RAGE Reusable Game Software Components and Their Integration into Serious Game Engines

This paper presents and validates a methodology for integrating reusable software components in diverse game engines. While conforming to the RAGE com-ponent-based architecture described elsewhere, the paper explains how the interac-tions and data exchange processes between a reusable software component and a game engine should be implemented for procuring seamless integration. To this end, a RAGE-compliant C# software component providing a difficulty adaptation routine was integrated with an exemplary strategic tile-based game “TileZero”. Implementa-tions in MonoGame, Unity and Xamarin, respectively, have demonstrated successful portability of the adaptation component. Also, portability across various delivery platforms (Windows desktop, iOS, Android, Windows Phone) was established. Thereby this study has established the validity of the RAGE architecture and its un-derlying interaction processes for the cross-platform and cross-game engine reuse of software components. The RAGE architecture thereby accommodates the large scale development and application of reusable software components for serious gaming

Serum bactericidal activity of three different dosing regimens of colistin with implications for optimum clinical use

Although colistin methanesulfonate (CMS) has been used extensively in critically ill patients infected with multidrug-resistant organisms, the optimum dosing regimen remains to be determined. Herein, we examined the pharmacokinetics of three different dosing regimens of CMS, 3 million units every 8 h (regimen A), 4.5 million units every 12 h (regimen B), 9 million units every 24 h (regimen C) and evaluated the bactericidal activity of serum containing various concentrations of colistin against Pseudomonas aeruginosa with a minimum inhibitory concentration (MIC) of 1 μg/ml. The means ± SE serum Cmax of colistin for regimens A, B, and C were 3.34±0.35, 2.98±0.27, and 5.63±0.87 μg/ml, respectively. All serum samples containing colistin >4 μg/ml (serum concentration/MIC >4) eliminated P. aeruginosa whereas only 40% of samples containing colistin <4 μg/ml resulted in complete bacterial killing. These findings indicate that the currently used dosing regimens might not provide the most effective therapy with CMS and justify administering larger dosages in longer intervals. © E.S.I.F.T. srl

Efficacy of teicoplanin, administered in two different regimens, in the treatment of experimental endocarditis due to Enterococcus faecalis

Using a rabbit model of endocarditis, we studied the efficacy of teicoplanin against a strain of Enterococcus faecalis resistant to ampicillin. Rabbits were randomly assigned to receive no antibiotics, teicoplanin 12 or 18 mg/kg of body weight every 12h, for 9 days. The effect of treatment on bacterial counts of vegetations and survival of the animals was evaluated at the end of treatment and 10 days thereafter. The two treatment regimens of teicoplanin produced peak serum levels 18.51±1.84 and 34.66±4.19 μg/ml, and trough levels above 1 OxMIC of teicoplanin for the infecting organism. Both regimens resulted in significant bacterial reduction in the vegetations as compared to the control group (p<0.001). The drug prevented relapse of the infection 10 days after discontinuation of treatment. By increasing the teicoplanin dosage no additional therapeutic benefit was observed in terms of bacterial killing, sterilization of the vegetations, and survival of the animals, although the higher doses gave numerically superior results. These findings may have meaning for the optimum use of teicoplanin in the treatment of enterococcal endocarditis. © E.S.I.F.T. srl

Excluded versus included patients in a randomized controlled trial of infections caused by carbapenem-resistant Gram-negative bacteria: relevance to external validity

Background: Population external validity is the extent to which an experimental study results can be generalized from a specific sample to a defined population. In order to apply the results of a study, we should be able to assess its population external validity. We performed an investigator-initiated randomized controlled trial (RCT) (AIDA study), which compared colistin-meropenem combination therapy to colistin monotherapy in the treatment of patients infected with carbapenem-resistant Gram-negative bacteria. In order to examine the study’s population external validity and to substantiate the use of AIDA study results in clinical practice, we performed a concomitant observational trial. Methods: The study was conducted between October 1st, 2013 and January 31st, 2017 (during the RCTs recruitment period) in Greece, Israel and Italy. Patients included in the observational arm of the study have fulfilled clinical and microbiological inclusion criteria but were excluded from the RCT due to receipt of colistin for > 96 h, refusal to participate, or prior inclusion in the RCT. Non-randomized cases were compared to randomized patients. The primary outcome was clinical failure at 14 days of infection onset. Results: Analysis included 701 patients. Patients were infected mainly with Acinetobacter baumannii [78.2% (548/701)]. The most common reason for exclusion was refusal to participate [62% (183/295)]. Non-randomized and randomized patients were similar in most of the demographic and background parameters, though randomized patients showed minor differences towards a more severe infection. Combination therapy was less common in non-randomized patients [31.9% (53/166) vs. 51.2% (208/406), p = 0.000]. Randomized patients received longer treatment of colistin [13 days (IQR 10–16) vs. 8.5 days (IQR 0–15), p = 0.000]. Univariate analysis showed that non-randomized patients were more inclined to clinical failure on day 14 from infection onset [82% (242/295) vs. 75.5% (307/406), p = 0.042]. After adjusting for other variables, non-inclusion was not an independent risk factor for clinical failure at day 14. Conclusion: The similarity between the observational arm and RCT patients has strengthened our confidence in the population external validity of the AIDA trial. Adding an observational arm to intervention studies can help increase the population external validity and improve implementation of study results in clinical practice. Trial registration: The trial was registered with ClinicalTrials.gov, number NCT01732250 on November 22, 2012

Molecular epidemiology of MRSA in 13 ICUs from eight European countries

Objectives: The European epidemiology of MRSA is changing with the emergence of community-associated MRSA (CA-MRSA) and livestock-associated MRSA (LA-MRSA). In this study,we investigated the molecular epidemiology of MRSA during 2 years in 13 ICUs in France, Greece, Italy, Latvia, Luxemburg, Portugal, Slovenia and Spain. Methods: Surveillance cultures for MRSA from nose and wounds were obtained on admission and twice weekly from all patients admitted to an ICU for ≥3 days. The first MRSA isolate per patient was genotyped in a central laboratory by MLST, spa typing, agr typing and SCCmec (sub)typing. Risk factors for patients with an unknown history of MRSA colonization were identified. Results: Overall, 14390 ICU patients were screened, of whom 8519 stayed in an ICU for ≥3 days. Overall MRSA admission prevalence was 3.9% and ranged from 1.0% to 7.0% for individual ICUs. Overall MRSA acquisition rate was 2.5/1000 patient days at risk and ranged from 0.2 to 8/1000 patient days at risk per ICU. In total, 557 putative MRSA isolates were submitted to the central laboratory for typing, of which 511 (92%) were confirmed as MRSA. Each country had a distinct epidemiology, with ST8-IVc (UK-EMRSA-2/-6, USA500) being most prevalent, especially in France and Spain, and detected in ICUs in five of eight countries. Seventeen (3%) and three (70 years and hospitalization within 1 year prior to ICU admission. Conclusions: The molecular epidemiology of MRSA in 13 European ICUs in eight countries was homogeneous within, but heterogeneous between, countries. CA-MRSA and LA-MRSA genotypes and Panton-Valentine leucocidin-producing isolates were detected sporadically

Colistin plus meropenem for carbapenem-resistant Gram-negative infections: in vitro synergism is not associated with better clinical outcomes

Objectives: In vitro models showing synergism between polymyxins and carbapenems support combination treatment for carbapenem-resistant Gram-negative (CRGN) infections. We tested the association between the presence of in vitro synergism and clinical outcomes in patients treated with colistin plus meropenem. Methods: This was a secondary analysis of AIDA, a randomized controlled trial comparing colistin with colistin–meropenem for severe CRGN infections. We tested in vitro synergism using a checkerboard assay. Based on the fractional inhibitory concentration (ΣFIC) index for each colistin–meropenem combination, we categorized results as synergistic, antagonistic or additive/indifferent. The primary outcome was clinical failure at 14 days. Secondary outcomes were 14- and 28-day mortality and microbiological failure. Results: The sample included 171 patients with infections caused by carbapenem-resistant Acinetobacter baumannii (n = 131), Enterobacteriaceae (n = 37) and Pseudomonas aeuruginosa (n = 3). In vitro testing showed synergism for 73 isolates, antagonism for 20 and additivism/indifference for 78. In patients who received any colistin plus meropenem, clinical failure at 14 days was 59/78 (75.6%) in the additivism/indifference group (reference category), 54/73 (74.0%) in the synergism group (adjusted odds ratio (aOR) 0.76, 95% CI 0.31–1.83), and 11/20 (55%) in the antagonism group (aOR 0.77, 95% CI 0.22–2.73). There was no significant difference between groups for any secondary outcome. Comparing the synergism group to patients treated with colistin monotherapy, synergism was not protective against 14-day clinical failure (aOR 0.52, 95% CI 0.26–1.04) or 14-day mortality (aOR1.09, 95% CI 0.60–1.96). Discussion: In vitro synergism between colistin and meropenem via checkerboard method did not translate into clinical benefit. © 2020 European Society of Clinical Microbiology and Infectious Disease

Treatment Outcomes of Colistin- And Carbapenem-resistant Acinetobacter baumannii Infections: An Exploratory Subgroup Analysis of a Randomized Clinical Trial

Background: We evaluated the association between mortality and colistin resistance in Acinetobacter baumannii infections and the interaction with antibiotic therapy. Methods: This is a secondary analysis of a randomized controlled trial of patients with carbapenem-resistant gram-negative bacterial infections treated with colistin or colistin-meropenem combination. We evaluated patients with infection caused by carbapenem-resistant A. baumannii (CRAB) identified as colistin susceptible (CoS) at the time of treatment and compared patients in which the isolate was confirmed as CoS with those whose isolates were retrospectively identified as colistin resistant (CoR) when tested by broth microdilution (BMD). The primary outcome was 28-day mortality. Results: Data were available for 266 patients (214 CoS and 52 CoR isolates). Patients with CoR isolates had higher baseline functional capacity and lower rates of mechanical ventilation than patients with CoS isolates. All-cause 28-day mortality was 42.3% (22/52) among patients with CoR strains and 52.8% (113/214) among patients with CoS isolates (P =. 174). After adjusting for variables associated with mortality, the mortality rate was lower among patients with CoR isolates (odds ratio [OR], 0.285 [95% confidence interval {CI},. 118-.686]). This difference was associated with treatment arm: Mortality rates among patients with CoR isolates were higher in those randomized to colistin-meropenem combination therapy compared to colistin monotherapy (OR, 3.065 [95% CI, 1.021-9.202]). Conclusions: Colistin resistance determined by BMD was associated with lower mortality among patients with severe CRAB infections. Among patients with CoR isolates, colistin monotherapy was associated with a better outcome compared to colistin-meropenem combination therapy. Clinical Trials Registration: NCT01732250. © 2018 The Author(s) 2018