Prophylactic and therapeutic treatment with a synthetic analogue of a parasitic worm product prevents experimental arthritis and inhibits IL-1β production via NRF2-mediated counter-regulation of the inflammasome

Rheumatoid arthritis (RA) remains a debilitating autoimmune condition as many patients are refractory to existing conventional and biologic therapies, and hence successful development of novel treatments remains a critical requirement. Towards this, we now describe a synthetic drug-like small molecule analogue, SMA-12b, of an immunomodulatory parasitic worm product, ES-62, which acts both prophylactically and therapeutically against collagen-induced arthritis (CIA) in mice. Mechanistic analysis revealed that SMA-12b modifies the expression of a number of inflammatory response genes, particularly those associated with the inflammasome in mouse bone marrow-derived macrophages and indeed IL-1β was the most down-regulated gene. Consistent with this, IL-1β was significantly reduced in the joints of mice with CIA treated with SMA-12b. SMA-12b also increased the expression of a number of genes associated with anti-oxidant responses that are controlled by the transcription factor NRF2 and critically, was unable to inhibit expression of IL-1β by macrophages derived from the bone marrow of NRF2−/− mice. Collectively, these data suggest that SMA-12b could provide the basis of an entirely novel approach to fulfilling the urgent need for new treatments for RA

Staphylococcus aureus bacteriuria as a prognosticator for outcome of Staphylococcus aureus bacteremia: a case-control study

<p>Abstract</p> <p>Background</p> <p>When <it>Staphylococcus aureus </it>is isolated in urine, it is thought to usually represent hematogenous spread. Because such spread might have special clinical significance, we evaluated predictors and outcomes of <it>S. aureus </it>bacteriuria among patients with <it>S. aureus </it>bacteremia.</p> <p>Methods</p> <p>A case-control study was performed at John H. Stroger Jr. Hospital of Cook County among adult inpatients during January 2002-December 2006. Cases and controls had positive and negative urine cultures, respectively, for <it>S. aureus</it>, within 72 hours of positive blood culture for <it>S. aureus</it>. Controls were sampled randomly in a 1:4 ratio. Univariate and multivariable logistic regression analyses were done.</p> <p>Results</p> <p>Overall, 59% of patients were African-American, 12% died, 56% of infections had community-onset infections, and 58% were infected with methicillin-susceptible <it>S. aureus </it>(MSSA). Among 61 cases and 247 controls, predictors of <it>S. aureus </it>bacteriuria on multivariate analysis were urological surgery (OR = 3.4, p = 0.06) and genitourinary infection (OR = 9.2, p = 0.002). Among patients who died, there were significantly more patients with bacteriuria than among patients who survived (39% vs. 17%; p = 0.002). In multiple Cox regression analysis, death risks in bacteremic patients were bacteriuria (hazard ratio 2.9, CI 1.4-5.9, p = 0.004), bladder catheter use (2.0, 1.0-4.0, p = 0.06), and Charlson score (1.1, 1.1-1.3, p = 0.02). Neither length of stay nor methicillin-resistant <it>Staphylococcus aureus </it>(MRSA) infection was a predictor of <it>S. aureus </it>bacteriuria or death.</p> <p>Conclusions</p> <p>Among patients with <it>S. aureus </it>bacteremia, those with <it>S. aureus </it>bacteriuria had 3-fold higher mortality than those without bacteriuria, even after adjustment for comorbidities. Bacteriuria may identify patients with more severe bacteremia, who are at risk of worse outcomes.</p

Impact of ethnicity and socio-economic status on Staphylococcus aureus bacteremia incidence and mortality: a heavy burden in Indigenous Australians

Extent: 9p.Background: Investigations of the impact of ethnicity and socio-economic status on incidence and outcomes of Staphylococcus aureus bacteraemia are limited. Methods: We prospectively identified all S. aureus bacteraemia episodes in the Australian New Zealand Cooperative on Outcomes in Staphylococcal Sepsis cohort study between 2007 and 2010. We calculated population level incidence rates using regional postcodes and stratified the analysis by ethnicity, age and socio-economic status indexes. Results: There were 7539 episodes of S. aureus bacteraemia with an annual incidence of 11·2 episodes per 100,000 population. The age-adjusted incidence in the Indigenous population was 62·5 per 100,000 population with an age standardized incidence rate ratio of 5·9 compared to the non-Indigenous population and an incidence rate ratio of 29.2 for community-associated methicillin-resistant S. aureus (MRSA). Populations in the lowest socio-economic status quintile had an increased S. aureus bacteraemia incidence compared to higher quintiles. However, there was a disparity between Indigenous and non-Indigenous populations across all socio-economic status quintiles. The lower 30-day mortality for Indigenous patients (7%) compared to non-Indigenous patients (17%) was explained by differences in age. Conclusions: Indigenous Australians suffer from a higher rate of S. aureus bacteraemia than non-Indigenous Australians, particularly for community-associated MRSA. Ethnicity and socio-economic status had little impact on subsequent mortality, with other host factors contributing more significantly.Steven Y C Tong, Sebastian J van Hal, Lloyd Einsiedel, Bart J Currie, John D Turnidg

Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data

Supporting information for a paper titled "Evidence for Community Transmission of Community-Associated but Not Health-Care-Associated Methicillin-Resistant Staphylococcus Aureus Strains Linked to Social and Material Deprivation: Spatial Analysis of Cross-sectional Data". This includes: an MS Word document that describes the modelling approach (S1 Methods), Summary statistics for area-level variables in 513 LSOAs within catchment areas of the hospital cohort (S1 Table), data from the 2011 England and Wales census that outlines population structure of 513 LSOAs within catchment areas of the hospital cohort. (S2 Table), Individual patient-level metadata (S1 Text), and LSOA-level aggregated metadata (S2 Text

Post-partum, post-sterilization tubo-ovarian abscess caused by <it>Fusobacterium necrophorum</it>: a case report

<p>Abstract</p> <p>Introduction</p> <p>Post-partum, post-sterilization tubo-ovarian abscess is a rare event. <it>Fusobacterium necrophorum</it> subspecies <it>funduliforme</it>, a normal flora found mainly in the oral cavity, appears to be the etiologic organism.</p> <p>Case presentation</p> <p>In this case report, a 25-year-old Thai woman had a post-partum, post-sterilization tubo-ovarian abscess caused by the strictly anaerobic bacterium, <it>Fusobacterium necrophorum</it> subspecies <it>funduliforme</it>. Progressively severe symptoms started 3 weeks after her third vaginal delivery with a tubal sterilization on the following day. On admission, she presented with peritonitis and impending shock. An exploratory laparotomy showed a ruptured left tubo-ovarian abscess. A segment of her ileum had to be resected because of severe inflammation.</p> <p>Conclusions</p> <p><it>Fusobacterium necrophorum</it> subspecies <it>funduliforme</it> can be an etiologic organism of a ruptured tubo-ovarian abscess following tubal sterilization in a healthy host.</p

The burden of Legionnaires' disease in New Zealand (LegiNZ): A national surveillance study

Background: Legionnaires' disease is under-diagnosed because of inconsistent use of diagnostic tests and uncertainty about whom to test. We assessed the increase in case detection following large-scale introduction of routine PCR testing of respiratory specimens in New Zealand. Methods: LegiNZ was a national surveillance study done over 1-year in which active case-finding was used to maximise the identification of cases of Legionnaires' disease in hospitals. Respiratory specimens from patients of any age with pneumonia, who could provide an eligible lower respiratory specimen, admitted to one of 20 participating hospitals, covering a catchment area of 96% of New Zealand's population, were routinely tested for legionella by PCR. Additional cases of Legionnaires' disease in hospital were identified through mandatory notification. Findings: Between May 21, 2015, and May 20, 2016, 5622 eligible specimens from 4862 patients were tested by PCR. From these, 197 cases of Legionnaires' disease were detected. An additional 41 cases were identified from notification data, giving 238 cases requiring hospitalisation. The overall incidence of Legionnaires' disease cases in hospital in the study area was 5·4 per 100 000 people per year, and Legionella longbeachae was the predominant cause, found in 150 (63%) of 238 cases. Interpretation: The rate of notified disease during the study period was three-times the average over the preceding 3 years. Active case-finding through systematic PCR testing better clarified the regional epidemiology of Legionnaires' disease and uncovered an otherwise hidden burden of disease. These data inform local Legionnaires' disease testing strategies, allow targeted antibiotic therapy, and help identify outbreaks and effective prevention strategies. The same approach might have similar benefits if applied elsewhere in the world. Funding: Health Research Council of New Zealand