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IntroductionSepsis is a complex immunological response to infection characterized by early hyper-inflammation followed by severe and protracted immunosuppression, suggesting that a multi-marker approach has the greatest clinical utility for early detection, within a clinical environment focused on Systemic Inflammatory Response Syndrome (SIRS) differentiation. Pre-clinical research using an equine sepsis model identified a panel of gene expression biomarkers that define the early aberrant immune activation. Thus, the primary objective was to apply these gene expression biomarkers to distinguish patients with sepsis from those who had undergone major open surgery and had clinical outcomes consistent with systemic inflammation due to physical trauma and wound healing.MethodsThis was a multi-centre, prospective clinical trial conducted across four tertiary critical care settings in Australia. Sepsis patients were recruited if they met the 1992 Consensus Statement criteria and had clinical evidence of systemic infection based on microbiology diagnoses (n = 27). Participants in the post-surgical (PS) group were recruited pre-operatively and blood samples collected within 24 hours following surgery (n = 38). Healthy controls (HC) included hospital staff with no known concurrent illnesses (n = 20). Each participant had minimally 5 ml of PAXgene blood collected for leucocyte RNA isolation and gene expression analyses. Affymetrix array and multiplex tandem (MT)-PCR studies were conducted to evaluate transcriptional profiles in circulating white blood cells applying a set of 42 molecular markers that had been identified a priori. A LogitBoost algorithm was used to create a machine learning diagnostic rule to predict sepsis outcomes.ResultsBased on preliminary microarray analyses comparing HC and sepsis groups, a panel of 42-gene expression markers were identified that represented key innate and adaptive immune function, cell cycling, WBC differentiation, extracellular remodelling and immune modulation pathways. Comparisons against GEO data confirmed the definitive separation of the sepsis cohort. Quantitative PCR results suggest the capacity for this test to differentiate severe systemic inflammation from HC is 92%. The area under the curve (AUC) receiver operator characteristics (ROC) curve findings demonstrated sepsis prediction within a mixed inflammatory population, was between 86 and 92%.ConclusionsThis novel molecular biomarker test has a clinically relevant sensitivity and specificity profile, and has the capacity for early detection of sepsis via the monitoring of critical care patients.

Although the global deleterious impact of antibiotics on the intestinal microbiota is well known, temporal changes in microbial diversity during and after an antibiotic treatment are still poorly characterized. We used plasma and fecal samples collected frequently during treatment and up to one month after from 22 healthy volunteers assigned to a 5-day treatment by moxifloxacin (n = 14) or no intervention (n = 8). Moxifloxacin concentrations were measured in both plasma and feces, and bacterial diversity was determined in feces by 16S rRNA gene profiling and quantified using the Shannon index and number of operational taxonomic units (OTUs). Nonlinear mixed effect models were used to relate drug pharmacokinetics and bacterial diversity over time. Moxifloxacin reduced bacterial diversity in a concentration-dependent manner, with a median maximal loss of 27.5% of the Shannon index (minimum [min], 17.5; maximum [max], 27.7) and 47.4% of the number of OTUs (min, 30.4; max, 48.3). As a consequence of both the long fecal half-life of moxifloxacin and the susceptibility of the gut microbiota to moxifloxacin, bacterial diversity indices did not return to their pretreatment levels until days 16 and 21, respectively. Finally, the model characterized the effect of moxifloxacin on bacterial diversity biomarkers and provides a novel framework for analyzing antibiotic effects on the intestinal microbiome.

No correlation was identified between vincristine clearance, vincristine neurotoxicity, age, sex or concomitant steroid therapy. The limited sampling methodology proved acceptable to patients and families and would be suitable for larger scale studies including a wider range of genotypic variants and more detailed prospective evaluation of neurotoxicity.

PurposeThe purpose of this paper is to investigate factors affecting Vietnamese farmer's intention toward organic agricultural production based on research model integrating theories: theory of planned behavior (TPB) and norm activation model (NAM).Design/methodology/approachAfter in-depth interviews with 5 agricultural researchers and 5 farmers, the authors determined the official research model and built a complete survey. Data were collected from 318 farmers in the Hanoi, Vietnam by directly survey. Statistical methods, such as Cronbach's alpha analysis, exploratory factor analysis (EFA), confirmatory factor analysis (CFA) and structural equation modeling (SEM), were used to analyze the data.FindingsThis paper shows that attitude, subjective norms, perceived behavioral control and personal norm were significantly related to intention of the farmers; awareness of consequences was positively related to ascription of responsibility, personal norm, attitude and subjective norms; ascription of responsibility has a positive relationship with personal norm. The TPB-NAM integration model is proven to be superior to the original TPB model when studying factors affecting Vietnamese farmer's intention toward organic agricultural production.Research limitations/implicationsThe main limitation of this paper is that the sampling method is not representative for the whole country and just stops at researching the intentions of farmers without understanding the practices of organic agricultural production.Practical implicationsThe findings indicate that state management agencies in Vietnam need to pay attention to raise awareness among farmers about the role of organic farming, communicate to farmers through different channels about the benefits of organic farming compared to conventional agriculture and form information spillover groups between farmers who have produced organic agriculture and have not yet produced organic agriculture.Originality/valueThis paper contributes to the existing literature by focusing on integrating TPB and NAM when understanding farmers' intention toward organic agricultural production in Vietnam. This integrated model has proven the suitability of combining two approaches, a rational approach and an ethical approach, when studying farmer intentions.

We assessed in a piglet model the relationship between fecal ciprofloxacin concentrations and ciprofloxacin-resistant Enterobacteriaceae counts. Twenty-nine piglets were orally treated with placebo or with 1.5 or 15 mg ciprofloxacin/kg of body weight/day from day 1 (D1) to D5. Areas under the curve (AUC) of concentrations increased sharply with dose and correlated positively with AUC of resistant bacteria log counts between D1 and D9. Removing residual colonic quinolones could help to control the emergence of resistance in fecal flora. Increasing resistance to fluoroquinolones in Gram-negative bacilli is of major concern, because it compromises their therapeutic use (6, 7). Colonic flora is the reservoir of many of the Enterobacteriaceae species with clinical significance (2) which are exposed to antibiotic residues during fluoroquinolone treatments (9). It has been shown that administration of enrofloxacin, a fluoroquinolone used in animals, could promote the emergence of quinolone-resistant enterobacteria in fecal flora of pigs (12). We also found that administration of oral ciprofloxacin is associated with the emergence of quinolone-resistant strains of Enterobacteriaceae in fecal flora from human volunteers (3). However, rates of emergence of resistance were not significantly different even though the volunteers were exposed to different antibiotic dosages. Of note, detection of resistance was only qualitative in that study, i.e., absence versus presence of detectable resistant bacteria, and not quantitative, expressing the densities of resistant bacteria in the feces. Indeed, several lines of evidence suggest that quantitative aspects of emergence of resistance should also be analyzed. For instance, in neutropenic patients, Gram-negative bacillus bacteremias are caused by the predominant fecal clone of this type (11). Also, the density of a given Escherichia coli strain in a subject's fecal flora can influence to some extent its ability to cause urinary tract infection (8). In order to explore further the dynamics of fluoroquinolone resistance in the fecal flora during treatments, we assessed here in a prospective randomized study in piglets the relationship between fecal concentrations of ciprofloxacin and amounts of excreted ciprofloxacin-resistant Enterobacteriaceae.Twenty-nine piglets from a single farm were included 4 weeks after birth. They were born from sows that were treated at the time of parturition with 2 g oxytetracycline given intramuscularly but had not received directly any antimicrobials. Piglets were housed in individual boxes for 21 days before the start of treatment (day 1 [D1]) and were randomly assigned to oral treatment with placebo (9 piglets), 1.5 mg ciprofloxacin/kg of body weight/day (10 piglets), or 15 mg ciprofloxacin/kg/day (10 piglets) from D1 to D5. Ciprofloxacin suspension (Ciflox; Bayer) or mineral water (placebo group) was administered once a day at least 4 h before food to animals fasted for at least 12 h. The protocol was approved by the local ethical committee.Fecal sam...

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Fecal excretion of antibiotics and resistant bacteria in the environment are major public health threats associated with extensive farming and modern medical care. Innovative strategies that can reduce the intestinal antibiotic concentrations during treatments are in development. However, the effect of lower exposure on the amount of resistant enterobacteria excreted has not been quantified, making it difficult to anticipate the impact of these strategies. Here, we introduce a bacterial kinetic model to capture the complex relationships between drug exposure, loss of susceptible enterobacteria and growth of resistant strains in the feces of piglets receiving placebo, 1.5 or 15 mg/kg/day ciprofloxacin, a fluoroquinolone, for 5 days. The model could well describe the kinetics of drug susceptible and resistant enterobacteria observed during treatment, and up to 22 days after treatment cessation. Next, the model was used to predict the expected amount of resistant enterobacteria excreted over an average piglet's lifetime (150 days) when varying drug exposure and treatment duration. For the clinically relevant dose of 15 mg/kg/day for 5 days, the total amount of resistant enterobacteria excreted was predicted to be reduced by 75% and 98% when reducing treatment duration to 3 and 1 day treatment, respectively. Alternatively, for a fixed 5-days treatment, the level of resistance excreted could be reduced by 18%, 33%, 57.5% and 97% if 3, 5, 10 and 30 times lower levels of colonic drug concentrations were achieved, respectively. This characterization on in vivo data of the dynamics of resistance to antibiotics in the colonic flora could provide new insights into the mechanism of dissemination of resistance and can be used to design strategies aiming to reduce it.