Jennifer Stephens

Antibiotic treatment patterns across Europe in patients with complicated skin and soft-tissue infections due to meticillin-resistant Staphylococcus aureus: a plea for implementation of early switch and early discharge criteria.

This retrospective observational medical chart review aimed to describe country-specific variations across Europe in real-world meticillin-resistant Staphylococcus aureus (MRSA) complicated skin and soft-tissue infection (cSSTI) treatment patterns, antibiotic stewardship activity, and potential opportunities for early switch (ES) from intravenous (i.v.) to oral formulations and early discharge (ED) from hospital using standardised data collection and criteria and economic implications of these opportunities. Patients were randomly sampled from 12 countries (Austria, Czech Republic, France, Germany, Greece, Ireland, Italy, Poland, Portugal, Slovakia, Spain and the UK), aged ≥18 years, with documented MRSA cSSTI, hospitalised between 1 July 2010 and 30 June 2011, discharged alive by 31 July 2011. Of 1502 patients, 1468 received MRSA-targeted therapy. Intravenous-to-oral switch rates ranged from 2.0% to 20.2%, i.v. length of therapy from 10.1 to 18.6 days and hospital length of stay (LoS) from 15.2 to 25.0 days across Europe. Of 341 sites, 82.9% had antibiotic steering committees, 23.7% had i.v.-to-oral switch antibiotic protocols and 12.9% had ED protocols for MRSA cSSTI. ES and ED eligibility ranged from 12.0% (Slovakia) to 56.3% (Greece) and from 10% (Slovakia) to 48.2% (Portugal), respectively. Potential cost savings per ED-eligible patient ranged from €414 (Slovakia) to €2703 (France). MRSA cSSTI treatment patterns varied widely across countries, but further reductions in i.v. therapy, hospital LoS and associated costs could be realised. These data provide insight into clinical practice patterns across diverse European healthcare systems and identify potential opportunities for local clinicians and policy-makers to improve clinical care and cost-effectiveness of this therapeutic area.

48-Week Efficacy and Safety of Dolutegravir Relative to Commonly Used Third Agents in Treatment-Naive HIV-1–Infected Patients: A Systematic Review and Network Meta-Analysis

Background A network meta-analysis can provide estimates of relative efficacy for treatments not directly studied in head-to-head randomized controlled trials. We estimated the relative efficacy and safety of dolutegravir (DTG) versus third agents currently recommended by guidelines, including ritonavir-boosted atazanavir (ATV/r), ritonavir-boosted darunavir (DRV/r), efavirenz (EFV), cobicistat-boosted elvitegravir (EVG/c), ritonavir-boosted lopinavir (LPV/r), raltegravir (RAL), and rilpivirine (RPV), in treatment-naive HIV-1–infected patients. Methods A systematic review of published literature was conducted to identify phase 3/4 randomized controlled clinical trials (up to August 2013) including at least one third agent of interest in combination with a backbone nucleoside reverse transcriptase inhibitor (NRTI) regimen. Bayesian fixed-effect network meta-analysis models adjusting for the type of nucleoside reverse transcriptase inhibitor backbone (tenofovir disoproxil fumarate/emtricitabine [TDF/FTC] or abacavir/lamivudine [ABC/3TC]) were used to evaluate week 48 efficacy (HIV-RNA suppression to <50 copies/mL and change in CD4+ cells/µL) and safety (lipid changes, adverse events, and discontinuations due to adverse events) of DTG relative to all other treatments. Sensitivity analyses assessing the impact of NRTI treatment adjustment and random-effects models were performed. Results Thirty-one studies including 17,000 patients were combined in the analysis. Adjusting for the effect of NRTI backbone, treatment with DTG resulted in significantly higher odds of virologic suppression (HIV RNA<50 copies/mL) and increase in CD4+ cells/µL versus ATV/r, DRV/r, EFV, LPV/r, and RPV. Dolutegravir had better or equivalent changes in total cholesterol, LDL, triglycerides, and lower odds of adverse events and discontinuation due to adverse events compared to all treatments. Random-effects and unadjusted models resulted in similar conclusions. Conclusion Three clinical trials of DTG have demonstrated comparable or superior efficacy and safety to DRV, RAL, and EFV in HIV-1–infected treatment-naive patients. This network meta-analysis suggests DTG is also favorable or comparable to other commonly used third agents (ATV/r, LPV/r, RPV, and EVG/c).

Syringyl Lignin Is Unaltered by Severe Sinapyl Alcohol Dehydrogenase Suppression in Tobacco

This study identifies cinnamyl alcohol dehydrogenase as the predominant enzyme that catalyzes the final step in S lignin biosynthesis in woody angiosperm xylem and challenges the widely held view that sinapyl alcohol dehydrogenase regulates S lignin biosynthesis in angiosperms. The manipulation of lignin could, in principle, facilitate efficient biofuel production from plant biomass. Despite intensive study of the lignin pathway, uncertainty exists about the enzyme catalyzing the last step in syringyl (S) monolignol biosynthesis, the reduction of sinapaldehyde to sinapyl alcohol. Traditional schemes of the pathway suggested that both guaiacyl (G) and S monolignols are produced by a single substrate-versatile enzyme, cinnamyl alcohol dehydrogenase (CAD). This was challenged by the discovery of a novel sinapyl alcohol dehydrogenase (SAD) that preferentially uses sinapaldehyde as a substrate and that was claimed to regulate S lignin biosynthesis in angiosperms. Consequently, most pathway schemes now show SAD (or SAD and CAD) at the sinapaldehyde reduction step, although functional evidence is lacking. We cloned SAD from tobacco (Nicotiana tabacum) and suppressed it in transgenic plants using RNA interference–inducing vectors. Characterization of lignin in the woody stems shows no change to content, composition, or structure, and S lignin is normal. By contrast, plants additionally suppressed in CAD have changes to lignin structure and S:G ratio and have increased sinapaldehyde in lignin, similar to plants suppressed in CAD alone. These data demonstrate that CAD, not SAD, is the enzyme responsible for S lignin biosynthesis in woody angiosperm xylem.

Reducing Stomatal Density in Barley Improves Drought Tolerance without Impacting on Yield

Manipulation of a gene involved in the suppression of stomatal development in barley can reduce stomatal density, leading to improved drought tolerance without deleterious effects on yield. The epidermal patterning factor (EPF) family of secreted signaling peptides regulate the frequency of stomatal development in model dicot and basal land plant species. Here, we identify and manipulate the expression of a barley (Hordeum vulgare) ortholog and demonstrate that when overexpressed HvEPF1 limits entry to, and progression through, the stomatal development pathway. Despite substantial reductions in leaf gas exchange, barley plants with significantly reduced stomatal density show no reductions in grain yield. In addition, HvEPF1OE barley lines exhibit significantly enhanced water use efficiency, drought tolerance, and soil water conservation properties. Our results demonstrate the potential of manipulating stomatal frequency for the protection and optimization of cereal crop yields under future drier environments.

The Synaptonemal Complex Protein ZYP1 Is Required for Imposition of Meiotic Crossovers in Barley

The number of genetic crossovers during meiosis, and the potential for creating novel variation, is influenced by the ZYP1 protein. When ZYP1 is depleted in Arabidopsis, fewer crossovers occur, whereas in rice, more crossovers have been reported. Here, we show that barley plants with very reduced amounts of ZYP1 make far fewer crossovers, although the localization of crossovers is not affected. In many cereal crops, meiotic crossovers predominantly occur toward the ends of chromosomes and 30 to 50% of genes rarely recombine. This limits the exploitation of genetic variation by plant breeding. Previous reports demonstrate that chiasma frequency can be manipulated in plants by depletion of the synaptonemal complex protein ZIPPER1 (ZYP1) but conflict as to the direction of change, with fewer chiasmata reported in Arabidopsis thaliana and more crossovers reported for rice (Oryza sativa). Here, we use RNA interference (RNAi) to reduce the amount of ZYP1 in barley (Hordeum vulgare) to only 2 to 17% of normal zygotene levels. In the ZYP1RNAi lines, fewer than half of the chromosome pairs formed bivalents at metaphase and many univalents were observed, leading to chromosome nondisjunction and semisterility. The number of chiasmata per cell was reduced from 14 in control plants to three to four in the ZYP1-depleted lines, although the localization of residual chiasmata was not affected. DNA double-strand break formation appeared normal, but the recombination pathway was defective at later stages. A meiotic time course revealed a 12-h delay in prophase I progression to the first labeled tetrads. Barley ZYP1 appears to function similarly to ZIP1/ZYP1 in yeast and Arabidopsis, with an opposite effect on crossover number to ZEP1 in rice, another member of the Poaceae.

Rising United States Hospital Admissions for Acute Bacterial Skin and Skin Structure Infections: Recent Trends and Economic Impact.

Background The number of ambulatory patients seeking treatment for skin and skin structure infections (SSSI) are increasing. The objective of this study is to determine recent trends in hospital admissions and healthcare resource utilization and identify covariates associated with hospital costs and mortality for hospitalized adult patients with a primary SSSI diagnosis in the United States. Methods We performed a retrospective cross-sectional analysis (years 2005–2011) of data from the US Healthcare Cost and Utilization Project National Inpatient Sample. Recent trends, patient characteristics, and healthcare resource utilization for patients hospitalized with a primary SSSI diagnosis were evaluated. Descriptive and bivariate analyses were conducted to assess patient and hospital characteristics. Results A total of 1.8% of hospital admissions for the years 2005 through 2011 were for adult patients with a SSSI primary diagnosis. SSSI-related hospital admissions significantly changed during the study period (P < .001 for trend) ranging from 1.6% (in 2005) to 2.0% (in 2011). Mean hospital length of stay (LOS) decreased from 5.4 days in the year 2005 to 5.0 days in the year 2011 (overall change, P < .001) with no change in hospital costs. Patients with postoperative wound infections had the longest hospital stays (adjusted mean, 5.81 days; 95% confidence interval (CI), 5.80–5.83) and highest total costs (adjusted mean,

An Overview of CRISPR-Based Tools and Their Improvements: New Opportunities in Understanding Plant–Pathogen Interactions for Better Crop Protection

9388; 95% CI,

The prevalence of transmitted resistance to first-generation non-nucleoside reverse transcriptase inhibitors and its potential economic impact in HIV-infected patients.

9366-

Economic burden of inpatient and outpatient antibiotic treatment for methicillin-resistant Staphylococcus aureus complicated skin and soft-tissue infections: a comparison of linezolid, vancomycin, and daptomycin.

9410). Year of hospital admission was strongly associated with mortality; infection type, all patient refined diagnosis related group severity of illness level, and LOS were strongly associated with hospital costs. Conclusions Hospital admissions for adult patients in the United States with a SSSI primary diagnosis continue to increase. Decreasing hospital inpatient LOS and mortality rate may be due to improved early treatment. Future research should focus on identifying alternative treatment processes for patients with SSSI that could shift management from inpatient to outpatient treatment settings.

Health Economic Evaluation of Patients Treated for Nosocomial Pneumonia Caused by Methicillin-resistant Staphylococcus aureus: Secondary Analysis of a Multicenter Randomized Clinical Trial of Vancomycin and Linezolid

Modern omics platforms have made the determination of susceptible/resistance genes feasible in any species generating huge numbers of potential targets for crop protection. However, the efforts to validate these targets have been hampered by the lack of a fast, precise, and efficient gene targeting system in plants. Now, the repurposing of clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) system has solved this problem. CRISPR/Cas9 is the latest synthetic endonuclease that has revolutionized basic research by allowing facile genome editing in prokaryotes and eukaryotes. Gene knockout is now feasible at an unprecedented efficiency with the possibility of multiplexing several targets and even genome-wide mutagenesis screening. In a short time, this powerful tool has been engineered for an array of applications beyond gene editing. Here, we briefly describe the CRISPR/Cas9 system, its recent improvements and applications in gene manipulation and single DNA/RNA molecule analysis. We summarize a few recent tests targeting plant pathogens and discuss further potential applications in pest control and plant–pathogen interactions that will inform plant breeding for crop protection.