Detection of Rare Antimicrobial Resistance Profiles by Active and Passive Surveillance Approaches.

Antimicrobial resistance (AMR) surveillance systems are generally not specifically designed to detect emerging resistances and usually focus primarily on resistance to individual drugs. Evaluating the diversity of resistance, using ecological metrics, allows the assessment of sampling protocols with regard to the detection of rare phenotypes, comprising combinations of resistances. Surveillance data of phenotypic AMR of Canadian poultry Salmonella Heidelberg and swine Salmonella Typhimurium var. 5- were used to contrast active (representative isolates derived from healthy animals) and passive (diagnostic isolates) surveillance and assess their suitability for detecting emerging resistance patterns. Although in both datasets the prevalences of resistance to individual antimicrobials were not significantly different between the two surveillance systems, analysis of the diversity of entire resistance phenotypes demonstrated that passive surveillance of diagnostic isolates detected more unique phenotypes. Whilst the most appropriate surveillance method will depend on the relevant objectives, under the conditions of this study, passive surveillance of diagnostic isolates was more effective for the detection of rare and therefore potentially emerging resistance phenotypes.AEM was supported by the William Stewart Fellowship whilst at the University of Glasgow, and is currently supported by Biotechnology and Biological Sciences Research Council (BBSRC) grant BB/ M014088/1; RR is supported by BBSRC grant BB/ E010326/1 and BB/L004070/1; LM is supported by BB/K01126X/1, BB/L004070/1, BB/F015313/1, National Science Foundation DEB1216040 and an EU-funded Marie Curie Initial Training Network (MCITN) program (NEMATODE SYSTEM HEALTH project (FP7-PEOPLE-2010-ITN- ID:264639)).This is the final version of the article. It first appeared from the Public Library of Science via http://dx.doi.org/10.1371/journal.pone.015851

Demonstration of a novel technique to quantitatively assess inflammatory mediators and cells in rat knee joints

<p>Abstract</p> <p>Background</p> <p>The inflammation that accompanies the pain and swelling associated with osteo- and rheumatoid arthritis is mediated by complex interactions of inflammatory mediators. Cytokines play a pivotal role in orchestrating many of these processes, including inflammatory cell recruitment, adhesion and activation. In addition, prostaglandins are secreted into the synovial cavity and are involved in perpetuation of local inflammation, vasodilatation and vasoconstriction, and also with bone resorption. Pre-clinical models have been developed in order to correlate to the human disease and principle among these is the adjuvant-induced arthritis model in the rat.</p> <p>Methods</p> <p>We have developed a technique to quantitatively assess the contents of synovial fluid samples from rat joints. Two needles joined together are inserted into the knee joint of anaesthetised rats and connected to a Watson-Marlow perfusion pump. Sterile saline is infused and withdrawn at 100 μl min^-1until a 250 μl sample is collected.</p> <p>Results</p> <p>Our results demonstrate up to 125 fold increases in synovial IL1α and IL1β concentrations, approximately 30 fold increases in levels of IL6 and IL10 and a 200–300 fold elevation in synovial concentrations of TNFα during FCA-induced experimental arthritis. Finally, this novel technique has demonstrated a dose-response relationship between FCA and the total cell counts of synovial perfusates.</p> <p>Conclusion</p> <p>In summary, this new technique provides a robust method for quantifying inflammatory mediators and cells from the synovial cavity itself, thereby detailing the inflammatory processes from within the capsule and excluding those processes occurring in other tissues surrounding the entire articulation.</p

Large-Scale Evidence for the Effect of the COLIA1 Sp1 Polymorphism on Osteoporosis Outcomes: The GENOMOS Study

BACKGROUND: Osteoporosis and fracture risk are considered to be under genetic control. Extensive work is being performed to identify the exact genetic variants that determine this risk. Previous work has suggested that a G/T polymorphism affecting an Sp1 binding site in the COLIA1 gene is a genetic marker for low bone mineral density (BMD) and osteoporotic fracture, but there have been no very-large-scale studies of COLIA1 alleles in relation to these phenotypes. METHODS AND FINDINGS: Here we evaluated the role of COLIA1 Sp1 alleles as a predictor of BMD and fracture in a multicenter study involving 20,786 individuals from several European countries. At the femoral neck, the average (95% confidence interval [CI]) BMD values were 25 mg/cm (2) (CI, 16 to 34 mg/cm (2)) lower in TT homozygotes than the other genotype groups ( p < 0.001), and a similar difference was observed at the lumbar spine; 21 mg/cm (2) (CI, 1 to 42 mg/cm (2)), ( p = 0.039). These associations were unaltered after adjustment for potential confounding factors. There was no association with fracture overall (odds ratio [OR] = 1.01 [CI, 0.95 to 1.08]) in either unadjusted or adjusted analyses, but there was a non-significant trend for association with vertebral fracture and a nominally significant association with incident vertebral fractures in females (OR = 1.33 [CI, 1.00 to 1.77]) that was independent of BMD, and unaltered in adjusted analyses. CONCLUSIONS: Allowing for the inevitable heterogeneity between participating teams, this study—which to our knowledge is the largest ever performed in the field of osteoporosis genetics for a single gene—demonstrates that the COLIA1 Sp1 polymorphism is associated with reduced BMD and could predispose to incident vertebral fractures in women, independent of BMD. The associations we observed were modest however, demonstrating the importance of conducting studies that are adequately powered to detect and quantify the effects of common genetic variants on complex diseases

American Gut: an Open Platform for Citizen Science Microbiome Research

McDonald D, Hyde E, Debelius JW, et al. American Gut: an Open Platform for Citizen Science Microbiome Research. mSystems. 2018;3(3):e00031-18

New genetic loci link adipose and insulin biology to body fat distribution.

Body fat distribution is a heritable trait and a well-established predictor of adverse metabolic outcomes, independent of overall adiposity. To increase our understanding of the genetic basis of body fat distribution and its molecular links to cardiometabolic traits, here we conduct genome-wide association meta-analyses of traits related to waist and hip circumferences in up to 224,459 individuals. We identify 49 loci (33 new) associated with waist-to-hip ratio adjusted for body mass index (BMI), and an additional 19 loci newly associated with related waist and hip circumference measures (P < 5 × 10(-8)). In total, 20 of the 49 waist-to-hip ratio adjusted for BMI loci show significant sexual dimorphism, 19 of which display a stronger effect in women. The identified loci were enriched for genes expressed in adipose tissue and for putative regulatory elements in adipocytes. Pathway analyses implicated adipogenesis, angiogenesis, transcriptional regulation and insulin resistance as processes affecting fat distribution, providing insight into potential pathophysiological mechanisms

Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial.

Importance: Evidence regarding corticosteroid use for severe coronavirus disease 2019 (COVID-19) is limited. Objective: To determine whether hydrocortisone improves outcome for patients with severe COVID-19. Design, Setting, and Participants: An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020. Interventions: The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108). Main Outcomes and Measures: The primary end point was organ support-free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned -1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%). Results: After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support-free days were 0 (IQR, -1 to 15), 0 (IQR, -1 to 13), and 0 (-1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support-free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively. Conclusions and Relevance: Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support-free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions. Trial Registration: ClinicalTrials.gov Identifier: NCT02735707