Discovery of antivirulence agents against methicillin-resistant staphylococcus aureus

Antivirulence agents inhibit the production of disease-causing virulence factors but are neither bacteriostatic nor bactericidal. Antivirulence agents against methicillin-resistant Staphylococcus aureus (MRSA) strain USA300, the most widespread community-associated MRSA strain in the United States, were discovered by virtual screening against the response regulator AgrA, which acts as a transcription factor for the expression of several of the most prominent S. aureus toxins and virulence factors involved in pathogenesis. Virtual screening was followed by similarity searches in the databases of commercial vendors. The small-molecule compounds discovered inhibit the production of the toxins alpha-hemolysin and phenol-soluble modulin α in a dose-dependent manner without inhibiting bacterial growth. These antivirulence agents are small-molecule biaryl compounds in which the aromatic rings either are fused or are separated by a short linker. One of these compounds is the FDA-approved nonsteroidal anti-inflammatory drug diflunisal. This represents a new use for an old drug. Antivirulence agents might be useful in prophylaxis and as adjuvants in antibiotic therapy for MRSA infections

One-carbon metabolism in children with marasmus and kwashiorkor

BACKGROUND: Kwashiorkor is a childhood syndrome of edematous malnutrition. Its precise nutritional precipitants remain uncertain despite nine decades of study. Remarkably, kwashiorkor\u27s disturbances resemble the effects of experimental diets that are deficient in one-carbon nutrients. This similarity suggests that kwashiorkor may represent a nutritionally mediated syndrome of acute one-carbon metabolism dysfunction. Here we report findings from a cross-sectional exploration of serum one-carbon metabolites in Malawian children. METHODS: Blood was collected from children aged 12-60 months before nutritional rehabilitation: kwashiorkor (N = 94), marasmic-kwashiorkor (N = 43) marasmus (N = 118), moderate acute malnutrition (N = 56) and controls (N = 46). Serum concentrations of 16 one-carbon metabolites were quantified using LC/MS techniques, and then compared across participant groups. FINDINGS: Twelve of 16 measured one-carbon metabolites differed significantly between participant groups. Measured outputs of one-carbon metabolism, asymmetric dimethylarginine (ADMA) and cysteine, were lower in marasmic-kwashiorkor (median µmol/L (± SD): 0·549 (± 0·217) P = 0·00045 & 90 (± 40) P \u3c 0·0001, respectively) and kwashiorkor (0·557 (± 0·195) P \u3c 0·0001 & 115 (± 50) P \u3c 0·0001), relative to marasmus (0·698 (± 0·212) & 153 (± 42)). ADMA and cysteine were well correlated with methionine in both kwashiorkor and marasmic-kwashiorkor. INTERPRETATION: Kwashiorkor and marasmic-kwashiorkor were distinguished by evidence of one-carbon metabolism dysfunction. Correlative observations suggest that methionine deficiency drives this dysfunction, which is implicated in the syndrome\u27s pathogenesis. The hypothesis that kwashiorkor can be prevented by fortifying low quality diets with methionine, along with nutrients that support efficient methionine use, such as choline, requires further investigation. FUNDING: The Hickey Family Foundation, the American College of Gastroenterology, the NICHD, and the USDA/ARS

Developing the Global Health Cost Consortium Unit Cost Study Repository for HIV and TB: methodology and lessons learned.

Consistently defined, accurate, and easily accessible cost data are a valuable resource to inform efficiency analyses, budget preparation, and sustainability planning in global health. The Global Health Cost Consortium (GHCC) designed the Unit Cost Study Repository (UCSR) to be a resource for standardised HIV and TB intervention cost data displayed by key characteristics such as intervention type, country, and target population. To develop the UCSR, the GHCC defined a typology of interventions for each disease; aligned interventions according to the standardised principles, methods, and cost and activity categories from the GHCC Reference Case for Estimating the Costs of Global Health Services and Interventions; completed a systematic literature review; conducted extensive data extraction; performed quality assurance; grappled with complex methodological issues such as the proper approach to the inflation and conversion of costs; developed and implemented a study quality rating system; and designed a web-based user interface that flexibly displays large amounts of data in a user-friendly way. Key lessons learned from the extraction process include the importance of assessing the multiple uses of extracted data; the critical role of standardising definitions (particularly units of measurement); using appropriate classifications of interventions and components of costs; the efficiency derived from programming data checks; and the necessity of extraction quality monitoring by senior analysts. For the web interface, lessons were: understanding the target audiences, including consulting them regarding critical characteristics; designing the display of data in "levels"; and incorporating alert and unique trait descriptions to further clarify differences in the data

Reference case for estimating the costs of global health services and Interventions

Estimates of the costs of implementing health interventions are required for informing a wide range of decisions in global health. Costs are used in economic evaluations, such as benefit-cost or cost-effectiveness analysis, and other economic analyses to inform priority setting. Cost interventions are also needed for financial planning and management, and the formulation of resource requirements and budgets. In addition, cost estimates can provide additional detail on how interventions are implemented, which can be useful for assessing the efficiency of service delivery. Costs are typically estimated using a range of approaches and assumptions, often combining data obtained as part of research studies with data collected as part of routine program implementation. While numerous textbooks and guideline documents exist, analysts apply and interpret such guidance based on their prior training, professional experience, and context. However, there is no widely agreed-upon common guidance on principles, methods, and reporting standards specifically aimed at cost estimation across global health. The variation in applying the methods and reporting of costs for global health interventions has long been recognized. This variation can have an impact on estimates of cost-effectiveness, which should be comparable across interventions. A review of economic evaluations in the Tufts Medical Center Cost-Effectiveness Analysis (CEA) Registry found a high level of variation in costing methods, although the review noted an improvement in consistency over time. Differences in data collection methods and in the application of analytic methods, a general lack of comprehensiveness, and inconsistent compliance to existing guidance were all observed. As a result, reviews of global health costs conclude that methodological heterogeneity and lack of transparency make it impossible to compare studies over setting and time, and several papers point to the need to develop standardized methods for cost estimation in global health

A Courageous Report on the Management of Malnutrition

Globally, childhood undernutrition continues to be a major public health concern, with an estimated 165 million children classified as stunted and 51.5 million suffering from acute malnutrition.[...

Amphibian pathogens in southeast asian frog trade

10.1007/s10393-013-0817-7EcoHealth94386-39