Effect of Algorithm-Based Therapy vs Usual Care on Clinical Success and Serious Adverse Events in Patients with Staphylococcal Bacteremia: A Randomized Clinical Trial

Importance: The appropriate duration of antibiotics for staphylococcal bacteremia is unknown. Objective: To test whether an algorithm that defines treatment duration for staphylococcal bacteremia vs standard of care provides noninferior efficacy without increasing severe adverse events. Design, Setting, and Participants: A randomized trial involving adults with staphylococcal bacteremia was conducted at 16 academic medical centers in the United States (n = 15) and Spain (n = 1) from April 2011 to March 2017. Patients were followed up for 42 days beyond end of therapy for those with Staphylococcus aureus and 28 days for those with coagulase-negative staphylococcal bacteremia. Eligible patients were 18 years or older and had 1 or more blood cultures positive for S aureus or coagulase-negative staphylococci. Patients were excluded if they had known or suspected complicated infection at the time of randomization. Interventions: Patients were randomized to algorithm-based therapy (n = 255) or usual practice (n = 254). Diagnostic evaluation, antibiotic selection, and duration of therapy were predefined for the algorithm group, whereas clinicians caring for patients in the usual practice group had unrestricted choice of antibiotics, duration, and other aspects of clinical care. Main Outcomes and Measures: Coprimary outcomes were (1) clinical success, as determined by a blinded adjudication committee and tested for noninferiority within a 15% margin; and (2) serious adverse event rates in the intention-to-treat population, tested for superiority. The prespecified secondary outcome measure, tested for superiority, was antibiotic days among per-protocol patients with simple or uncomplicated bacteremia. Results: Among the 509 patients randomized (mean age, 56.6 [SD, 16.8] years; 226 [44.4%] women), 480 (94.3%) completed the trial. Clinical success was documented in 209 of 255 patients assigned to algorithm-based therapy and 207 of 254 randomized to usual practice (82.0% vs 81.5%; difference, 0.5% [1-sided 97.5% CI, -6.2% to ∞]). Serious adverse events were reported in 32.5% of algorithm-based therapy patients and 28.3% of usual practice patients (difference, 4.2% [95% CI, -3.8% to 12.2%]). Among per-protocol patients with simple or uncomplicated bacteremia, mean duration of therapy was 4.4 days for algorithm-based therapy vs 6.2 days for usual practice (difference, -1.8 days [95% CI, -3.1 to -0.6]). Conclusions and Relevance: Among patients with staphylococcal bacteremia, the use of an algorithm to guide testing and treatment compared with usual care resulted in a noninferior rate of clinical success. Rates of serious adverse events were not significantly different, but interpretation is limited by wide confidence intervals. Further research is needed to assess the utility of the algorithm. Trial Registration: ClinicalTrials.gov Identifier: NCT01191840

Evaluation of a Desktop 3D Printed Rigid Refractive-Indexed-Matched Flow Phantom for PIV Measurements on Cerebral Aneurysms

Purpose Fabrication of a suitable flow model or phantom is critical to the study of biomedical fluid dynamics using optical flow visualization and measurement methods. The main difficulties arise from the optical properties of the model material, accuracy of the geometry and ease of fabrication. Methods Conventionally an investment casting method has been used, but recently advancements in additive manufacturing techniques such as 3D printing have allowed the flow model to be printed directly with minimal post-processing steps. This study presents results of an investigation into the feasibility of fabrication of such models suitable for particle image velocimetry (PIV) using a common 3D printing Stereolithography process and photopolymer resin. Results An idealised geometry of a cerebral aneurysm was printed to demonstrate its applicability for PIV experimentation. The material was shown to have a refractive index of 1.51, which can be refractive matched with a mixture of de-ionised water with ammonium thiocyanate (NH4SCN). The images were of a quality that after applying common PIV pre-processing techniques and a PIV cross-correlation algorithm, the results produced were consistent within the aneurysm when compared to previous studies. Conclusions This study presents an alternative low-cost option for 3D printing of a flow phantom suitable for flow visualization simulations. The use of 3D printed flow phantoms reduces the complexity, time and effort required compared to conventional investment casting methods by removing the necessity of a multi-part process required with investment casting techniques

Ad-blocking Games: Monetizing Online Content Under the Threat of Ad Avoidance

Much of the Internet economy relies on online advertising for monetizing digital content: Users are expected to accept the presence of online advertisements in exchange for content being free. However, online advertisements have become a serious problem for many Internet users: while some are merely annoyed by the incessant display of distracting ads cluttering Web pages, others are highly concerned about the privacy implications - as ad providers typically track users' behavior for ad targeting purposes. Similarly, security problems related to technologies and practices employed for online advertisement have frustrated many users. Consequently, a number of software solutions have emerged that block online ads from being downloaded and displayed on users' screens as they browse the Web. We focus on these advertisement avoidance technologies for online content and their economic ramifications for the monetization of websites. More specifically, our work addresses the interplay between users' attempts to avoid commercial messages and content providers' design of countermeasures. Our investigation is substantiated by the development of a game-theoretic model that serves as a framework usable by content providers to ponder their options to mitigate the consequences of ad avoidance techniques. We complement our analytical approach with simulation results, addressing different assumptions about user heterogeneity. Our findings show that publishers who treat each user individually, and strategically deploy fee-financed or ad-financed monetization strategy, obtain higher revenues, compared to deploying one monetization strategy across all users. In addition, our analysis shows that understanding the distribution of users' aversion to ads and valuation of the content is essential for publishers to make a well-informed decision

Modifying effect of dual antiplatelet therapy on incidence of stent thrombosis according to implanted drug-eluting stent type

Aim To investigate the putative modifying effect of dual antiplatelet therapy (DAPT) use on the incidence of stent thrombosis at 3 years in patients randomized to Endeavor zotarolimus-eluting stent (E-ZES) or Cypher sirolimus-eluting stent (C-SES). Methods and results Of 8709 patients in PROTECT, 4357 were randomized to E-ZES and 4352 to C-SES. Aspirin was to be given indefinitely, and clopidogrel/ticlopidine for ≥3 months or up to 12 months after implantation. Main outcome measures were definite or probable stent thrombosis at 3 years. Multivariable Cox regression analysis was applied, with stent type, DAPT, and their interaction as the main outcome determinants. Dual antiplatelet therapy adherence remained the same in the E-ZES and C-SES groups (79.6% at 1 year, 32.8% at 2 years, and 21.6% at 3 years). We observed a statistically significant (P = 0.0052) heterogeneity in treatment effect of stent type in relation to DAPT. In the absence of DAPT, stent thrombosis was lower with E-ZES vs. C-SES (adjusted hazard ratio 0.38, 95% confidence interval 0.19, 0.75; P = 0.0056). In the presence of DAPT, no difference was found (1.18; 0.79, 1.77; P = 0.43). Conclusion A strong interaction was observed between drug-eluting stent type and DAPT use, most likely prompted by the vascular healing response induced by the implanted DES system. These results suggest that the incidence of stent thrombosis in DES trials should not be evaluated independently of DAPT use, and the optimal duration of DAPT will likely depend upon stent type (Clinicaltrials.gov number NCT00476957

SPARC: a matricellular regulator of tumorigenesis

Although many clinical studies have found a correlation of SPARC expression with malignant progression and patient survival, the mechanisms for SPARC function in tumorigenesis and metastasis remain elusive. The activity of SPARC is context- and cell-type-dependent, which is highlighted by the fact that SPARC has shown seemingly contradictory effects on tumor progression in both clinical correlative studies and in animal models. The capacity of SPARC to dictate tumorigenic phenotype has been attributed to its effects on the bioavailability and signaling of integrins and growth factors/chemokines. These molecular pathways contribute to many physiological events affecting malignant progression, including extracellular matrix remodeling, angiogenesis, immune modulation and metastasis. Given that SPARC is credited with such varied activities, this review presents a comprehensive account of the divergent effects of SPARC in human cancers and mouse models, as well as a description of the potential mechanisms by which SPARC mediates these effects. We aim to provide insight into how a matricellular protein such as SPARC might generate paradoxical, yet relevant, tumor outcomes in order to unify an apparently incongruent collection of scientific literature