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Even in the setting of optimal resuscitation in high-income countries severe sepsis and septic shock have a mortality of 20-40%, with antibiotic resistance dramatically increasing this mortality risk. To develop a reference dataset enabling the identification of common bacterial targets for therapeutic intervention, we applied a standardized genomic, transcriptomic, proteomic and metabolomic technological framework to multiple clinical isolates of four sepsis-causing pathogens: Escherichia coli, Klebsiella pneumoniae species complex, Staphylococcus aureus and Streptococcus pyogenes. Exposure to human serum generated a sepsis molecular signature containing global increases in fatty acid and lipid biosynthesis and metabolism, consistent with cell envelope remodelling and nutrient adaptation for osmoprotection. In addition, acquisition of cholesterol was identified across the bacterial species. This detailed reference dataset has been established as an open resource to support discovery and translational research.

Despite the importance of encapsulation in bacterial pathogenesis, the biochemical mechanisms and forces that underpin retention of capsule by encapsulated bacteria are poorly understood. In Gram-negative bacteria, there may be interactions between lipopolysaccharide (LPS) core and capsule polymers, between capsule polymers with retained acyl carriers and the outer membrane, and in some bacteria, between the capsule polymers and Wzi, an outer membrane protein lectin. Our transposon studies in Klebsiella pneumoniae B5055 identified additional genes that, when insertionally inactivated, resulted in reduced encapsulation. Inactivation of the gene waaL, which encodes the ligase responsible for attaching the repeated O antigen of LPS to the LPS core, resulted in a significant reduction in capsule retention, measured by atomic force microscopy. This reduction in encapsulation was associated with increased sensitivity to human serum and decreased virulence in a murine model of respiratory infection and, paradoxically, with increased biofilm formation. The capsule in the WaaL mutant was physically smaller than that of the Wzi mutant of K. pneumoniae B5055. These results suggest that interactions between surface carbohydrate polymers may enhance encapsulation, a key phenotype in bacterial virulence, and provide another target for the development of antimicrobials that may avoid resistance issues associated with growth inhibition. IMPORTANCE Bacterial capsules, typically comprised of complex sugars, enable pathogens to avoid key host responses to infection, including phagocytosis. These capsules are synthesized within the bacteria, exported through the outer envelope, and then secured to the external surface of the organism by a force or forces that are incompletely described. This study shows that in the important hospital pathogen Klebsiella pneumoniae, the polysaccharide capsule is retained by interactions with other surface sugars, especially the repeated sugar molecule o

BACKGROUND: Typhoid fever is endemic in some Pacific Island Countries including Fiji and Samoa yet genomic surveillance is not routine in such settings. Previous studies suggested imports of the global H58 clade of Salmonella enterica var Typhi (Salmonella Typhi) contribute to disease in these countries which, given the MDR potential of H58, does not auger well for treatment. The objective of the study was to define the genomic epidemiology of Salmonella Typhi in Fiji. METHODS: Genomic sequencing approaches were implemented to study the distribution of 255 Salmonella Typhi isolates from the Central Division of Fiji. We augmented epidemiological surveillance and Bayesian phylogenomic approaches with a multi-year typhoid case-control study to define geospatial patterns among typhoid cases. FINDINGS: Genomic analyses showed Salmonella Typhi from Fiji resolved into 2 non-H58 genotypes with isolates from the two dominant ethnic groups, the Indigenous (iTaukei) and non-iTaukei genetically indistinguishable. Low rates of international importation of clones was observed and overall, there were very low levels an antibiotic resistance within the endemic Fijian typhoid genotypes. Genomic epidemiological investigations were able to identify previously unlinked case clusters. Bayesian phylodynamic analyses suggested that genomic variation within the larger endemic Salmonella Typhi genotype expanded at discreet times, then contracted. INTERPRETATION: Cyclones and flooding drove 'waves' of typhoid outbreaks in Fiji which, through population aggregation, poor sanitation and water safety, and then mobility of the population, spread clones more widely. Minimal international importations of new typhoid clones suggest that targeted local intervention strategies may be useful in controlling endemic typhoid infection. These findings add to our understanding of typhoid transmission networks in an endemic island country with broad implications, particularly across Pacific Island Countries

Early-age thermal cracking and delayed ettringite formation (DEF) are short-term and long-term major issues to the durability of mass concrete and require a high level of consideration in the development of a suitable concrete mix design in placement and curing strategies, particularly in mixes of high cement content. Where DEF risk proves to be significant, contractors are required to adopt risk mitigation strategies including lowering concrete's temperature during placement by adding cool water or ice, for example, to the mix, embedding cooling pipes in the cast element and/or sequential placement of the concrete. These strategies can be implemented at different levels, as needed, to minimise the risk of cracking and DEF. Determining the most suitable and cost-efficient risk mitigation strategy, however, together with its implementation, is a complex task that requires consideration of each complex strategy under project-specific conditions. While a significant research effort has been invested to develop an improved understanding of the effectiveness of different early age thermal cracking and DEF risk mitigation strategies, the lack of reliable models capable of simulating and comparing the effectiveness of all scenarios remains elusive and considerably limits the ability of the practitioners in identifying the optimal approach. This paper presents a Multiphysics model developed to predict the effect of early-age thermal cracking and DEF risk mitigation scenarios. The model is validated using four real-life project Case Studies and is demonstrated to provide reliable results. In addition, the paper studies the comparative effectiveness of key risk mitigation strategies and the important parameters influencing their effectiveness.

Early-age thermal cracking and delayed ettringite formation (DEF) are major durability risks associated with mass concrete casting with high cement content. Among various strategies to mitigate the risk of early-age thermal cracking and DEF, concrete mix optimisation is favoured by the industry due to its minimal required operational adjustments and insignificant implementation cost. The existing concrete mix design optimization methods are, however, incapable of accounting for the risk of early-age thermal cracking and DEF; and have been designed solely to meet the mechanical performance targets. Mitigating the risk of DEF could be challenging mainly because limiting the temperature rise in concrete requires moderating the hydration heat/rate to minimize the risk of early-age thermal cracking and DEF which could contradict the traditional objectives associated with the concrete's mechanical performance. Further, early-age thermal cracking can be influenced by project-specific factors including the dimensions of the concrete element, ambient conditions, and external restraints which do not come into the picture in a conventional mix design approach. These issues add to the complexity of the mix design problem. This paper presents a mix design approach based on integrated numerical simulation of heat transfer in concrete and genetic algorithm optimisation that minimises the risk of early-age cracking within the limits specified for the mechanical performance of concrete. The results of the optimization framework applied to three case studies show a significant decrease in peak temperature, as well as the ratio of induced tensile stresses to developed tensile strength for optimized concrete mixes.

Background Demoralisation syndrome (DS) has been advanced as a construct that features hopelessness, meaninglessness, and existential distress. Demoralisation and DS have predominantly been considered secondary only to illness; hence there is scant research on demoralisation or DS in populations affected by extreme environmental stress. Aims The current study aimed to determine the prevalence of demoralisation, its predictors, and the relevance of DS in a community-based forced-migrant population. Method A convenience sample of 131 adult asylum-seekers (n = 98) and refugees (n = 33) without recognised mental disorders in Melbourne, Australia, were assessed cross-sectionally on posttraumatic stress, anxiety, depression, post-migration stress, and demoralisation. Socio-demographic data were analysed with relevant clinical data. Predictive aims were investigated using bivariate statistical tests and exploratory aims were investigated using correlational and linear regression analyses. Results Seventy nine percent of the sample met criteria for demoralisation (asylum-seekers = 83%; refugees = 66%), with asylum-seekers being 2.55 (95% C.I. = 1.03-6.32, Z = 2.03, p =.04) times more likely to be demoralised than refugees. No relationship between demoralisation and time in the refugee determination process emerged. The regression model explained 47.5% of variance in demoralisation scores for the total sample F(9,111) = 13.07, p <.0001, with MDD and anxiety score making unique significant contributions. Conclusions Demoralisation was widespread through the asylum-seeker and refugee population and its prevalence was attributable to a range of social and psychiatric factors. However, DS had little explanatory power for psychiatric morbidity, which was more suggestive of a pan-distress symptom complex.Copyright © 2015 Elsevier Inc. All rights reserved.

© 2015, American Society for Microbiology. The evolution of pathogenic bacteria is a multifaceted and complex process, which is strongly influenced by the horizontal acquisition of genetic elements and their subsequent expression in their new hosts. A well-studied example is the RegA regulon of the enteric pathogen Citrobacter rodentium. The RegA regulatory protein is a member of the AraC/XylS superfamily, which coordinates the expression of a gene repertoire that is necessary for full pathogenicity of this murine pathogen. Upon stimulation by an exogenous, gut-associated signal, namely, bicarbonate ions, RegA activates the expression of a series of genes, including virulence factors, such as autotransporters, fimbriae, a dispersin-like protein, and the grlRA operon on the locus of enterocyte effacement pathogenicity island. Interestingly, the genes encoding RegA homologues are distributed across the genus Escherichia, encompassing pathogenic and nonpathogenic subtypes. In this study, we carried out a series of bioinformatic, transcriptional, and functional analyses of the RegA regulons of these bacteria. Our results demonstrated that regA has been horizontally transferred to Escherichia spp. and C. rodentium. Comparative studies of two RegA homologues, namely, those from C. rodentium and E. coli SMS-3-5, a multiresistant environmental strain of E. coli, showed that the two regulators acted similarly in vitro but differed in terms of their abilities to activate the virulence of C. rodentium in vivo, which evidently was due to their differential activation of grlRA. Our data indicate that RegA from C. rodentium has strain-specific adaptations that facilitate infection of its murine host. These findings shed new light on the development of virulence by C. rodentium and on the evolution of virulence- regulatory genes of bacterial pathogens in general.

The fragile X-associated tremor/ataxia syndrome (FXTAS) is a late-onset neurodegenerative disorder affecting a subset of carriers of the FMR1 (fragile X mental retardation 1) premutation. Penetrance and expression appear to be significantly higher in males than females. Although the most obvious aspect of the phenotype is the movement disorder that gives FXTAS its name, the disorder is also accompanied by progressive cognitive impairment. In this review, we address the cognitive neuropsychological and neurophysiological phenotype for males and females with FXTAS, and for male and female unaffected carriers. Despite differences in penetrance and expression, the cognitive features of the disorder appear similar for both genders, with impairment of executive functioning, working memory, and information processing the most prominent. Deficits in these functional systems may be largely responsible for impairment on other measures, including tests of general intelligence and declarative learning. FXTAS is to a large extent a white matter disease, and the cognitive phenotypes observed are consistent with what some have described as white matter dementia, in contrast to the impaired cortical functioning more characteristic of Alzheimer's disease and related disorders. Although some degree of impaired executive functioning appears to be ubiquitous among persons with FXTAS, the data suggest that only a subset of unaffected carriers of the premutation - both female and male - demonstrate such deficits, which typically are mild. The best-studied phenotype is that of males with FXTAS. The manifestations of cognitive impairment among asymptomatic male carriers, and among women with and without FXTAS, are less well understood, but have come under increased scrutiny.