5-Hydroxyethyl-3-tetradecanoyltetramic acid represents a novel treatment for intravascular catheter infections due to Staphylococcus aureus

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

1022-107 Outcome of Different Reperfusion Strategies in Thrombolytic “Eligible” versus “Ineligible” Patients with Acute Myocardial Infarction

Pts considered “not eligible” for inclusion in most early U.S. thrombolytic trials because of advanced age, late presentation, prior CABG or shock have avery poor prognosis; thus, some have suggested broadening the criteria for lyric eligibility. To examine the role of different reperfusion strategies in pts traditionally considered lytic “eligible” vs. “ineligible” (age>70, MI onset>4 hours, or prior CABG), we examined the PAMI database in which 395 pts of any age within 12 hours onset of MI were randomized to t-PA or primary PTCA (pts with shock were excluded). Compared to lyric eligible pts, ineligible pts were o1der(67 vs. 56 yrs, p<0.0001). more frequently female (38% vs. 20%, P<0.0001), diabetic (17% vs. 10%, P=0.03), had prior CABG (8% vs. 0%, P<0.0001), presented later (4.4 vs. 2.2 hours, p<0.0001), and were more likely to present in CI-1F (20% vs. 11%, P=0.01). Endpoints included death (D), reinfarction (R), recurrent ischemic events (RIE) and stroke:Thrombolytic eligibleThrombolytic ineligiblePTCA (n=127)t-PA (n=117)PPTCA (n=68)t-PA (n=83)Pin-hosp. D2.4%1.7%NS2.9%13.3%0.025in-hosp. D or R5.5%9.4%NS4.4%15.7%0.026in-hosp. RIE11.8%29.1%0.00087.4%26.6%0.002in-hasp. stroke0%1.7%NS0%6.0%0.046 month D3.9%1.7%NS2.9%15.7%0.0096 month D or R8.7%12.8%NS7.4%22.9%0.009In conclusion: Pts traditionally considered thrombolytic eligible comprise a low risk cohort, and have a favorable prognosis whether treated with primary PTCA or t-PA. In contrast, pts historically excluded from most early lytic trials because of advanced age, late presentation or prior CABG are at increased risk, and may have improved survival with primary PTCA rather than thrompresented laterbolysis

Socially-critical software systems: Is extended regulation required?

Data has become a prevailing aspect of our daily lives, becoming ever more present since the beginning of the 21st century. It is a commodity in today’s world and the amount of data being produced has increased enormously. One of the major ways data is produced and collected is from the use of websites and web-based applications. This data is later used for many different purposes. This paper presents findings from a multivocal literature review, exploring the methods of how this data is collected, what the data is used for once it has been collected, the ethics of data and its collection, and the future of data collection. Among the possible futures, we introduce the concept of socially-critical applications, where data harvesting in web-based applications might require premarket disclosure and evaluation by notified bodies (instructed by regulation) as a means to break the existing cycle of technology companies outpacing under resourced and ill-equipped regulators. Rather than regulators continually falling short of enacting laws to satisfy the common good, a new class of socially-critical application could be created in law to permit pre-market evaluation of applications (or versions of applications) that could undermine or interrupt the common good

1022-103 Does Primary Angioplasty Improve the Prognosis of Patients with Diabetes and Acute Myocardial Infarction?

To examine the effect of different reperfusion modalities in pts with DM, the multicenter PAMI database was analyzed, in which 395 pts within 12 hours onset of acute MI were prospectively randomized to treatment with t-PA (n=200) vs. primary PTCA (n=195). DM was present in 50 (13%) pts. Compared to pts without DM, pts with DM were older (65 vs. 59 yrs, p=0.002), more often female (40% vs. 25%, p=0.03), more frequently had HTN (68% vs. 39%, P=0.0001), prior CHF (8% vs. 1%, P=0.0001). multivessel disease (76% vs. 51%, P=0.01) and presented later (3.8 vs. 3.0hours, p=0.03).In-hospital mortality was 10.0% in pts with DM vs. 3.8% in pts without DM (p<0.05). By multivariate analysis of 16 variables, however, advanced age and treatment by PTCA rather than t-PA, but not DM correlated with in-hospital mortality.Mortality stratified by treatment appears in the graph. Despite the apparently improved prognosis of pts with DM treated with PTCA vs. t-PA, the p value forthe x2 test for interaction effect between DM and treatment modality was 0.86; most of the benefit of PTCA was present in the elderly population.In conclusionPts with DM and acute MI have increased mortality, primarily because of advanced age. The outcome after PTCA compared to t-PA is improved in DM largely because of PTCA's beneficial effect in the elderly

Age-related fertility decline: is there a role for elective ovarian tissue cryopreservation?

Age-related fertility decline (ARFD) is a prevalent concern amongst western cultures due to the increasing age of first-time motherhood. Elective oocyte and embryo cryopreservation remain the most established methods of fertility preservation, providing women the opportunity of reproductive autonomy to preserve their fertility and extend their childbearing years to prevent involuntary childlessness. Whilst ovarian cortex cryopreservation has been used to preserve reproductive potential in women for medical reasons, such as in pre- or peripubertal girls undergoing gonadotoxic chemotherapy, it has not yet been considered in the context of ARFD. As artificial reproductive technology (ART) and surgical methods of fertility preservation continue to evolve, it is a judicious time to review current evidence and consider alternative options for women wishing to delay their fertility. This article critically appraises elective oocyte cryopreservation as an option for women who use it to mitigate the risk of ARFD and introduces the prospect of elective ovarian cortex cryopreservation as an alternative

Atrial CARdiac Magnetic resonance imaging in patients with embolic stroke of unknown source without documented Atrial Fibrillation (CARM-AF): Study design and clinical protocol

Background: Initiation of anticoagulation therapy in ischemic stroke patients is contingent on a clinical diagnosis of atrial fibrillation (AF). Results from previous studies suggest thromboembolic risk may predate clinical manifestations of AF. Early identification of this cohort of patients may allow early initiation of anticoagulation and reduce the risk of secondary stroke. Objective: This study aims to produce a substrate-based predictive model using cardiac magnetic resonance imaging (CMR) and baseline noninvasive electrocardiographic investigations to improve the identification of patients at risk of future thromboembolism. Methods: CARM-AF is a prospective, multicenter, observational cohort study. Ninety-two patients will be recruited following an embolic stroke of unknown source (ESUS) and undergo atrial CMR followed by insertion of an implantable loop recorder (ILR) as per routine clinical care within 3 months of index stroke. Remote ILR follow-up will be used to allocate patients to a study or control group determined by the presence or absence of AF as defined by ILR monitoring. Results: Baseline data collection, noninvasive electrocardiographic data analysis, and imaging postprocessing will be performed at the time of enrollment. Primary analysis will be performed following 12 months of continuous ILR monitoring, with interim and delayed analyses performed at 6 months and 2 and 3 years, respectively. Conclusion: The CARM-AF Study will use atrial structural and electrocardiographic metrics to identify patients with AF, or at high risk of developing AF, who may benefit from early initiation of anticoagulation

Examination of the Cytotoxic and Embryotoxic Potential and Underlying Mechanisms of Next-Generation Synthetic Trioxolane and Tetraoxane Antimalarials

Semisynthetic artemisinin-based therapies are the first-line treatment for P. falciparum malaria, but next-generation synthetic drug candidates are urgently required to improve availability and respond to the emergence of artemisinin-resistant parasites. Artemisinins are embryotoxic in animal models and induce apoptosis in sensitive mammalian cells. Understanding the cytotoxic propensities of antimalarial drug candidates is crucial to their successful development and utilization. Here, we demonstrate that, similarly to the model artemisinin artesunate (ARS), a synthetic tetraoxane drug candidate (RKA182) and a trioxolane equivalent (FBEG100) induce embryotoxicity and depletion of primitive erythroblasts in a rodent model. We also show that RKA182, FBEG100 and ARS are cytotoxic toward a panel of established and primary human cell lines, with caspase-dependent apoptosis and caspase-independent necrosis underlying the induction of cell death. Although the toxic effects of RKA182 and FBEG100 proceed more rapidly and are relatively less cell-selective than that of ARS, all three compounds are shown to be dependent upon heme, iron and oxidative stress for their ability to induce cell death. However, in contrast to previously studied artemisinins, the toxicity of RKA182 and FBEG100 is shown to be independent of general chemical decomposition. Although tetraoxanes and trioxolanes have shown promise as next-generation antimalarials, the data described here indicate that adverse effects associated with artemisinins, including embryotoxicity, cannot be ruled out with these novel compounds, and a full understanding of their toxicological actions will be central to the continuing design and development of safe and effective drug candidates which could prove important in the fight against malaria

A lightweight magnetically shielded room with active shielding

Magnetically shielded rooms (MSRs) use multiple layers of materials such as MuMetal to screen external magnetic fields that would otherwise interfere with high precision magnetic field measurements such as magnetoencephalography (MEG). Optically pumped magnetometers (OPMs) have enabled the development of wearable MEG systems which have the potential to provide a motion tolerant functional brain imaging system with high spatiotemporal resolution. Despite significant promise, OPMs impose stringent magnetic shielding requirements, operating around a zero magnetic field resonance within a dynamic range of ± 5 nT. MSRs developed for OPM-MEG must therefore effectively shield external sources and provide a low remnant magnetic field inside the enclosure. Existing MSRs optimised for OPM-MEG are expensive, heavy, and difficult to site. Electromagnetic coils are used to further cancel the remnant field inside the MSR enabling participant movements during OPM-MEG, but present coil systems are challenging to engineer and occupy space in the MSR limiting participant movements and negatively impacting patient experience. Here we present a lightweight MSR design (30% reduction in weight and 40–60% reduction in external dimensions compared to a standard OPM-optimised MSR) which takes significant steps towards addressing these barriers. We also designed a ‘window coil’ active shielding system, featuring a series of simple rectangular coils placed directly onto the walls of the MSR. By mapping the remnant magnetic field inside the MSR, and the magnetic field produced by the coils, we can identify optimal coil currents and cancel the remnant magnetic field over the central cubic metre to just |B|= 670 ± 160 pT. These advances reduce the cost, installation time and siting restrictions of MSRs which will be essential for the widespread deployment of OPM-MEG

The genomes of two key bumblebee species with primitive eusocial organization

Background: The shift from solitary to social behavior is one of the major evolutionary transitions. Primitively eusocial bumblebees are uniquely placed to illuminate the evolution of highly eusocial insect societies. Bumblebees are also invaluable natural and agricultural pollinators, and there is widespread concern over recent population declines in some species. High-quality genomic data will inform key aspects of bumblebee biology, including susceptibility to implicated population viability threats. Results: We report the high quality draft genome sequences of Bombus terrestris and Bombus impatiens, two ecologically dominant bumblebees and widely utilized study species. Comparing these new genomes to those of the highly eusocial honeybee Apis mellifera and other Hymenoptera, we identify deeply conserved similarities, as well as novelties key to the biology of these organisms. Some honeybee genome features thought to underpin advanced eusociality are also present in bumblebees, indicating an earlier evolution in the bee lineage. Xenobiotic detoxification and immune genes are similarly depauperate in bumblebees and honeybees, and multiple categories of genes linked to social organization, including development and behavior, show high conservation. Key differences identified include a bias in bumblebee chemoreception towards gustation from olfaction, and striking differences in microRNAs, potentially responsible for gene regulation underlying social and other traits. Conclusions: These two bumblebee genomes provide a foundation for post-genomic research on these key pollinators and insect societies. Overall, gene repertoires suggest that the route to advanced eusociality in bees was mediated by many small changes in many genes and processes, and not by notable expansion or depauperation

Connectivity guided theta burst transcranial magnetic stimulation versus repetitive transcranial magnetic stimulation for treatment-resistant moderate to severe depression: study protocol for a randomised double-blind controlled trial (BRIGhTMIND)

Introduction The BRIGhTMIND study aims to determine the clinical effectiveness, cost effectiveness and mechanism of action of connectivity guided intermittent Theta Burst Stimulation (cgiTBS) versus standard repetitive Transcranial Magnetic Stimulation (rTMS) in adults with moderate to severe treatment resistant depression. Methods and analysis The study is a randomised double-blind controlled trial with 1:1 allocation to either 20 sessions of (a) cgiTBS or (b) neuronavigated rTMS not using connectivity guidance. A total of 368 eligible participants with a diagnosis of current unipolar major depressive disorder that is both treatment resistant (defined as scoring 2 or more on the Massachusetts General Hospital (MGH) Staging Score) and moderate to severe (scoring >16 on the 17-item Hamilton Depression Rating Scale (HDRS-17)), will be recruited from primary and secondary care settings at four treatment centres in the United Kingdom. The primary outcome is depression response at 16 weeks (50% or greater reduction in HDRS-17 score from baseline). Secondary outcomes include assessments of self-rated depression, anxiety, psychosocial functioning, cognition and quality of life at 8, 16 and 26 weeks post randomisation. Cost effectiveness, patient acceptability, safety, mechanism of action and predictors of response will also be examined