A taxonomic study of the Burkholderia cepacia complex : an analysis of genotypic, phenotypic and susceptibility characteristics

The development of novel molecular tools has provided the scientific community with quick, easy, and scientifically sound ways of identifying individual strains belonging to the Burkholderia cepacia complex (Bcc). Bcc strains isolated from the sputum of 44 patients attending the Freeman Hospital Cardiopulmonary Transplant Unit were genotyped using recA PCR-RFLP analysis, and a clonality study performed using PFGE analysis. It was found that B. cenocepacia and B. multivorans were the predominant colonizing strains in these patients, and that infection with the ET-12 epidemic clone was the most prevalent strain amongst B. cenocepacia- infected patients. It was also found that pre-transplant strains remained responsible for post-transplant infections. Phenotypic methods for the identification of Bcc strains and closely related organisms have been difficult to develop. A collection of 493 strains including Burkholderia cepacia (genomovars I- IX), Pseudomonas aeruginosa, and other closely related organisms, were investigated for their abilities to produce a wide range of peptidases, glycosidases, esterases and other miscellaneous enzymes using both chromogenic and fluorogenic substrates. The 312 Bcc strains within the collection were also screened for their capacity to oxidise a number of carbohydrates. The heterogeneous nature of all nine Bcc species was confirmed by this study, as was the close phenotypic relationship of B. cepacia and B. cenocepacia. Some substrates, however, were shown to have some taxonomic utility for the differentiation of species within the Bcc and also for closely related organisms. Metabolic activities that showed diagnostic potential included production of 13-ribosidase, 13-xylosidase and 13-glucosidase, as well as oxidation of cellobiose, maltose and trehalose. Screening for palmitate esterase and a or 13-trypsin production was useful for the differentiation of Pandoraea sp. and Ralstonia picketti respectively. CF infections caused by P. aeruginosa and Bcc strains, are most successfully treated using two or three drug combinations. A number of cell wall-acting antibiotics were tested in combination with the phosphonopeptide alafosfalin for synergistic effects against Bcc and P. aeruginosa strains. Alafosfalin was most effective in combination with ceftazidime against Bcc strains, and in combination with tobramycin and ceftazidime as a triple combination against P. aeruginosa

Creating triple-wins for health, equity and environmental sustainability: elements of good practice based on learning from the INHERIT case studies

This report draws out dimensions of good practice for building this triple-win, based on learning from the INHERIT project’s 15 case studies. In the context of the project, good practice refers to ways that support changing contexts and create conditions to enable behaviour change to reach the triple-win. This report summarises key information for consideration by governmental and non-governmental policy-makers and practitioners planning to work across sectors to achieve the triple-win through behaviour change at every level. INHERIT researchers have focused their evaluations of the 15 INHERIT case studies on implementation, intersectoral cooperation, impacts and cost benefits. The researchers have taken dimensions of good practice from INHERIT research to be those elements that appear to be promising or necessary in the contexts in which the INHERIT cases studies are implemented. The extent to which these elements of good practice can be generalised to other contexts merits consideration in developing future initiatives towards creating synergies across sectors. INHERIT researchers have drawn out lessons learned from information gathered in evaluations about triggers for the initiatives, key elements for implementation, success factors in intersectoral cooperation, what could have been done better, what should be done in the future, and the most important learnings from the evaluation of outcomes, costs and benefits

Effects of control interventions on Clostridium difficile infection in England: an observational study

Background: The control of Clostridium difficile infections is an international clinical challenge. The incidence of C difficile in England declined by roughly 80% after 2006, following the implementation of national control policies; we tested two hypotheses to investigate their role in this decline. First, if C difficile infection declines in England were driven by reductions in use of particular antibiotics, then incidence of C difficile infections caused by resistant isolates should decline faster than that caused by susceptible isolates across multiple genotypes. Second, if C difficile infection declines were driven by improvements in hospital infection control, then transmitted (secondary) cases should decline regardless of susceptibility. Methods: Regional (Oxfordshire and Leeds, UK) and national data for the incidence of C difficile infections and antimicrobial prescribing data (1998–2014) were combined with whole genome sequences from 4045 national and international C difficile isolates. Genotype (multilocus sequence type) and fluoroquinolone susceptibility were determined from whole genome sequences. The incidence of C difficile infections caused by fluoroquinolone-resistant and fluoroquinolone-susceptible isolates was estimated with negative-binomial regression, overall and per genotype. Selection and transmission were investigated with phylogenetic analyses. Findings: National fluoroquinolone and cephalosporin prescribing correlated highly with incidence of C difficile infections (cross-correlations >0·88), by contrast with total antibiotic prescribing (cross-correlations 0·2). Interpretation: Restricting fluoroquinolone prescribing appears to explain the decline in incidence of C difficile infections, above other measures, in Oxfordshire and Leeds, England. Antimicrobial stewardship should be a central component of C difficile infection control programmes

Localized Plasticity in the Streamlined Genomes of Vinyl Chloride Respiring Dehalococcoides

Vinyl chloride (VC) is a human carcinogen and widespread priority pollutant. Here we report the first, to our knowledge, complete genome sequences of microorganisms able to respire VC, Dehalococcoides sp. strains VS and BAV1. Notably, the respective VC reductase encoding genes, vcrAB and bvcAB, were found embedded in distinct genomic islands (GEIs) with different predicted integration sites, suggesting that these genes were acquired horizontally and independently by distinct mechanisms. A comparative analysis that included two previously sequenced Dehalococcoides genomes revealed a contextually conserved core that is interrupted by two high plasticity regions (HPRs) near the Ori. These HPRs contain the majority of GEIs and strain-specific genes identified in the four Dehalococcoides genomes, an elevated number of repeated elements including insertion sequences (IS), as well as 91 of 96 rdhAB, genes that putatively encode terminal reductases in organohalide respiration. Only three core rdhA orthologous groups were identified, and only one of these groups is supported by synteny. The low number of core rdhAB, contrasted with the high rdhAB numbers per genome (up to 36 in strain VS), as well as their colocalization with GEIs and other signatures for horizontal transfer, suggests that niche adaptation via organohalide respiration is a fundamental ecological strategy in Dehalococccoides. This adaptation has been exacted through multiple mechanisms of recombination that are mainly confined within HPRs of an otherwise remarkably stable, syntenic, streamlined genome among the smallest of any free-living microorganism

Creating triple-wins for health, equity and environmental sustainability: elements of good practice based on learning from the INHERIT case studies

This report draws out dimensions of good practice for building this triple-win, based on learning from the INHERIT project’s 15 case studies. In the context of the project, good practice refers to ways that support changing contexts and create conditions to enable behaviour change to reach the triple-win. This report summarises key information for consideration by governmental and non-governmental policy-makers and practitioners planning to work across sectors to achieve the triple-win through behaviour change at every level. INHERIT researchers have focused their evaluations of the 15 INHERIT case studies on implementation, intersectoral cooperation, impacts and cost benefits. The researchers have taken dimensions of good practice from INHERIT research to be those elements that appear to be promising or necessary in the contexts in which the INHERIT cases studies are implemented. The extent to which these elements of good practice can be generalised to other contexts merits consideration in developing future initiatives towards creating synergies across sectors. INHERIT researchers have drawn out lessons learned from information gathered in evaluations about triggers for the initiatives, key elements for implementation, success factors in intersectoral cooperation, what could have been done better, what should be done in the future, and the most important learnings from the evaluation of outcomes, costs and benefits

The genetics of blood pressure regulation and its target organs from association studies in 342,415 individuals

To dissect the genetic architecture of blood pressure and assess effects on target-organ damage, we analyzed 128,272 SNPs from targeted and genome-wide arrays in 201,529 individuals of European ancestry and genotypes from an additional 140,886 individuals were used for validation. We identified 66 blood pressure loci, of which 17 were novel and 15 harbored multiple distinct association signals. The 66 index SNPs were enriched for cis-regulatory elements, particularly in vascular endothelial cells, consistent with a primary role in blood pressure control through modulation of vascular tone across multiple tissues. The 66 index SNPs combined in a risk score showed comparable effects in 64,421 individuals of non-European descent. The 66-SNP blood pressure risk score was significantly associated with target-organ damage in multiple tissues, with minor effects in the kidney. Our findings expand current knowledge of blood pressure pathways and highlight tissues beyond the classic renal system in blood pressure regulation

Genome-wide meta-analysis of 241,258 adults accounting for smoking behaviour identifies novel loci for obesity traits

Few genome-wide association studies (GWAS) account for environmental exposures, like smoking, potentially impacting the overall trait variance when investigating the genetic contribution to obesity-related traits. Here, we use GWAS data from 51,080 current smokers and 190,178 nonsmokers (87% European descent) to identify loci influencing BMI and central adiposity, measured as waist circumference and waist-to-hip ratio both adjusted for BMI. We identify 23 novel genetic loci, and 9 loci with convincing evidence of gene-smoking interaction (GxSMK) on obesity-related traits. We show consistent direction of effect for all identified loci and significance for 18 novel and for 5 interaction loci in an independent study sample. These loci highlight novel biological functions, including response to oxidative stress, addictive behaviour, and regulatory functions emphasizing the importance of accounting for environment in genetic analyses. Our results suggest that tobacco smoking may alter the genetic susceptibility to overall adiposity and body fat distribution.Peer reviewe

Genome-wide association identifies nine common variants associated with fasting proinsulin levels and provides new insights into the pathophysiology of type 2 diabetes.

OBJECTIVE: Proinsulin is a precursor of mature insulin and C-peptide. Higher circulating proinsulin levels are associated with impaired β-cell function, raised glucose levels, insulin resistance, and type 2 diabetes (T2D). Studies of the insulin processing pathway could provide new insights about T2D pathophysiology. RESEARCH DESIGN AND METHODS: We have conducted a meta-analysis of genome-wide association tests of ∼2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and fasting proinsulin levels in 10,701 nondiabetic adults of European ancestry, with follow-up of 23 loci in up to 16,378 individuals, using additive genetic models adjusted for age, sex, fasting insulin, and study-specific covariates. RESULTS: Nine SNPs at eight loci were associated with proinsulin levels (P < 5 × 10(-8)). Two loci (LARP6 and SGSM2) have not been previously related to metabolic traits, one (MADD) has been associated with fasting glucose, one (PCSK1) has been implicated in obesity, and four (TCF7L2, SLC30A8, VPS13C/C2CD4A/B, and ARAP1, formerly CENTD2) increase T2D risk. The proinsulin-raising allele of ARAP1 was associated with a lower fasting glucose (P = 1.7 × 10(-4)), improved β-cell function (P = 1.1 × 10(-5)), and lower risk of T2D (odds ratio 0.88; P = 7.8 × 10(-6)). Notably, PCSK1 encodes the protein prohormone convertase 1/3, the first enzyme in the insulin processing pathway. A genotype score composed of the nine proinsulin-raising alleles was not associated with coronary disease in two large case-control datasets. CONCLUSIONS: We have identified nine genetic variants associated with fasting proinsulin. Our findings illuminate the biology underlying glucose homeostasis and T2D development in humans and argue against a direct role of proinsulin in coronary artery disease pathogenesis

The prevalence of metabolic syndrome and metabolically healthy obesity in Europe: a collaborative analysis of ten large cohort studies

Peer reviewe

Finishing the euchromatic sequence of the human genome

The sequence of the human genome encodes the genetic instructions for human physiology, as well as rich information about human evolution. In 2001, the International Human Genome Sequencing Consortium reported a draft sequence of the euchromatic portion of the human genome. Since then, the international collaboration has worked to convert this draft into a genome sequence with high accuracy and nearly complete coverage. Here, we report the result of this finishing process. The current genome sequence (Build 35) contains 2.85 billion nucleotides interrupted by only 341 gaps. It covers ∼99% of the euchromatic genome and is accurate to an error rate of ∼1 event per 100,000 bases. Many of the remaining euchromatic gaps are associated with segmental duplications and will require focused work with new methods. The near-complete sequence, the first for a vertebrate, greatly improves the precision of biological analyses of the human genome including studies of gene number, birth and death. Notably, the human enome seems to encode only 20,000-25,000 protein-coding genes. The genome sequence reported here should serve as a firm foundation for biomedical research in the decades ahead