinear} case through mixtures of local linear classifiers, via Dirichlet processes. Fully local conjugacy of the model yields efficient inference with both Markov Chain Monte Carlo and variational Bayes approaches. Extensive experiments on benchmark and real data demonstrate superior performance of the proposed model and its potential for applications in computational biology.Comment: 14 pages, 7 figures, ICML 201

Caspian Oil Windfalls: Who Will Benefit?

Analyzes the systems that Azerbaijan and Kazakhstan use to manage their oil wealth, and provides comparisons from ten other countries to recommend the establishment of accountability and transparency in the management of oil and natural gas revenues

Die neurogene Entzündung bei rheumatischen Erkrankungen unter besonderer Berücksichtigung von Substanz P

In dieser Arbeit wurde der Einfluss von Substanz P auf die neurogene Entzündung bei sowohl systementzündlichen als auch bei degenerativen rheumatischen Erkrankungen als Metaanalyse dargestellt. Nach Durchsicht von rund 600 Publikationen wurden schließlich 387 Veröffentlichungen als Volltext ausgewertet. Nach dieser umfangreichen Recherche findet sich keine aktuelle systematische Analyse zu diesem Thema. Die letzte Zusammenfassung über die Rolle von Substanz P bei rheumatischen Erkrankungen erschien nach unserer Einsicht 1994 von den französischen Autoren Menkès und Renoux. In dieser Metaanalyse wurden primär die Vorgänge am Gelenk und an anderen Endorganen untersucht. Die Interpretation der Ergebnisse nimmt Bezug auf die Möglichkeiten und Grenzen eventueller therapeutischer Interventionen. Eine Schlüsselrolle im komplexen Pathomechanismus der rheumatischen Erkrankungen spielen pro- und antiinflammatorische Zytokine des Immunsystems. Zugleich hat das Nervensystem einen wesentlichen Einfluss auf autoimmune Vorgänge, so dass auch von Neuropeptiden und Transmittern eine immunmodulatorische Rolle erwartet werden kann. Substanz P ist ein aus elf Aminosäuren bestehendes Undeka-Peptid. Es wird im Spinalganglion synthetisiert und unter physiologischen Bedingungen als Transmitter in das Hinterhorn transportiert. Unter pathologischen Bedingungen wird Substanz P nach antidromem Transport am distalen Neuron mit einer erheblichen proinflammatorischen Wirkung sezerniert. Umfangreiche Daten fanden sich zu den Krankheitsbildern Rheumatoide Arthritis, Arthrose und Fibromyalgie. Untersuchungen zum Thema Kollagenosen und Vaskulitiden waren sehr begrenzt und beruhten im Wesentlichen auf tierexperimentellen Untersuchungen. In dieser Metaanalyse zeigte sich, dass eine deutliche Überexpression von Substanz P bei vielen rheumatischen Erkrankungen zu finden ist, obwohl auch widersprüchliche Ergebnisse vorlagen. Diese Eigenschaften ließen die Frage aufkommen, ob hieraus eventuell therapeutische Strategien abgeleitet werden können. Während eine selektive Rezeptorblockade für Substanz P (z. B. NK1-Antagonismus) keine Effekte zeigte, war die Depletion des Substanz P-Speichers durch Capsaicin erfolgreicher und fand bereits klinische Anwendung. Auch die Blockade der serotonininduzierten Entzündung bietet einen interessanten therapeutischen Ansatz und wird ebenfalls in klinischen Studien untersucht. Serotonin stimuliert die Freisetzung von Substanz P und anderen Transmittern aus dem Neuron. Durch eine selektive Blockade von Serotoninrezeptoren kann die Transmitterfreisetzung unterbunden und damit die Entstehung von Schmerz und Entzündung verhindert werden. Möglicherweise führt der Erfolg einer zukünftigen Therapie gegen Schmerz- und Entzündung nicht direkt über eine Blockierung von Substanz P, sondern indirekt über den Antagonismus von Serotoninrezeptoren mit anschließender Hemmung einer Reihe der Neuropeptide

Validation of a host response test to distinguish bacterial and viral respiratory infection.

BACKGROUND: Distinguishing bacterial and viral respiratory infections is challenging. Novel diagnostics based on differential host gene expression patterns are promising but have not been translated to a clinical platform nor extensively tested. Here, we validate a microarray-derived host response signature and explore performance in microbiology-negative and coinfection cases. METHODS: Subjects with acute respiratory illness were enrolled in participating emergency departments. Reference standard was an adjudicated diagnosis of bacterial infection, viral infection, both, or neither. An 87-transcript signature for distinguishing bacterial, viral, and noninfectious illness was measured from peripheral blood using RT-PCR. Performance characteristics were evaluated in subjects with confirmed bacterial, viral, or noninfectious illness. Subjects with bacterial-viral coinfection and microbiologically-negative suspected bacterial infection were also evaluated. Performance was compared to procalcitonin. FINDINGS: 151 subjects with microbiologically confirmed, single-etiology illness were tested, yielding AUROCs 0•85-0•89 for bacterial, viral, and noninfectious illness. Accuracy was similar to procalcitonin (88% vs 83%, p = 0•23) for bacterial vs. non-bacterial infection. Whereas procalcitonin cannot distinguish viral from non-infectious illness, the RT-PCR test had 81% accuracy in making this determination. Bacterial-viral coinfection was subdivided. Among 19 subjects with bacterial superinfection, the RT-PCR test identified 95% as bacterial, compared to 68% with procalcitonin (p = 0•13). Among 12 subjects with bacterial infection superimposed on chronic viral infection, the RT-PCR test identified 83% as bacterial, identical to procalcitonin. 39 subjects had suspected bacterial infection; the RT-PCR test identified bacterial infection more frequently than procalcitonin (82% vs 64%, p = 0•02). INTERPRETATION: The RT-PCR test offered similar diagnostic performance to procalcitonin in some subgroups but offered better discrimination in others such as viral vs. non-infectious illness and bacterial/viral coinfection. Gene expression-based tests could impact decision-making for acute respiratory illness as well as a growing number of other infectious and non-infectious diseases

A Broad-Spectrum Infection Diagnostic that Detects Pathogen-Associated Molecular Patterns (PAMPs) in Whole Blood

Background: Blood cultures, and molecular diagnostic tests that directly detect pathogen DNA in blood, fail to detect bloodstream infections inmost infected patients. Thus, there is a need for a rapid test that can diagnose the presence of infection to triage patients, guide therapy, and decrease the incidence of sepsis. Methods: An Enzyme-Linked Lectin-Sorbent Assay (ELLecSA) that uses magnetic microbeads coated with an engineered version of the human opsonin, Mannose Binding Lectin, containing the Fc immunoglobulin domain linked to its carbohydrate recognition domain (FcMBL) was developed to quantify pathogen-associated molecular patterns (PAMPs) in whole blood. This assay was tested in rats and pigs to explore whether it can detect infections and monitor disease progression, and in prospectively enrolled, emergency room patients with suspected sepsis. These results were also compared with data obtained from non-infected patients with or without traumatic injuries. Results: The FcMBL ELLecSA was able to detect PAMPS present on, or released by, 85% of clinical isolates representing 47 of 55 different pathogen species, including the most common causes of sepsis. The PAMP assay rapidly (<1 h) detected the presence of active infection in animals, even when blood cultures were negative and bacteriocidal antibiotics were administered. In patients with suspected sepsis, the FcMBL ELLecSA detected infection in 55 of 67 patients with high sensitivity (>81%), specificity (>89%), and diagnostic accuracy of 0.87. It also distinguished infection from trauma-related inflammation in the same patient cohorts with a higher specificity than the clinical sepsis biomarker, C-reactive Protein. Conclusion: The FcMBL ELLecSA-based PAMP assay offers a rapid, simple, sensitive and specific method for diagnosing infections, even when blood cultures are negative and antibiotic therapy has been initiated. It may help to triage patients with suspected systemic infections, and serve as a companion diagnostic to guide administration of emerging dialysis-like sepsis therapies.ope

Advancing diagnostics to address antibacterial resistance: The diagnostics and devices committee of the Antibacterial Resistance Leadership Group

Diagnostics are a cornerstone of the practice of infectious diseases. However, various limitations frequently lead to unmet clinical needs. In most other domains, diagnostics focus on narrowly defined questions, provide readily interpretable answers, and use true gold standards for development. In contrast, infectious diseases diagnostics must contend with scores of potential pathogens, dozens of clinical syndromes, emerging pathogens, rapid evolution of existing pathogens and their associated resistance mechanisms, and the absence of gold standards in many situations. In spite of these challenges, the importance and value of diagnostics cannot be underestimated. Therefore, the Antibacterial Resistance Leadership Group has identified diagnostics as 1 of 4 major areas of emphasis. Herein, we provide an overview of that development, highlighting several examples where innovation in study design, content, and execution is advancing the field of infectious diseases diagnostics

Dusp3 and Psme3 are associated with murine susceptibility to Staphylococcus aureus infection and human sepsis.

Using A/J mice, which are susceptible to Staphylococcus aureus, we sought to identify genetic determinants of susceptibility to S. aureus, and evaluate their function with regard to S. aureus infection. One QTL region on chromosome 11 containing 422 genes was found to be significantly associated with susceptibility to S. aureus infection. Of these 422 genes, whole genome transcription profiling identified five genes (Dcaf7, Dusp3, Fam134c, Psme3, and Slc4a1) that were significantly differentially expressed in a) S. aureus -infected susceptible (A/J) vs. resistant (C57BL/6J) mice and b) humans with S. aureus blood stream infection vs. healthy subjects. Three of these genes (Dcaf7, Dusp3, and Psme3) were down-regulated in susceptible vs. resistant mice at both pre- and post-infection time points by qPCR. siRNA-mediated knockdown of Dusp3 and Psme3 induced significant increases of cytokine production in S. aureus-challenged RAW264.7 macrophages and bone marrow derived macrophages (BMDMs) through enhancing NF-κB signaling activity. Similar increases in cytokine production and NF-κB activity were also seen in BMDMs from CSS11 (C57BL/6J background with chromosome 11 from A/J), but not C57BL/6J. These findings suggest that Dusp3 and Psme3 contribute to S. aureus infection susceptibility in A/J mice and play a role in human S. aureus infection