Co-circulation of Multidrug-resistant Shigella Among Men Who Have Sex With Men in Australia.

BACKGROUND: In urban Australia, the burden of shigellosis is either in returning travelers from shigellosis-endemic regions or in men who have sex with men (MSM). Here, we combine genomic data with comprehensive epidemiological data on sexual exposure and travel to describe the spread of multidrug-resistant Shigella lineages. METHODS: A population-level study of all cultured Shigella isolates in the state of Victoria, Australia, was undertaken from 1 January 2016 through 31 March 2018. Antimicrobial susceptibility testing, whole-genome sequencing, and bioinformatic analyses of 545 Shigella isolates were performed at the Microbiological Diagnostic Unit Public Health Laboratory. Risk factor data on travel and sexual exposure were collected through enhanced surveillance forms or by interviews. RESULTS: Rates of antimicrobial resistance were high, with 17.6% (95/541) and 50.6% (274/541) resistance to ciprofloxacin and azithromycin, respectively. There were strong associations between antimicrobial resistance, phylogeny, and epidemiology. Specifically, 2 major MSM-associated lineages were identified: a Shigellasonnei lineage (n = 159) and a Shigella flexneri 2a lineage (n = 105). Of concern, 147/159 (92.4%) of isolates within the S. sonnei MSM-associated lineage harbored mutations associated with reduced susceptibility to recommended oral antimicrobials: namely, azithromycin, trimethoprim-sulfamethoxazole, and ciprofloxacin. Long-read sequencing demonstrated global dissemination of multidrug-resistant plasmids across Shigella species and lineages, but predominantly associated with MSM isolates. CONCLUSIONS: Our contemporary data highlight the ongoing public health threat posed by resistant Shigella, both in Australia and globally. Urgent multidisciplinary public health measures are required to interrupt transmission and prevent infection

Systemic inflammatory response predicts outcome in patients undergoing resection for ductal adenocarcinoma head of pancreas

The aim of the present study was to examine the relationship between the clinicopathological status, the pre- and postoperative systemic inflammatory response and survival in patients undergoing potentially curative resection for ductal adenocarcinoma of the head of the pancreas. Patients (n=65) who underwent resection of ductal adenocarcinoma of the head of pancreas between 1993 and 2001, and had pre- and postoperative measurements of C-reactive protein, were included in the study. The majority of patients had stage III disease (International Union Against Cancer Criteria, IUCC), positive circumferential margin involvement (R1), tumour size greater than 25 mm with perineural and lymph node invasion and died within the follow-up period. On multivariate analysis, tumour size (hazard ratio (HR) 2.10, 95% confidence interval (CI) 1.20–3.68, P=0.009), vascular invasion (HR 2.58, 95% CI 1.48–4.50, P<0.001) and postoperative C-reactive protein (HR 2.00, 95% CI 1.14–3.52, P=0.015) retained independent significance. Those patients with a postoperative C-reactive protein ⩽10 mg l−1 had a median survival of 21.5 months compared with 8.4 months in those patients with a C-reactive protein >10 mg l−1 (P<0.001). The results of the present study indicate that, in patients who have undergone potentially curative resection for ductal adenocarcinoma of the head of pancreas, the presence of a systemic inflammatory response predicts poor outcome

Burkholderia lata Infections from Intrinsically Contaminated Chlorhexidine Mouthwash, Australia, 2016

"Emerging Infectious Diseases is an open access journal in the public domain"Burkholderia lata was isolated from 8 intensive care patients at 2 tertiary hospitals in Australia. Whole-genome sequencing demonstrated that clinical and environmental isolates originated from a batch of contaminated commercial chlorhexidine mouthwash. Genomic analysis identified efflux pump–encoding genes as potential facilitators of bacterial persistence within this biocide

Unstable chromosome rearrangements in Staphylococcus aureus cause phenotype switching associated with persistent infections

Staphylococcus aureus small-colony variants (SCVs) are associated with unusually chronic and persistent infections despite active antibiotic treatment. The molecular basis for this clinically important phenomenon is poorly understood, hampered by the instability of the SCV phenotype. Here we investigated the genetic basis for an unstable S. aureus SCV that arose spontaneously while studying rifampicin resistance. This SCV showed no nucleotide differences across its genome compared with a normal-colony variant (NCV) revertant, yet the SCV presented the hallmarks of S. aureus linked to persistent infection: down-regulation of virulence genes and reduced hemolysis and neutrophil chemotaxis, while exhibiting increased survival in blood and ability to invade host cells. Further genome analysis revealed chromosome structural variation uniquely associated with the SCV. These variations included an asymmetric inversion across half of the S. aureus chromosome via recombination between type I restriction modification system (T1RMS) genes, and the activation of a conserved prophage harboring the immune evasion cluster (IEC). Phenotypic reversion to the wild-type–like NCV state correlated with reversal of the chromosomal inversion (CI) and with prophage stabilization. Further analysis of 29 complete S. aureus genomes showed strong signatures of recombination between hsdMS genes, suggesting that analogous CI has repeatedly occurred during S. aureus evolution. Using qPCR and long-read amplicon deep sequencing, we detected subpopulations with T1RMS rearrangements causing CIs and prophage activation across major S. aureus lineages. Here, we have discovered a previously unrecognized and widespread mechanism of reversible genomic instability in S. aureus associated with SCV generation and persistent infections.A.H. is supported by the H2020-MSCA-Global Fellowship (Grant 657766). Doherty Applied Microbial Genomics is funded by the Department of Microbiology and Immunology at The University of Melbourn

Intestinal fatty-acid binding protein and gut permeability responses to exercise

Purpose Intestinal cell damage due to physiological stressors (e.g. heat, oxidative, hypoperfusion/ischaemic) may contribute to increased intestinal permeability. The aim of this study was to assess changes in plasma intestinal fatty acid-binding protein (I-FABP) in response to exercise (with bovine colostrum supplementation, Col, positive control) and compare this to intestinal barrier integrity/permeability (5 h urinary lactulose/rhamnose ratio, L/R). Methods In a double-blind, placebo-controlled, crossover design, 18 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac). For each arm participants performed two baseline (resting) intestinal permeability assessments (L/R) pre-supplementation and one post-exercise following supplementation. Blood samples were collected pre- and post-exercise to determine I-FABP concentration. Results Two-way repeated measures ANOVA revealed an arm?×?time interaction for L/R and I-FABP (P?<?0.001). Post hoc analyses showed urinary L/R increased post-exercise in Plac (273% of pre, P?<?0.001) and Col (148% of pre, P?<?0.001) with post-exercise values significantly lower with Col (P?<?0.001). Plasma I-FABP increased post-exercise in Plac (191% of pre-exercise, P?=?0.002) but not in the Col arm (107%, P?=?0.862) with post-exercise values significantly lower with Col (P?=?0.013). Correlations between the increase in I-FABP and L/R were evident for visit one (P?=?0.044) but not visit two (P?=?0.200) although overall plots/patterns do appear similar for each. Conclusion These findings suggest that exercise-induced intestinal cellular damage/injury is partly implicated in changes in permeability but other factors must also contribute

The effect of bovine colostrum supplementation on intestinal injury and circulating intestinal bacterial DNA following exercise in the heat

Purpose Exercise-induced changes in intestinal permeability are exacerbated in the heat. The aim of this study was to determine the effect of 14 days of bovine colostrum (Col) supplementation on intestinal cell damage (plasma intestinal fatty acid-binding protein, I-FABP) and bacterial translocation (plasma bacterial DNA) following exercise in the heat. Methods In a double-blind, placebo-controlled, crossover design, 12 males completed two experimental arms (14 days of 20 g/day supplementation with Col or placebo, Plac) consisting of 60 min treadmill running at 70% maximal aerobic capacity (30 ??C, 60% relative humidity). Blood samples were collected pre-exercise (Pre-Ex), post-exercise (Post-Ex) and 1 h post-exercise (1 h Post-Ex) to determine plasma I-FABP concentration, and bacterial DNA (for an abundant gut species, Bacteroides). Results Two-way repeated measures ANOVA revealed an arm ?~ time interaction for I-FABP (P = 0.005, with greater Post- Ex increase in Plac than Col, P = 0.01: Plac 407 ?} 194% of Pre-Ex vs Col, 311 ?} 134%) and 1 h Post-Ex (P = 0.036: Plac 265 ?} 80% of Pre-Ex vs Col, 229 ?} 56%). There was no interaction (P = 0.904) but there was a main effect of arm (P = 0.046) for plasma Bacteroides/total bacterial DNA, with lower overall levels evident in Col. Conclusion This is the first investigation to demonstrate that Col can be effective at reducing intestinal injury following exercise in the heat, but exercise responses (temporal pattern) of bacterial DNA were not influenced by Col (although overall levels may be lower).publishersversionPeer reviewe

Perceptual Rivalry: Reflexes Reveal the Gradual Nature of Visual Awareness

Rivalry is a common tool to probe visual awareness: a constant physical stimulus evokes multiple, distinct perceptual interpretations (“percepts”) that alternate over time. Percepts are typically described as mutually exclusive, suggesting that a discrete (all-or-none) process underlies changes in visual awareness. Here we follow two strategies to address whether rivalry is an all-or-none process: first, we introduce two reflexes as objective measures of rivalry, pupil dilation and optokinetic nystagmus (OKN); second, we use a continuous input device (analog joystick) to allow observers a gradual subjective report. We find that the “reflexes” reflect the percept rather than the physical stimulus. Both reflexes show a gradual dependence on the time relative to perceptual transitions. Similarly, observers' joystick deflections, which are highly correlated with the reflex measures, indicate gradual transitions. Physically simulating wave-like transitions between percepts suggest piece-meal rivalry (i.e., different regions of space belonging to distinct percepts) as one possible explanation for the gradual transitions. Furthermore, the reflexes show that dominance durations depend on whether or not the percept is actively reported. In addition, reflexes respond to transitions with shorter latencies than the subjective report and show an abundance of short dominance durations. This failure to report fast changes in dominance may result from limited access of introspection to rivalry dynamics. In sum, reflexes reveal that rivalry is a gradual process, rivalry's dynamics is modulated by the required action (response mode), and that rapid transitions in perceptual dominance can slip away from awareness

The Cysteine Protease α-Clostripain is Not Essential for the Pathogenesis of Clostridium perfringens-Mediated Myonecrosis

Clostridium perfringens is the causative agent of clostridial myonecrosis or gas gangrene and produces many different extracellular toxins and enzymes, including the cysteine protease α-clostripain. Mutation of the α-clostripain structural gene, ccp, alters the turnover of secreted extracellular proteins in C. perfringens, but the role of α-clostripain in disease pathogenesis is not known. We insertionally inactivated the ccp gene C. perfringens strain 13 using TargeTron technology, constructing a strain that was no longer proteolytic on skim milk agar. Quantitative protease assays confirmed the absence of extracellular protease activity, which was restored by complementation with the wild-type ccp gene. The role of α-clostripain in virulence was assessed by analysing the isogenic wild-type, mutant and complemented strains in a mouse myonecrosis model. The results showed that although α-clostripain was the major extracellular protease, mutation of the ccp gene did not alter either the progression or the development of disease. These results do not rule out the possibility that this extracellular enzyme may still have a role in the early stages of the disease process

Prognostic model to predict postoperative acute kidney injury in patients undergoing major gastrointestinal surgery based on a national prospective observational cohort study.

Background: Acute illness, existing co-morbidities and surgical stress response can all contribute to postoperative acute kidney injury (AKI) in patients undergoing major gastrointestinal surgery. The aim of this study was prospectively to develop a pragmatic prognostic model to stratify patients according to risk of developing AKI after major gastrointestinal surgery. Methods: This prospective multicentre cohort study included consecutive adults undergoing elective or emergency gastrointestinal resection, liver resection or stoma reversal in 2-week blocks over a continuous 3-month period. The primary outcome was the rate of AKI within 7 days of surgery. Bootstrap stability was used to select clinically plausible risk factors into the model. Internal model validation was carried out by bootstrap validation. Results: A total of 4544 patients were included across 173 centres in the UK and Ireland. The overall rate of AKI was 14·2 per cent (646 of 4544) and the 30-day mortality rate was 1·8 per cent (84 of 4544). Stage 1 AKI was significantly associated with 30-day mortality (unadjusted odds ratio 7·61, 95 per cent c.i. 4·49 to 12·90; P < 0·001), with increasing odds of death with each AKI stage. Six variables were selected for inclusion in the prognostic model: age, sex, ASA grade, preoperative estimated glomerular filtration rate, planned open surgery and preoperative use of either an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Internal validation demonstrated good model discrimination (c-statistic 0·65). Discussion: Following major gastrointestinal surgery, AKI occurred in one in seven patients. This preoperative prognostic model identified patients at high risk of postoperative AKI. Validation in an independent data set is required to ensure generalizability