Search

SARS-CoV-2 vaccination promises to improve outcomes for patients with COVID-19 pneumonia (most notably those with advanced age and at high risk for severe disease). Here, we examine serum 25-Hydroxyvitamin D (25(OH)D) status and outcomes in both old (>70 years) and young vaccinated (n = 80) and unvaccinated (n = 91) subjects, who were hospitalized due to COVID-19 pneumonia in a single center (Connolly Hospital Dublin). Outcomes included ICU admission and mortality. Serum 25(OH)D levels were categorized as D30 (

Central metabolic pathways controls virulence and antibiotic resistance, and constitute potential targets for antibacterial drugs. InStaphylococcus aureusthe role of the pentose phosphate pathway (PPP) remains largely unexplored. Mutation of the 6-phosphogluconolactonase genepgl,which encodes the only non-essential enzyme in the oxidative phase of the PPP, significantly increased MRSA resistance to β-lactam antibiotics, particularly in chemically defined media with glucose, and reduced oxacillin (OX)-induced lysis. Expression of the methicillin-resistance penicillin binding protein 2a and peptidoglycan architecture were unaffected. Carbon tracing and metabolomics revealed extensive metabolic reprogramming in thepglmutant including increased flux to glycolysis, the TCA cycle, and several cell envelope precursors, which was consistent with increased β-lactam resistance. Morphologically,pglmutant cells were smaller than wild-type with a thicker cell wall and ruffled surface when grown in OX. Further evidence of the pleiotropic effect of thepglmutation was reduced resistance to Congo Red, sulfamethoxazole and oxidative stress, and increased resistance to targocil, fosfomycin and vancomycin. Reduced binding of wheat germ agglutinin (WGA) topglwas indicative of lower wall teichoic acid/lipoteichoic acid levels or altered teichoic acid structures. Mutations in thevraFGorgraRSloci reversed the increased OX resistance phenotype and restored WGA binding to wild-type levels. VraFG/GraRS was previously implicated in susceptibility to cationic antimicrobial peptides and vancomycin, and these data reveal a broader role for this multienzyme membrane complex in the export of cell envelope precursors or modifying subunits required for resistance to diverse antimicrobial agents. Altogether our study highlights important roles for the PPP and VraFG/GraRS in β-lactam resistance, which will support efforts to identify new drug targets and reintroduce β-lactams in combination with adjuvants or other antibiotics for infections caused by MRSA and other β-lactam resistant pathogens.Author summaryHigh-level resistance to penicillin-type (β-lactam) antibiotics significantly limits the therapeutic options for patients with MRSA infections necessitating the use of newer agents, for which reduced susceptibility has already been described. Here we report for the first time that the central metabolism pentose phosphate pathway controls MRSA resistance to penicillin-type antibiotics. We comprehensively demonstrated that mutation of the PPP genepglperturbed metabolism in MRSA leading to increased flux to cell envelope precursors to drive increased antibiotic resistance. Moreover, increased resistance was dependent on the VraRG/GraRS multienzyme membrane complex previously implicated in resistance to antimicrobial peptides and vancomycin. Our data thus provide new insights on MRSA mechanisms of β-lactam resistance, which will support efforts to expand the treatment options for infections caused by this and other antimicrobial resistant pathogens.

Peer reviewed: True, Along with the prevalence of photovoltaic (PV) procurement contracts, the corruption between auctioneers and potential electricity suppliers has attracted the attention of energy regulators. This study considers a corruption-proof environment wherein corruption is strictly suppressed. It elaborates a mechanism to explore the impact of corruption-proof measures on PV procurement auctions. It adopts incentive compatible constraints based on revelation principle to reflect PV firms’ optimal utilities. It employs first-price and first-score auctions and uses the Bayesian Nash equilibrium to provide a description of market outcomes. The results show that several strategies have different impacts on social welfare, PV firms’ utility, and the benefits of corruption. First, a first-price auction cannot act as a suitable policy because it may encourage corruption. Second, the first-score choice is desirable for social welfare to fit the forthcoming high-quality and low-price surroundings. Third, the first-score strategy maximizes PV firms’ utility and total income. The implications suggest that regulators ought not to employ first-price auctions in the future PV market from the perspective of social welfare. Another disadvantage of the first-price approach is that it enables the PV firm to maintain the utmost benefit from corruption.

Introduction:. Sepsis is a life-threatening organ dysfunction that is caused by a dysregulated host response to the infection. Urosepsis contributes up to 25% of all sepsis cases. An important part of the management of urosepsis is to rule out possible surgical causes such as urolithiasis, obstructive uropathy, or abscess formation along the urogenital tract. Objective:. The aim of this study is to look at whether urological conditions and recent urological surgery contribute significantly to all patients admitted with urosepsis. Methods:. A total of 2679 urine cultures and 654 blood cultures performed in Connolly Hospital Emergency Department were reviewed between 2016 and 2018. Patients were included if they had a matching urine culture and blood culture performed within 24 hours of admission. A retrospective chart review was performed for all patients included in the study. Results:. Our study included 85 patients admitted with urosepsis between 2016 and 2018. The average age was 70.3 years (21–100 years), in which 61% (n = 52) of patients were female, 18% (n = 16) had a long-term indwelling catheter, 11.8% (n = 10) were admitted as urosepsis with a urological condition. The most common urological condition predisposing patients to urosepsis in this study was bladder outlet obstruction secondary to benign prostatic hyperplasia. A total of 4.7% (n = 4) of patients died during their admission. The complications as a result of urosepsis included a prostatic abscess, a psoas abscess, an ileus, an infected cyst, and 1 case of emphysematous pyelonephritis. Conclusion:. In this study, the majority of patients admitted with urosepsis did not have an underlying urological condition or recent urological instrumentation. Clinicians should be aware of potential complications as a result of a urosepsis.

China is the largest driver of growth in the global building sector. The longstanding construction boom across China has generated a massive flow of materials with significant associated embodied energy consumption and carbon emissions. Despite the serious implications for global emissions, there exist a very limited number of macro-level studies on embodied energy of Chinese buildings, with even fewer exploring future scenarios. There is therefore little in the way of an evidence base to offer policy makers. We develop a probabilistic model to forecast the possible trajectories of embodied energy of residential buildings over the medium to long term in the Chinese urban context. Our results provide clear evidence to substantiate the importance of embodied energy of new construction, which we find to be over 0.3 times the operational energy of existing stock between 2010 and 2018. If current trajectories are followed, embodied energy is likely to peak around 2027, with a 95% credible interval ranging from 87 to 283 Mtce (61 to 198 Mtoe) and a mean of 170 Mtce (119 Mtoe). We show that building lifetime has a substantial impact on future annual and cumulative embodied energy. Our findings reinforce the need to take a whole-life perspective to formulate policies addressing building energy as part of China's efforts to meet the announced overarching target of achieving carbon neutrality by 2060.

Urosepsis accounts for up to 20–30% of all sepsis cases; however, increasing antimicrobial resistance is posing a significant threat to patient’s outcomes. The aim of this study was to look at the prevalence of multi-drug resistant (MDR) organisms in patients admitted with urosepsis and their effect on the treatment and outcome of patients in our hospital. A total of 2679 urine cultures and 654 blood cultures performed in Connolly Hospital Emergency Department were reviewed between 2016 and 2018. Patients were included if they had a matching urine culture and blood culture performed within 24 h of admission. We compared patient demographics and underlying co-morbidities between patients admitted with urosepsis secondary to MDR organisms and non-MDR organisms. Our study included 85 patients admitted with urosepsis. The most common causative pathogen was Escherichia coli, and 34.1% (n = 29) of pathogens were classified as an MDR organism. Patients admitted with urosepsis from long-term care facilities were 2.3 times more likely to have urosepsis due to a MDR organism compared with patients admitted from the community. Patients admitted with urosepsis secondary to a MDR organism were also more likely to have co-morbidities such as diabetes and dementia. The high rate of antimicrobial resistance in patients admitted with urosepsis poses a challenge in prescribing the most appropriate antibiotics. It is crucial that prescribers follow local antibiotic guidelines for the treatment of urosepsis and are cognisant of the risk of specific patient groups presenting with urosepsis due to MDR organisms.

China's power grid sector, which combines transmission and distribution, has grown rapidly after the restructuring reform in 2002. We evaluate the scale effect in the sector by employing a parametric Malmquist index based on a heteroscedastic true fixed-effects stochastic frontier model to estimate technical efficiency and total factor productivity for China's 30 grid companies from 2002 to 2017. The results show that there exists a scale effect. Most companies exhibit increasing returns to scale, total factor productivity experiences a significant growth driven by scale expansion. Companies with different scales should take differentiated actions to meet the challenges of market-oriented reform.

Introduction Our hospital found itself at the epicentre of the Irish COVID-19 pandemic. We describe the organisational challenges faced in managing the surge and identified risk factors for mortality and ICU admission among hospitalised SARS-CoV-2-infected patients. Methods All hospitalised SARS-CoV-2 patients diagnosed between March 13 and May 1, 2020, were included. Demographic, referral, deprivation, ethnicity and clinical data were recorded. Multivariable regression, including age-adjusted hazard ratios (HR (95% CI), was used to explore risk factors associated with adverse outcomes. Results Of 257 inpatients, 174 were discharged (68%) and 39 died (15%) in hospital. Two hundred three (79%) patients presented from the community, 34 (13%) from care homes and 20 (8%) were existing inpatients. Forty-five percent of community patients were of a non-Irish White or Black, Asian or minority ethnic (BAME) population, including 34 Roma (13%) compared to 3% of care home and 5% of existing inpatients, (p

Knowing the size of building stock is perhaps the most basic determinant in assessing energy use in buildings. However, official statistics on urban residential stock for many countries are piecemeal at best. Previous studies estimating stock size and energy use make various debateable methodological assumptions and only produce deterministic results. This paper presents a Bayesian approach to characterise stock turnover dynamics and estimate stock size uncertainties, applied here to China. Firstly, a probabilistic dynamic building stock turnover model is developed to describe the building aging and demolition process, governed by a hazard function specified by a parametric survival model. Secondly, using five candidate parametric survival models, the building stock turnover model is simulated through Markov Chain Monte Carlo to obtain posterior distributions of model-specific parameters, estimate marginal likelihood, and make predictions of stock size. Thirdly, Bayesian Model Averaging is applied to create a model ensemble that combines model-specific posterior predictive distributions of the recent historical stock evolution pathway in proportion to posterior model probabilities. Finally, the Bayesian Model Averaging model ensemble is extended to forecast future trajectories of residential stock development through 2100. The modelling results suggest that the total stock in China will peak around 2065, at between 42.4 and 50.1 billion m2. This Bayesian modelling framework produces probability distributions of annual total stock, age-specific substocks, annual new buildings and annual demolition rates. This can support future analysis of policy trade-offs across embodied-versus-operational energy consumption, in the context of sector-wide decarbonisation.

Staphylococcus aureus is a leading cause of healthcare-associated infections. The ability of S. aureus to attach and subsequently accumulate on the surfaces of implanted medical devices and in host tissues makes infections caused by this pathogen difficult to treat. Current treatments have been shown to have limited effect on surface-associated S. aureus, and may be enhanced by the addition of a dispersal agent. This study assessed the enzymatic agents dispersin B, lysostaphin, alpha amylase, V8 protease and serrapeptase, alone and in combination with vancomycin and rifampicin, against biofilms formed by meticillin-resistant and -susceptible strains of S. aureus. The efficacy of both antibiotics was enhanced when combined with any of the dispersal agents. Lysostaphin and serrapeptase were the most effective dispersal agents against all strains tested. These data indicate that combinations of biofilm dispersal agents and antibiotics may extend the therapeutic options for the treatment of S. aureus biofilm-associated infections.

Prolonging the clinical effectiveness of {beta}-lactams, which remain first-line antibiotics for many infections, is an important part of efforts to address antimicrobial resistance. We report here that inactivation of the predicted D-cycloserine (DCS) transporter gene cycA gene re-sensitizes MRSA to {beta}-lactam antibiotics. The cycA mutation also resulted in hyper-susceptibility to DCS, an alanine analogue antibiotic that inhibits the alanine racemase and D-Alanine ligase enzymes required for D-Alanine incorporation into peptidoglycan. Amino acid transport studies showed that CycA functions as an alanine permease, and the cycA mutation was accompanied by increased accumulation of muropeptides with tripeptide stems lacking the terminal D-Ala-D-Ala, and reduced peptidoglycan cross linking. Exposure of MRSA to DCS was also associated with a dose-dependent accumulation of muropeptides with tripeptide stems and reduced PG crosslinking. Because impaired alanine transport or DCS-treatment have similar effects on PG structure, synergism between {beta}-lactams and DCS was investigated. Therapeutically achievable concentrations of DCS re-sensitised MRSA to {beta}-lactam antibiotics in vitro and significantly enhanced MRSA eradication in a mouse bacteraemia model. The susceptibility of several other ESKAPE group pathogens to {beta}-lactams was also increased by DCS. These data reveal the potential of DCS, or new drugs targeting CycA, to facilitate the reintroduction of {beta}-lactam antibiotics for the treatment of infections caused by MRSA.nnAuthor SummaryTreatment options for infections caused by ESKAPE group pathogens continue to dwindle with increasing antimicrobial resistance. Particularly important are the {beta}-lactams, which remain first line antibiotics for many infections, and finding new ways to maintain their clinical effectiveness is a priority. Here we report that mutation of cycA in MRSA, which was found to encode an alanine permease, was associated with hyper-susceptibility to {beta}-lactam antibiotics and D-cycloserine (DCS), used in the treatment of multi-drug resistant tuberculosis infections. DCS re-sensitised MRSA to oxacillin and other {beta}-lactams in vitro and significantly enhanced oxacillin activity in a mouse model of bacteraemia. DCS also sensitised other ESKAPE pathogens to {beta}-lactams revealing the therapeutic potential of DCS as an adjunct drug for these important antibiotics.

Prevention of device related infections due to Staphylococcus aureus biofilms on devices represents a significant challenge. Such infections have recently been shown to be dependent on the coagulation pathway via activation of pro-thrombin and fibrin production. Three direct-thrombin inhibitors, argatroban, hirudin and dabigatran, were examined to determine their effect on preventing S. aureus biofilm on plastic biochip surfaces under shear stress using an in vivo relevant model of infection. Surface functionalization of polyurethane discs via dityrosine covalent crosslinking with hirudin was performed and changes in bacterial density and microscopic appearances determined. The three direct-thrombin inhibitors prevented S. aureus biofilm formation on plasma-coated surfaces treated with these agents. Coating of polyurethane with one of these agents, hirudin, significantly inhibited biofilm formation on the modified surface. These findings reveal the exciting potential for coating biomaterial surfaces with direct thrombin inhibitors to prevent staphylococcal binding and subsequent device-related infections.

Innovative approaches to the use of existing antibiotics is an important strategy in efforts to address the escalating antimicrobialresistance crisis. We report a new approach to the treatment of methicillin-resistant Staphylococcus aureus (MRSA) infectionsby demonstrating that oxacillin can be used to significantly attenuate the virulence of MRSA despite the pathogen being resistantto this drug. Using mechanistic in vitro assays and in vivo models of invasive pneumonia and sepsis, we show that oxacillin treated MRSAstrains are significantly attenuated in virulence. This effect is based primarily on the oxacillin-dependent repressionof the accessory gene regulator quorum-sensing system and altered cell wall architecture, which in turn lead to increased susceptibilityto host killing of MRSA. Our data indicate that β-lactam antibiotics should be included in the treatment regimen as anadjunct antivirulence therapy for patients with MRSA infections. This would represent an important change to current clinicalpractice for treatment of MRSA infection, with the potential to significantly improve patient outcomes in a safe, cost-effectivemanner.Keywords. MRSA; antibiotic; beta-lactam; virulence; attenuation.

Staphylococci are a leading cause of catheter-related infections (CRIs) due to biofilm formation. CRIs are typically managed by either device removal or systemic antibiotics, often in combination with catheter lock solutions (CLSs). CLSs provide high concentrations of the antimicrobial agent at the site of infection. However, the most effective CLSs against staphylococcal biofilm-associated infections have yet to be determined. The purpose of this study was to evaluate the efficacy and suitability of two newly described antimicrobial agents, ML:8 and Citrox, as CLSs against Staphylococcus aureus biofilms. ML:8 (1% [vol/vol]) and Citrox (1% [vol/vol]), containing caprylic acid and flavonoids, respectively, were used to treat S. aureus biofilms grown in vitro using newly described static and flow biofilm assays. Both agents reduced biofilm viability >97% after 24 h of treatment. Using a rat model of CRI, ML:8 was shown to inactivate early-stage S. aureus biofilms in vivo , while Citrox inactivated established, mature in vivo biofilms. Cytotoxicity and hemolytic activity of ML:8 and Citrox were equivalent to those of other commercially available CLSs. Neither ML:8 nor Citrox induced a cytokine response in human whole blood, and exposure of S. aureus to either agent for 90 days was not associated with any increase in resistance. Taken together, these data reveal the therapeutic potential of these agents for the treatment of S. aureus catheter-related biofilm infections.

Infection of intravascular catheters by Staphylococcus aureus is a significant risk factor within the health care setting. To treat these infections and attempt salvage of an intravascular catheter, antimicrobial lock solutions (ALSs) are being increasingly used. However, the most effective ALSs against these biofilm-mediated infections have yet to be determined, and clinical practice varies greatly. The purpose of this study was to evaluate and compare the efficacies of antibiotics and antiseptics in current clinical use against biofilms produced by reference and clinical isolates of S. aureus . Static and flow biofilm assays were developed using newly described in vivo -relevant conditions to examine the effect of each agent on S. aureus within the biofilm matrix. The antibiotics daptomycin, tigecycline, and rifampin and the antiseptics ethanol and Taurolock inactivated established S. aureus biofilms, while other commonly used antistaphylococcal antibiotics and antiseptic agents were less effective. These findings were confirmed by live/dead staining of S. aureus biofilms formed and treated within a flow cell model. The results from this study demonstrate the most effective clinically used agents and their concentrations which should be used within an ALS to treat S. aureus -mediated intravascular catheter-related infections.

To promote the development of the electricity trading market, China launched a new round of power system reform in 2015. Considering environmental and service factors, this study adopts a dynamic data envelopment analysis model with a network structure based on a slacks-based measure approach to evaluate the performance of the power system and its divisions in the 30 provincial-level administrative regions from 2011 to 2016. To better reflect the practical situation of the power system, we develop an improved network model which includes both free link and fixed link variables at the same time. This study further employs scenario analysis to investigate the effect of the unbundling reform on the power system and its divisions. It reaches the following conclusions: First, inter-regional transmission and environmental factors should be taken into account in evaluating the productive efficiency of the power system. Second, the separation of distribution from transmission has a positive impact on productive efficiency, and the effects of the unbundling reform on the power system differ significantly among divisions. Third, the introduction of an incomplete electricity trading market has a negative impact on the dynamic productive efficiency of the power system compared with the scenario without market reform, while complete market-oriented reform can improve dynamic productive efficiency and narrow the gap between regions. Nevertheless, a complete market reform has less influence on the efficiency than the changing power supply and demand situation caused by economic development.

Long-distance tiebacks are becoming more prevalent for subsea projects and present many unique challenges for successful operation. Flow assurance challenges arising from different operational regimes as well a high capital cost for enabling reliable production pose a unique challenge for long-distance tiebacks. A potential mitigation is the use of a pipe-in-pipe system for insulating purposes. The multifunctional pipeline system (MFPS) aims to provide further functionality and flexibility to the pipeline system by utilizing the annulus of the pipe-in-pipe system as an additional transportation line thus, providing the flexibility and added functionality to the pipe-in-pipe system to increase operational flexibility, reduce capex and opex, and improve system availability to drive capital efficiency. The MFPS station can also be used to detect a plug location, monitor pressure on both sides of a plug, circulate hot fluid in the annulus and bypass the affected section. This technology was developed in joint collaboration with Chevron and Schlumberger. This paper will highlight the overall functionality of the MFPS, the concepts that were investigated during the development of the MFPS, and the benefits that each unique concept provides to the overall field architecture.

Staphylococcal infections involving biofilms represent a significant challenge in the treatment of patients with device-related infections. Staphylococcus aureus biofilms have been shown to be SaeRS regulated and dependent on the coagulase-catalyzed conversion of fibrinogen into fibrin on surfaces coated with human plasma. Here we investigated the treatment of staphylococcal biofilm device-related infections by digesting the fibrin biofilm matrix with and without existing antimicrobials. The fibrinolytic agents plasmin, streptokinase, and nattokinase, and TrypLE, a recombinant trypsin-like protease, were used to digest and treat S. aureus biofilms grown in vitro using in vivo -like static biofilm assays with and without antimicrobials. Cytotoxicity, the potential to induce a cytokine response in whole human blood, and the risk of induction of tolerance to fibrinolytic agents were investigated. A rat model of intravascular catheter infection was established to investigate the efficacy of selected fibrinolytic agents in vivo . Under biomimetic conditions, the fibrinolytic agents effectively dispersed established S. aureus biofilms and, in combination with common antistaphylococcal antimicrobials, effectively killed bacterial cells being released from the biofilm. These fibrinolytic agents were not cytotoxic and did not affect the host immune response. The rat model of infection successfully demonstrated the activity of the selected fibrinolytic agents alone and in combination with antimicrobials on established biofilms in vivo . TrypLE and nattokinase most successfully removed adherent cells from plasma-coated surfaces and significantly improved the efficacy of existing antimicrobials against S. aureus biofilms in vitro and in vivo . These biofilm dispersal agents represent a viable future treatment option for S. aureus device-related infections.

High-level resistance to antimicrobial drugs is a major factor in the pathogenesis of chronic Staphylococcus aureus biofilm-associated, medical device-related infections. Antimicrobial susceptibility analysis revealed that biofilms grown for 48 hours) but were always susceptible to dispersal by the fibrinolytic enzymes plasmin or nattokinase. Biofilms recovered from infected central venous catheters in a rat model of device-related infection were dispersed by nattokinase, supporting the important role of the biofilm phenotype and identifying a potentially new therapeutic approach with anti-microbials and fibrinolytic drugs, particularly during the early stages of device-related infection.

Subsea pipelines play a significant role in E&P systems and are often called the lifelines of offshore oil and gas fields. These pipeline systems now cover greater areas and therefore traverse greater distances, go to deeper regions, and use larger-diameter pipelines. These developments present several challenges, including: ■ geohazards due to scarp or canyon crossings ■ multidiameter requirements ■ reduced-diameter risers to interface with large bore pipelines ■ ultra-deepwaters where top tensions become installation limitations ■ piggability of varying pipeline diameters, branching, and materials Most current approaches for these new frontiers rely on stretching the current design and installation practices that involve pushing materials and equipment to their limits, which increases risks and leads to very expensive solutions (high capex and high opex) for developing, installing, maintaining, and operating subsea pipeline systems. A subsea pipeline smart crossing system was developed to be a cost-effective solution that enables interconnectivity of different types and sizes of pipes to address the previously mentioned challenges and simplify subsea field architecture. This paper presents the challenges and constraints for two different field architectures, outlines the subsea pipeline smart crossing solution, and presents its associated technical and commercial benefits that allow operators to optimize their spend on development, installation, and operation of subsea pipeline systems.

Purpose. The treatment of device-related infections is challenging and current anti-microbial compounds have poor anti-biofilm activity. We aimed to identify and characterize novel compounds effective in the eradication of Staphylococcus aureus biofilms. Methodology. Two novel compounds, MMV665953 {1-(3-chloro-4-fluorophenyl)-3-(3,4-dichlorophenyl)urea} and MMV665807{5-chloro-2-hydroxy-N-[3-(trifluoromethyl)phenyl]benzamide}, effective in killing S. aureus biofilms, were identified by screening of the open access 'malaria box' chemical library. The minimum bactericidal concentrations, half-maximal inhibition concentration (IC50) values and minimal biofilm killing concentrations effective in the killing of biofilm were determined against meticillin-resistant S. aureus and meticillin-sensitive S. aureus. Fibrin-embedded biofilms were grown under in vivo-relevant conditions, and viability was measured using a resazurin-conversion assay and confocal microscopy. The potential for the development of resistance and cytotoxicity was also assessed. Results. MMV665953 and MMV665807 were bactericidal against S. aureus isolates. The IC50 against S. aureus biofilms was at 0.15–0.58 mg l−1 after 24 h treatment, whereas the concentration required to eradicate all tested biofilms was 4 mg l−1, making the compounds more bactericidal than conventional antibiotics. The cytotoxicity against human keratinocytes and primary endothelial cells was determined as IC50 7.47 and 0.18 mg l−1 for MMV665953, and as 1.895 and 0.076 mg l−1 for MMV665807. Neither compound was haemolytic nor caused platelet activation. MMV665953 and MMV665807 derivatives with reduced cytotoxicity exhibited a concomitant loss in anti-staphylococcal activity. Conclusion. MMV665953 and MMV665807 are more bactericidal against S. aureus biofilms than currently used anti-staphylococcal antibiotics and represent a valuable structural basis for further investigation in the treatment of staphylococcal biofilm-related infections.

Objectives: Biofilm infections of intravascular catheters caused by Staphylococcus aureus may be treated with catheter lock solutions (CLSs). Here we investigated the antibacterial activity, cytotoxicity and CLS potential of 5-hydroxyethyl-3-tetradecanoyltetramic acid (5HE-C14-TMA) compared with the related compounds 3-tetradecanoyltetronic (C14-TOA) and 3-tetradecanoylthiotetronic (C14-TTA), which are variants of quorum sensing signalling molecules produced by Pseudomonas aeruginosa. Methods: Antibacterial activity and mechanism of action of 5HE-C14-TMA, C14-TOA and C14-TTA were determined via MIC, bacterial killing, membrane potential and permeability assays. Susceptibility of S. aureus biofilms formed in the presence of plasma in vitro was investigated, MTT cytotoxicity testing was undertaken and cytokine release in human blood upon exposure to 5HE-C14-TMA and/or S. aureus biofilms was quantified. The effectiveness of 5HE-C14-TMA as CLS therapy in vivo was assessed using a rat intravascular catheter biofilm infection model. Results: MICs of 5HE-C14-TMA, C14-TOA and C14-TTA ranged from 2 to 4 mg/L. 5HE-C14-TMA and C14-TTA were bactericidal; all three compounds perturbed the staphylococcal membrane by increasing membrane permeability, depolarized the transmembrane potential and caused ATP leakage. Cytotoxicity and haemolytic activity were compound and target cell type-dependent. 5HE-C14-TMA reduced S. aureus biofilm viability in a dose-dependent manner in vitro and in vivo and did not trigger release of cytokines in human blood, but inhibited the high levels of IL-8 and TNF-α induced by S. aureus biofilms. Conclusions: 5HE-C14-TMA, C14-TOA and C14-TTA are membrane-active agents. 5HE-C14-TMA was the most potent, eradicating S. aureus biofilms at 512–1024 mg/L both in vitro and in vivo as a CLS.

Staphylococci, in particular Staphylococcus aureus and Staphylococcus epidermidis, are a leading cause of healthcare-associated infections. Patients who have a medical device inserted are at particular risk of an infection with these organisms as staphylococci possess a wide range of immune evasion mechanisms, one of which being their ability to form biofilm. Once embedded in a biofilm, bacteria are inherently more resistant to treatment with antibiotics. Despite advances in our understanding of the pathogenesis of staphylococcal biofilm formation, medical devices colonised with biofilms frequently require removal. New and novel approaches to prevent and treat biofilm infections are urgently required. In recent years, progress has been made on approaches that include antiadhesive strategies to prevent surface adhesion or production of bacterial adhesins, dissolution of already established biofilm, targeting of biofilm matrix for degradation and interference with biofilm regulation. Several obstacles need to be overcome in the further development of these and other novel anti-biofilm agents. Most notably, although in vitro investigation has progressed over recent years, the need for biofilm models to closely mimic the in vivo situation is of paramount importance followed by controlled clinical trials. In this review we highlight the issues associated with staphylococcal colonisation of medical devices and potential new treatment options for the prevention and control of these significant infections.

Here, we demonstrate that antimicrobial peptides (AMPs) are an effective antibiofilm treatment when applied as catheter lock solutions (CLSs) against S. aureus biofilm infections. The activity of synthetic AMPs (Bac8c, HB43, P18, Omiganan, WMR, Ranalexin, and Polyphemusin) was measured against early and mature biofilms produced by methicillin-resistant S. aureus and methicillin-susceptible S. aureus isolates from patients with device-related infections grown under in vivo-relevant biofilm conditions. The cytotoxic and hemolytic activities of the AMPs against human cells and their immunomodulatory potential in human blood were also characterized. The D-Bac8c2,5Leu variant emerged as the most effective AMP during in vitro studies and was also highly effective in eradicating S. aureus biofilm infection when used in a CLS rat central venous catheter infection model. These data support the potential use of D-Bac8c2,5Leu, alone or in combination with other AMPs, in the treatment of S. aureus intravenous catheter infections.

In-Memory Databases (IMDBs), such as SAP HANA, enable new levels of database performance by removing the disk bottleneck and by compressing data in memory. The consequence of this improved performance means that reports and analytic queries can now be processed on demand. Therefore, the goal is now to provide near real-time responses to compute and data intensive analytic queries. To facilitate this, much work has investigated the use of acceleration technologies within the database context. While current research into the application of these technologies has yielded positive results, they have tended to focus on single database tasks or on isolated single user requests. This paper uses SHEPARD, a framework for managing accelerated tasks across shared heterogeneous resources, to introduce acceleration into an IMDB. Results show how, using SHEPARD, multiple simultaneous user queries all receive speed-up by using a shared pool of accelerators. Results also show that offloading analytic tasks onto accelerators can have indirect benefits for other database workloads by reducing contention for CPU resources.

The major Staphylococcus aureus autolysin, Atl, has been implicated in attachment to surfaces and release of extracellular DNA during biofilm formation under laboratory conditions. Consistent with this, polyclonal antibodies to the amidase and glucosaminidase domains of Atl inhibited in vitro biofilm formation. However, in a murine model of device-related infection the community-associated S. aureus strain USA300 LAC JE2 established a successful infection in the absence of atl. These data indicate that Atl activity is not required for biofilm production in this infection model and reveal the importance of characterizing the contribution of biofilm phenotypes to virulence under in vivo conditions.

Objectives.(1) To determine whether rapid screening with polymerase chain reaction (PCR) assays leads to the earlier isolation of patients at risk for methicillin-resistantStaphylococcus aureus(MRSA) colonization, (2) to assess compliance with routine MRSA screening protocols, (3) to confirm the diagnostic accuracy of the Xpert MRSA real-time PCR assay (Cepheid) by comparison with culture, and (4) to compare turnaround times for PCR assay results with those for culture results.Design.Before-and-after study conducted in a 700-bed acute tertiary care referral hospital. Study periods were (1) a 5-week period before PCR testing began, (2) a 10-week period when the PCR assay was used, and (3) a 5-week period after PCR testing was discontinued.Results.Among 489 at-risk patients, MRSA was isolated from 20 (33%) of 60 patients during period 1, 77 (22%) of 349 patients during period 2, and 18 (23%) of 80 patients during period 3. Twenty-two (27%) of 82 at-risk patients were not screened during period 1, compared with 40 (10%) of 389 at-risk patients not screened during period 2 (P< .001). More MRSA-positive patients were preemptively isolated during periods 1 and 3 compared with period 2 (34 [24%] of 140 vs 28 [8%] of 389;P< .001); however, more MRSA-positive patients were isolated after notification of MRSA-positive results during period 2 (47 [13%] of 349) compared with periods 1 and 3 (2 [1%] of 140;P< .001). The sensitivity, specificity, positive predictive value, and negative predictive value of the PCR assay were 95%, 97%, 82%, and 99%, respectively. The mean turnaround time from receipt of specimens in the laboratory to PCR assay result was 2.6 hours.Conclusions.Rapid screening with the Xpert MRSA PCR assay facilitated compliance with screening policies and the earlier isolation of MRSA-positive Patients. Discrepant results confirm that PCR testing should be used as a screening tool rather than as a diagnostic tool.

Healthcare-associated or nosocomial infection (HCAI) is of increasing importance to healthcare providers and the public. Surveillance is crucial but must be adjusted for risk, especially when used for interhospital comparisons or for public reporting.Surveillance data are increasingly adjusted for risk factors for HCAI if meaningful comparisons are made between institutions or across national boundaries. Postdischarge surveillance is important in detecting those infections that may not present to the institution in which the original procedure occurred. Caution is urged when comparing data from two sources, for example, an active surveillance program and administrative datasets. The public reporting of HCAI rates can assist in improving the quality of healthcare, but to date there is little evidence that this is happening. In the United States, a number of states have introduced mandatory reporting of HCAIs, but there is considerable variation in what data are released, how these are reported and the rigor of the validation of the dataset.The consumerization of healthcare requires a response from healthcare providers to engage with the public on how, when and what risk-adjusted surveillance data to release. Information campaigns are required to ensure the public understand any publicly released data and its limitations.

Production of icaADBC -encoded polysaccharide intercellular adhesin, or poly- N -acetylglucosamine (PIA/PNAG), represents an important biofilm mechanism in staphylococci. We previously described a glucose-induced, ica -independent biofilm mechanism in four methicillin-resistant Staphylococcus aureus (MRSA) isolates. Here, biofilm regulation by NaCl and glucose was characterized in 114 MRSA and 98 methicillin-sensitive S. aureus (MSSA) isolates from diagnosed device-related infections. NaCl-induced biofilm development was significantly more prevalent among MSSA than MRSA isolates, and this association was independent of the isolate's genetic background as assessed by spa sequence typing. Among MSSA isolates, PIA/PNAG production correlated with biofilm development in NaCl, whereas in MRSA isolates grown in NaCl or glucose, PIA/PNAG production was not detected even though icaADBC was transcribed and regulated. Glucose-induced biofilm in MRSA was ica independent and apparently mediated by a protein adhesin(s). Experiments performed with strains that were amenable to genetic manipulation revealed that deletion of icaADBC had no effect on biofilm in a further six MRSA isolates but abolished biofilm in four MSSA isolates. Mutation of sarA abolished biofilm in seven MRSA and eight MSSA isolates. In contrast, mutation of agr in 13 MRSA and 8 MSSA isolates substantially increased biofilm (more than twofold) in only 5 of 21 (23%) isolates and had no significant impact on biofilm in the remaining 16 isolates. We conclude that biofilm development in MRSA is ica independent and involves a protein adhesin(s) regulated by SarA and Agr, whereas SarA-regulated PIA/PNAG plays a more important role in MSSA biofilm development.

Background Assessment of antibiotic prescribing is an important component of antimicrobial stewardship for the prevention of the misuse of antibiotics [1]. The aim of this study was to assess the prescribed antibiotics given to patients admitted through the Emergency Department (ED) of Connolly Hospital Blanchardstown (CHB) for compliance with the current CHB Guidelines for the use of Antibiotics [2].

Background The dosing of vancomycin and gentamicin relies largely on the weight and renal function of a patient. Due to their narrow therapeutic index, these drugs also require therapeutic drug monitoring (TDM) during treatment to ensure efficacy, reduce potential for otoand nephrotoxicity, and reduce potential for resistance. Guidelines for the use of vancomycin and gentamicin, as well as a dosing calculator, is in place in CHB. This audit was performed around the appropriate prescribing and monitoring of these two antibiotics in CHB and findings were compared to similar audits carried out in 2010 and 2012.

Antibiotic resistance and biofilm-forming capacity contribute to the success of Staphylococcus aureus as a human pathogen in both healthcare and community settings. These virulence factors do not function independently of each other and the biofilm phenotype expressed by clinical isolates of S. aureus is influenced by acquisition of the methicillin resistance gene mecA. Methicillin-sensitive S. aureus (MSSA) strains commonly produce an icaADBC operon-encoded polysaccharide intercellular adhesin (PIA)-dependent biofilm. In contrast, the release of extracellular DNA (eDNA) and cell surface expression of a number of sortase-anchored proteins, and the major autolysin have been implicated in the biofilm phenotype of methicillin-resistant S. aureus (MRSA) isolates. Expression of high level methicillin resistance in a laboratory MSSA strain resulted in (i) repression of PIA-mediated biofilm production, (ii) down-regulation of the accessory gene regulator (Agr) system, and (iii) attenuation of virulence in murine sepsis and device infection models. Here we review the mechanisms of MSSA and MRSA biofilm production and the relationships between antibiotic resistance, biofilm and virulence gene regulation in S. aureus.

Objectives The treatment of meningitis caused by Gram-negative bacilli in neurosurgical patients is a major challenge because of the complexity of these patients, the emergence of antibiotic resistance in many of the causative organisms and the restricted choice of antibiotics suitable for use, owing to a failure to achieve high enough concentrations in the CSF. We reviewed the incidence, aetiology, treatment and outcome of all patients with Gram-negative bacillary meningitis (GNBM) in our centre over a 7 year period. Methods Beaumont Hospital, Dublin is a 720 bed tertiary referral hospital and contains the national neurosurgical centre for the Republic of Ireland. The case notes and microbiological records of all patients with GNBM between 1998 and 2004 inclusive were reviewed retrospectively. Only patients with positive CSF culture and clinical features compatible with meningitis were included. Results Forty separate episodes of GNBM involving 34 different patients occurred during the study period. The most common causative organisms were Enterobacter spp. (35%), Escherichia coli (22.5%) and Pseudomonas aeruginosa (15%). Twenty-five per cent of isolates were resistant to third-generation cephalosporins. The median duration of treatment was 19.2 days and a combination of intravenous and intraventricular antibiotics was the most common treatment regimen used. Mortality directly related to GNBM was 2.5%. Conclusions Although the mortality directly related to GNBM was low, the emergence of strains resistant to third-generation cephalosporins represents a therapeutic challenge. Treatment with combined intravenous and intraventricular antibiotics is recommended for 2-3 weeks, but more studies are required to determine the optimal management of this difficult condition.

Significant application performance improvements can be achieved by heterogeneous compute technologies, such as multi-core CPUs, GPUs and FPGAs. The HARNESS project is developing architectural principles that enable the next generation cloud platforms to incorporate such devices thereby vastly increasing performance, reducing energy consumption, and lowering associated cost profiles. Along with management and integration of such devices in a cloud environment, a key issue is enabling enterprise-level software to make effective use of such compute devices. A major obstacle in adopting heterogeneous compute resources is the requirement that at design time the developer must decide on which device to execute portions of the application. For an interactive application, such as SAP HANA where there are many on-going tasks and processes, this type of decision is impossible to predict at design time. What is required is the ability to decide, at run-time, the optimal compute device to execute a task. This paper extends upon existing work on SHEPARD to support non-OpenCL devices. SHEPARD decouples application development from the target platform and enables the required run-time allocation of tasks to heterogeneous computing devices. This paper establishes SHEPARD's capability to: (1) select the appropriate compute device to execute tasks, (2) dynamically load the device application code at runtime, and (3) execute the application logic. Experiments demonstrate how SHEPARD optimises the execution of a SAP HANA database management function across heterogeneous compute devices and perform automatic run-time task allocation.

Most cloud service offerings are based on homogeneous commodity resources, such as large numbers of inexpensive machines interconnected by off-the-shelf networking equipment and disk drives, to provide low-cost application hosting. However, cloud service providers have reached a limit in satisfying performance and cost requirements for important classes of applications, such as geo-exploration and real-time business analytics. The HARNESS project aims to fill this gap by developing architectural principles that enable the next generation cloud platforms to incorporate heterogeneous technologies such as reconfigurable Dataflow Engines (DFEs), programmable routers, and SSDs, and provide as a result vastly increased performance, reduced energy consumption, and lower cost profiles. In this paper we focus on three challenges for supporting heterogeneous computing resources in the context of a cloud platform, namely: (1) cross-optimisation of heterogeneous computing resources, (2) resource virtualisation and (3) programming heterogeneous platforms.

Acute chiasmal compression has several aetiologies including pituitary apoplexy, a medical emergency caused by acute haemorrhagic or ischemic infarction in pituitary macroadenomas. Clinical diagnosis can often be difficult as the patient is frequently unaware of an existing adenoma. Delayed diagnosis may lead to increased morbidity and mortality. We describe a rarely presenting case report of acute chiasmal compression with unusual visual symptoms of hemifield slide, with initial delayed diagnosis. Knowledge of this infrequently presenting visual phenomenon may aid in rapid diagnosis, appropriate imaging and intervention leading to improved visual and systemic outcomes.

Rapid screening of biofilm forming capacity by Staphylococcus epidermidis is possible using in vitro assays with 96-well plates. This method first developed by Christensen et al. in 1985 is fast and does not require specialized instruments. Thus, laboratories with standard microbiology infrastructure and a 96-well plate reader can easily use this technique to generate data on the biofilm phenotypes of multiple S. epidermidis strains and clinical isolates. Furthermore, this method can be adapted to gain insights into biofilm regulation and the characteristics of biofilms produced by different S. epidermidis isolates. Although this assay is extremely useful for showing whether individual strains are biofilm-positive or biofilm-negative and distinguishing between form weak, moderate or strong biofilm, it is important to acknowledge that the absolute levels of biofilm produced by an individual strain can vary significantly between experiments meaning that strict adherence to the protocol used is of paramount importance. Furthermore, measuring biofilm under static conditions does not generally reflect in vivo conditions in which bacteria are often subjected to shear stresses under flow conditions. Hence, the biofilm characteristics of some strains are dramatically different under flow and static conditions. Nevertheless, rapid measurement of biofilm production under static conditions is a useful tool in the analysis of the S. epidermidis biofilm phenotype.

Rapid screening of biofilm forming capacity by Staphylococcus epidermidis is possible using in vitro assays with 96-well plates. This method first developed by Christensen et al. in 1985 is fast and does not require specialized instruments. Thus, laboratories with standard microbiology infrastructure and a 96-well plate reader can easily use this technique to generate data on the biofilm phenotypes of multiple S. epidermidis strains and clinical isolates. Furthermore, this method can be adapted to gain insights into biofilm regulation and the characteristics of biofilms produced by different S. epidermidis isolates. Although this assay is extremely useful for showing whether individual strains are biofilm-positive or biofilm-negative and distinguishing between form weak, moderate or strong biofilm, it is important to acknowledge that the absolute levels of biofilm produced by an individual strain can vary significantly between experiments meaning that strict adherence to the protocol used is of paramount importance. Furthermore, measuring biofilm under static conditions does not generally reflect in vivo conditions in which bacteria are often subjected to shear stresses under flow conditions. Hence, the biofilm characteristics of some strains are dramatically different under flow and static conditions. Nevertheless, rapid measurement of biofilm production under static conditions is a useful tool in the analysis of the S. epidermidis biofilm phenotype.

An online infection prevention and control programme for medical students was developed and assessed. There was a statistically significant improvement (P0.0001) in the knowledge base among 517 students after completing two modules. The majority of students who completed the evaluation were positive about the learning experience.