The effects of chlorhexidine, povidone-iodine, and vancomycin on growth and biofilms of pathogens that cause prosthetic joint infections: an in vitro model.

BACKGROUND: Chlorhexidine gluconate (CHG) and povidone-iodine (PI) are commonly used to prevent prosthetic joint infection (PJI) during total joint replacement; however, their effective concentrations and impact on biofilms are not well defined. AIM: To determine: (1) the in vitro minimum inhibitory concentration of CHG and PI against model PJI-causing organisms and clinical isolates; (2) their impact on biofilm formation; (3) if there is a synergistic benefit to combining the two solutions; and (4) if adding the antibiotic vancomycin impacts antiseptic activity. METHODS: We measured in vitro growth and biofilm formation of Staphylococcus epidermidis, methicillin-sensitive and methicillin-resistant S. aureus, Escherichia coli, Pseudomonas aeruginosa, and Candida albicans, as well as recent clinical isolates, in the presence of increasing concentrations of CHG and/or PI. Checkerboard assays were used to measure potential synergy of the solutions together and with vancomycin. FINDINGS: CHG and PI inhibited growth and biofilm formation of all model organisms tested at concentrations of 0.0004% and 0.33% or lower, respectively; highly dilute concentrations paradoxically increased biofilm formation. The solutions did not synergize with one another and acted independently of vancomycin. CONCLUSION: CHG and PI are effective at lower concentrations than typically used, establishing baselines to support further clinical trials aimed at optimizing wound disinfection. There is no synergistic advantage to using both in combination. Vancomycin is effective at inhibiting the growth of S. epidermidis and S. aureus; however, it stimulates P. aeruginosa biofilm production, suggesting in the rare case of P. aeruginosa PJI, it could exacerbate infection.

Trade-offs between risks of predation and starvation in larvae make the shelf break an optimal spawning location for Atlantic bluefin tuna.

Atlantic bluefin tuna (ABT) (Thunnus thynnus) travel long distances to spawn in oligotrophic regions of the Gulf of Mexico (GoM) which suggests these regions offer some unique benefit to offspring survival. To better understand how larval survival varies within the GoM a spatially explicit, Lagrangian, individual-based model was developed that simulates dispersal and mortality of ABT early life stages within realistic predator and prey fields during the spawning periods from 1993 to 2012. The model estimates that starvation is the largest cumulative source of mortality associated with an early critical period. However, elevated predation on older larvae is identified as the main factor limiting survival to late postflexion. As a result, first-feeding larvae have higher survival on the shelf where food is abundant, whereas older larvae have higher survival in the open ocean with fewer predators, making the shelf break an optimal spawning area. The modeling framework developed in this study explicitly simulates both physical and biological factors that impact larval survival and hence could be used to support ecosystem based management efforts for ABT under current and future climate conditions.

Exploration of BAY 11-7082 as a Potential Antibiotic.

Exposure of the Gram-negative pathogen Pseudomonas aeruginosa to subinhibitory concentrations of antibiotics increases the formation of biofilms. We exploited this phenotype to identify molecules with potential antimicrobial activity in a biofilm-based high-throughput screen. The anti-inflammatory compound BAY 11-7082 induced dose-dependent biofilm stimulation, indicative of antibacterial activity. We confirmed that BAY 11-7082 inhibits the growth of P. aeruginosa and other priority pathogens, including methicillin-resistant Staphylococcus aureus (MRSA). We synthesized 27 structural analogues, including a series based on the related scaffold 3-(phenylsulfonyl)-2-pyrazinecarbonitrile (PSPC), 10 of which displayed increased anti-Staphylococcal activity. Because the parent molecule inhibits the NLR Family Pyrin Domain Containing 3 (NLRP3) inflammasome, we measured the ability of select analogues to reduce interleukin-1ß (IL-1ß) production in mammalian macrophages, identifying minor differences in the structure-activity relationship for the anti-inflammatory and antibacterial properties of this scaffold. Although we could evolve stably resistant MRSA mutants with cross-resistance to BAY 11-7082 and PSPC, their lack of shared mutations suggested that the two molecules could have multiple targets. Finally, we showed that BAY 11-7082 and its analogues synergize with penicillin G against MRSA, suggesting that this scaffold may serve as an interesting starting point for the development of antibiotic adjuvants.

How to kill Pseudomonas-emerging therapies for a challenging pathogen.

As the number of effective antibiotics dwindled, antibiotic resistance (AR) became a pressing concern. Some Pseudomonas aeruginosa isolates are resistant to all available antibiotics. In this review, we identify the mechanisms that P. aeruginosa uses to evade antibiotics, including intrinsic, acquired, and adaptive resistance. Our review summarizes many different approaches to overcome resistance. Antimicrobial peptides have potential as therapeutics with low levels of resistance evolution. Rationally designed bacteriophage therapy can circumvent and direct evolution of AR and virulence. Vaccines and monoclonal antibodies are highlighted as immune-based treatments targeting specific P. aeruginosa antigens. This review also identifies promising drug combinations, antivirulence therapies, and considerations for new antipseudomonal discovery. Finally, we provide an update on the clinical pipeline for antipseudomonal therapies and recommend future avenues for research.

The costs of treating vaginal and vulval cancer in England (2009-2015).

BACKGROUND: Human papillomavirus (HPV) infection is a pre-requisite for cervical cancer, which represents the third most common cancer among women worldwide. A causal relationship also exists between HPV and cancer in other areas of the female reproductive system including the vagina and vulva. Whilst the incidence of vaginal cancer in the UK has remained relatively stable over the past 25 years, vulval cancer rates are increasing. A body of literature exists on the epidemiology and aetiology of vaginal and vulval cancer, but little is known about the economic burden. The objective of this study was to quantify the costs of treating these cancers on the National Health Service (NHS) in England. METHODS: Inpatient and outpatient episodes were derived from Hospital Episode Statistics (HES). Health Resource Group (HRG) tariffs and National Reference Costs were used to estimate the cost of treating pre-cancerous and invasive vaginal and vulval lesions in England. RESULTS: The study showed that for the 5 years from 2009/2010 to 2014/2015 the total cost associated with pre-cancerous and invasive vaginal and vulval lesions was over £14 million per year on average (95% of which was attributed to inpatient costs). Vulval cancer accounted for the largest proportion; an estimated 60% of the total cost (£8.82 million). On average 4316 patients per year in England were admitted to hospital and 912 patients attended outpatient settings for pre-cancerous and invasive disease of the vagina and vulva. CONCLUSION: The results indicate that vaginal and vulval cancer cost the English health care system over £14 million per year. Given the causal role of HPV in a proportion of these cancers, preventative measures such as the national HPV immunisation programme have the potential to reduce the economic burden. To ensure optimal use of NHS resources, it is important that future economic evaluations of such preventative measures consider the full burden of HPV related disease.

Bacterial Biogeography across the Amazon River-Ocean Continuum.

Spatial and temporal patterns in microbial biodiversity across the Amazon river-ocean continuum were investigated along ∼675 km of the lower Amazon River mainstem, in the Tapajós River tributary, and in the plume and coastal ocean during low and high river discharge using amplicon sequencing of 16S rRNA genes in whole water and size-fractionated samples (0.2-2.0 µm and >2.0 µm). River communities varied among tributaries, but mainstem communities were spatially homogeneous and tracked seasonal changes in river discharge and co-varying factors. Co-occurrence network analysis identified strongly interconnected river assemblages during high (May) and low (December) discharge periods, and weakly interconnected transitional assemblages in September, suggesting that this system supports two seasonal microbial communities linked to river discharge. In contrast, plume communities showed little seasonal differences and instead varied spatially tracking salinity. However, salinity explained only a small fraction of community variability, and plume communities in blooms of diatom-diazotroph assemblages were strikingly different than those in other high salinity plume samples. This suggests that while salinity physically structures plumes through buoyancy and mixing, the composition of plume-specific communities is controlled by other factors including nutrients, phytoplankton community composition, and dissolved organic matter chemistry. Co-occurrence networks identified interconnected assemblages associated with the highly productive low salinity near-shore region, diatom-diazotroph blooms, and the plume edge region, and weakly interconnected assemblages in high salinity regions. This suggests that the plume supports a transitional community influenced by immigration of ocean bacteria from the plume edge, and by species sorting as these communities adapt to local environmental conditions. Few studies have explored patterns of microbial diversity in tropical rivers and coastal oceans. Comparison of Amazon continuum microbial communities to those from temperate and arctic systems suggest that river discharge and salinity are master variables structuring a range of environmental conditions that control bacterial communities across the river-ocean continuum.

Expression patterns of elemental cycling genes in the Amazon River Plume.

Metatranscriptomics and metagenomics data sets benchmarked with internal standards were used to characterize the expression patterns for biogeochemically relevant bacterial and archaeal genes mediating carbon, nitrogen, phosphorus and sulfur uptake and metabolism through the salinity gradient of the Amazon River Plume. The genes were identified in 48 metatranscriptomic and metagenomic data sets summing to >500 million quality-controlled reads from six locations in the plume ecosystem. The ratio of transcripts per gene copy (a direct measure of expression made possible by internal standard additions) showed that the free-living bacteria and archaea exhibited only small changes in the expression levels of biogeochemically relevant genes through the salinity and nutrient zones of the plume. In contrast, the expression levels of genes in particle-associated cells varied over orders of magnitude among the stations, with the largest differences measured for genes mediating aspects of nitrogen cycling (nifH, amtB and amoA) and phosphorus acquisition (pstC, phoX and phoU). Taxa varied in their baseline gene expression levels and extent of regulation, and most of the spatial variation in the expression level could be attributed to changes in gene regulation after removing the effect of shifting taxonomic composition. We hypothesize that changes in microbial element cycling along the Amazon River Plume are largely driven by shifting activities of particle-associated cells, with most activities peaking in the mesohaline regions where N2 fixation rates are elevated.

Patterns of Transcript Abundance of Eukaryotic Biogeochemically-Relevant Genes in the Amazon River Plume.

The Amazon River has the largest discharge of all rivers on Earth, and its complex plume system fuels a wide array of biogeochemical processes, across a large area of the western tropical North Atlantic. The plume thus stimulates microbial processes affecting carbon sequestration and nutrient cycles at a global scale. Chromosomal gene expression patterns of the 2.0 to 156 µm size-fraction eukaryotic microbial community were investigated in the Amazon River Plume, generating a robust dataset (more than 100 million mRNA sequences) that depicts the metabolic capabilities and interactions among the eukaryotic microbes. Combining classical oceanographic field measurements with metatranscriptomics yielded characterization of the hydrographic conditions simultaneous with a quantification of transcriptional activity and identity of the community. We highlight the patterns of eukaryotic gene expression for 31 biogeochemically significant gene targets hypothesized to be valuable within forecasting models. An advantage to this targeted approach is that the database of reference sequences used to identify the target genes was selectively constructed and highly curated optimizing taxonomic coverage, throughput, and the accuracy of annotations. A coastal diatom bloom highly expressed nitrate transporters and carbonic anhydrase presumably to support high growth rates and enhance uptake of low levels of dissolved nitrate and CO2. Diatom-diazotroph association (DDA: diatoms with nitrogen fixing symbionts) blooms were common when surface salinity was mesohaline and dissolved nitrate concentrations were below detection, and hence did not show evidence of nitrate utilization, suggesting they relied on ammonium transporters to aquire recently fixed nitrogen. These DDA blooms in the outer plume had rapid turnover of the photosystem D1 protein presumably caused by photodegradation under increased light penetration in clearer waters, and increased expression of silicon transporters as silicon became limiting. Expression of these genes, including carbonic anhydrase and transporters for nitrate and phosphate, were found to reflect the physiological status and biogeochemistry of river plume environments. These relatively stable patterns of eukaryotic transcript abundance occurred over modest spatiotemporal scales, with similarity observed in sample duplicates collected up to 2.45 km in space and 120 minutes in time. These results confirm the use of metatranscriptomics as a valuable tool to understand and predict microbial community function.

Sources and Characteristics of Utility Weights for Economic Evaluation of Pediatric Vaccines: A Systematic Review.

BACKGROUND: Cost-effectiveness analysis of pediatric vaccines for infectious diseases often requires quality-of-life (utility) weights. OBJECTIVE: To investigate how utility weights have been elicited and used in this context. METHODS: A systematic review was conducted of studies published between January 1990 and July 2013 that elicited or used utility weights in cost-effectiveness analyses of vaccines for pediatric populations. The review focused on vaccines for 17 infectious diseases and is presented following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology. RESULTS: A total of 6410 titles and abstracts and 225 full-text articles were reviewed. Of those selected for inclusion (n = 101), 15 articles described the elicitation of utility weights and 86 described economic modeling studies using utilities. Various methods were used to generate utilities, including time trade-off, contingent valuation, and willingness to pay, as well as a preference-based measure with associated value sets, such as the EuroQol five-dimensional questionnaire or the Health Utilities Index. In modeling studies, the source of utilities used was often unclear, poorly reported, or based on weak underlying evidence. We found no articles that reported on the elicitation or use of utilities in diphtheria, polio, or tetanus. CONCLUSIONS: The scarcity of appropriate utility weights for vaccine-preventable infectious diseases in children and a lack of standardization in their use in economic assessments limit the ability to accurately assess the benefits associated with interventions to prevent infectious diseases. This is an issue that should be of concern to those making decisions regarding the prevention and treatment of infectious childhood illnesses.

Assessing Patient-Reported Outcomes in Pediatric Populations With Vaccine-Preventable Infectious Diseases: A Systematic Review of the Literature (the PROCHID Study).

OBJECTIVE: To investigate the use of patient-reported outcomes (PROs) in pediatric populations with vaccine-preventable infectious diseases in high-income Western countries. METHODS: Systematic review of PRO use in populations younger than 18 years with any of 17 infectious diseases for which vaccines are available or in development. The search was limited to studies performed in Europe, North America, Australia, and New Zealand and published between January 1, 1990, and July 31, 2013. Searches were conducted in Scopus and PsycINFO, and reference lists were manually searched. Results are reported using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Of 6410 titles and abstracts and 174 full-text articles reviewed, 17 full-text articles were included for data extraction. The largest number of PRO studies was carried out in patients with anogenital warts and rotavirus gastroenteritis. No PRO studies were identified for nine conditions. A total of 24 PRO measures (12 generic and 12 disease-specific) were used in the studies reviewed. Most of the instruments used were of high quality. Proxy responses were occasionally obtained when self-report would have been feasible. No validated disease-specific instruments for children with any of the conditions studied were found. CONCLUSIONS: The paucity of studies and PRO instruments to assess pediatric health status in vaccine-preventable infectious diseases, and the lack of a standardized approach to measurement, makes it difficult to capture the impact of disease and the benefit of vaccination and could potentially hinder decision making. Guidelines from relevant bodies to steer research in this area would be useful.

The association of human papillomavirus vaccination with sexual behaviours and human papillomavirus knowledge: a systematic review.

Since the 2008 introduction of the human papillomavirus (HPV) vaccination programme for adolescent girls in the UK, parents and other groups have expressed fears that immunisation condones sexual activity, promotes promiscuity and encourages risky sexual behaviour. This study aimed to explore whether HPV vaccination programmes have increased knowledge surrounding HPV and associated disease and whether uptake has influenced sexual behaviour. MEDLINE, Embase, Cochrane Library and PsycINFO electronic databases were interrogated. Studies of behaviour, attitudes and knowledge associated with HPV vaccination (or vaccination intent) in subjects of any age and gender in programmes reflective of UK practice were included in the review (n = 58). The evidence regarding the association of HPV vaccination with high-risk sexual behaviour was varied, primarily due to the heterogeneous nature of the included studies. Young females typically exhibited better knowledge than males, and vaccinated respondents (or those with vaccination intent) had higher levels of knowledge than the unvaccinated. However, knowledge surrounding HPV and genital warts was generally poor. This review highlights the need to provide effective education regarding the HPV vaccine and HPV-associated disease to adolescents of vaccination age, nurses, teachers, parents and guardians to ultimately allow informed decisions to be made regarding receipt of the HPV vaccine.

Microspatial gene expression patterns in the Amazon River Plume.

We investigated expression of genes mediating elemental cycling at the microspatial scale in the ocean's largest river plume using, to our knowledge, the first fully quantitative inventory of genes and transcripts. The bacterial and archaeal communities associated with a phytoplankton bloom in Amazon River Plume waters at the outer continental shelf in June 2010 harbored ∼ 1.0 × 10(13) genes and 4.7 × 10(11) transcripts per liter that mapped to several thousand microbial genomes. Genomes from free-living cells were more abundant than those from particle-associated cells, and they generated more transcripts per liter for carbon fixation, heterotrophy, nitrogen and phosphorus uptake, and iron acquisition, although they had lower expression ratios (transcripts ⋅ gene(-1)) overall. Genomes from particle-associated cells contributed more transcripts for sulfur cycling, aromatic compound degradation, and the synthesis of biologically essential vitamins, with an overall twofold up-regulation of expression compared with free-living cells. Quantitatively, gene regulation differences were more important than genome abundance differences in explaining why microenvironment transcriptomes differed. Taxa contributing genomes to both free-living and particle-associated communities had up to 65% of their expressed genes regulated differently between the two, quantifying the extent of transcriptional plasticity in marine microbes in situ. In response to patchiness in carbon, nutrients, and light at the micrometer scale, Amazon Plume microbes regulated the expression of genes relevant to biogeochemical processes at the ecosystem scale.