Anti-microbial Use in Animals: How to Assess the Trade-offs

Antimicrobials are widely used in preventive and curative medicine in animals. Benefits from curative use are clear – it allows sick animals to be healthy with a gain in human welfare. The case for preventive use of antimicrobials is less clear cut with debates on the value of antimicrobials as growth promoters in the intensive livestock industries. The possible benefits from the use of antimicrobials need to be balanced against their cost and the increased risk of emergence of resistance due to their use in animals. The study examines the importance of animals in society and how the role and management of animals is changing including the use of antimicrobials. It proposes an economic framework to assess the trade-offs of anti-microbial use and examines the current level of data collection and analysis of these trade-offs. An exploratory review identifies a number of weaknesses. Rarely are we consistent in the frameworks applied to the economic assessment anti-microbial use in animals, which may well be due to gaps in data or the prejudices of the analysts. There is a need for more careful data collection that would allow information on (i) which species and production systems antimicrobials are used in, (ii) what active substance of antimicrobials and the application method and (iii) what dosage rates. The species need to include companion animals as well as the farmed animals as it is still not known how important direct versus indirect spread of resistance to humans is. In addition, research is needed on pricing antimicrobials used in animals to ensure that prices reflect production and marketing costs, the fixed costs of anti-microbial development and the externalities of resistance emergence. Overall, much work is needed to provide greater guidance to policy, and such work should be informed by rigorous data collection and analysis systems

A World Full of Privacy and Security (Mis)conceptions? Findings of a Representative Survey in 12 Countries

Misconceptions about digital security and privacy topics in the general public frequently lead to insecure behavior. However, little is known about the prevalence and extent of such misconceptions in a global context. In this work, we present the results of the first large-scale survey of a global population on misconceptions: We conducted an online survey with n = 12, 351 participants in 12 countries on four continents. By investigating influencing factors of misconceptions around eight common security and privacy topics (including E2EE, Wi-Fi, VPN, and malware), we find the country of residence to be the strongest estimate for holding misconceptions. We also identify differences between non-Western and Western countries, demonstrating the need for region-specific research on user security knowledge, perceptions, and behavior. While we did not observe many outright misconceptions, we did identify a lack of understanding and uncertainty about several fundamental privacy and security topics

Cellular Cardiomyoplasty: Clinical Application

Myocardial regeneration can be induced with the implantation of a variety of myogenic and angiogenic cell types. More than 150 patients have been treated with cellular cardiomyoplasty worldwide, 18 patients have been treated by our group. Cellular cardiomyoplasty seems to reduce the size and fibrosis of infarct scars, limit postischemic remodelling, and restore regional myocardial contractility. Techniques for skeletal myoblasts culture and ex vivo expansion using autologous patient serum (obtained from plasmapheresis) have been developed by our group. In this article we propose (1) a total autologous cell culture technique and procedures for cell delivery and (2) a clinical trial with appropriate endpoints structured to determine the efficacy of cellular cardiomyoplasty

Pulsed Feedback Defers Cellular Differentiation

Environmental signals induce diverse cellular differentiation programs. In certain systems, cells defer differentiation for extended time periods after the signal appears, proliferating through multiple rounds of cell division before committing to a new fate. How can cells set a deferral time much longer than the cell cycle? Here we study Bacillus subtilis cells that respond to sudden nutrient limitation with multiple rounds of growth and division before differentiating into spores. A well-characterized genetic circuit controls the concentration and phosphorylation of the master regulator Spo0A, which rises to a critical concentration to initiate sporulation. However, it remains unclear how this circuit enables cells to defer sporulation for multiple cell cycles. Using quantitative time-lapse fluorescence microscopy of Spo0A dynamics in individual cells, we observed pulses of Spo0A phosphorylation at a characteristic cell cycle phase. Pulse amplitudes grew systematically and cell-autonomously over multiple cell cycles leading up to sporulation. This pulse growth required a key positive feedback loop involving the sporulation kinases, without which the deferral of sporulation became ultrasensitive to kinase expression. Thus, deferral is controlled by a pulsed positive feedback loop in which kinase expression is activated by pulses of Spo0A phosphorylation. This pulsed positive feedback architecture provides a more robust mechanism for setting deferral times than constitutive kinase expression. Finally, using mathematical modeling, we show how pulsing and time delays together enable “polyphasic” positive feedback, in which different parts of a feedback loop are active at different times. Polyphasic feedback can enable more accurate tuning of long deferral times. Together, these results suggest that Bacillus subtilis uses a pulsed positive feedback loop to implement a “timer” that operates over timescales much longer than a cell cycle

Creativity and Innovation under Constraints: A Cross-Disciplinary Integrative Review

Generating creative ideas and turning them into innovations is key for competitive advantage. However, endeavors toward creativity and innovation are bounded by constraints such as rules and regulations, deadlines, and scarce resources. The effect of constraints on creativity and innovation has attracted substantial interest across the fields of strategic management, entrepreneurship, industrial organization, technology and operations management, organizational behavior, and marketing. Research in these fie ds has focused on various constraints that trigger distinct mediating mechanisms but is fragmented and yields conflicting findings. We develop a taxonomy of constraints and mediating mechanisms and provide an integrative synthesis that explains how constraints impact creativity and innovation. Our review thus facilitates cross-disciplinary learning and sets the stage for further theoretical development

Do Aphid Colonies Amplify their Emission of Alarm Pheromone?

When aphids are attacked by natural enemies, they emit alarm pheromone to alert conspecifics. For most aphids tested, (E)-β-farnesene (EBF) is the main, or only, constituent of the alarm pheromone. In response to alarm pheromone, alerted aphids drop off the plant, walk away, or attempt to elude predators. However, under natural conditions, EBF concentration might be low due to the low amounts emitted, to rapid air movement, or to oxidative degradation. To ensure that conspecifics are warned, aphids might conceivably amplify the alarm signal by emitting EBF in response to EBF emitted by other aphids. To examine whether such amplification occurs, we synthesized deuterated EBF (DEBF), which allowed us to differentiate between applied and aphid-derived chemical. Colonies of Acyrthosiphon pisum were treated with DEBF, and headspace volatiles were collected and analyzed for evidence of aphid-derived EBF. No aphid-derived EBF was detected, suggesting that amplification of the alarm signal does not occur. We discuss the disadvantages of alarm signal reinforcement

The first three-dimensional visualization of a thrombus in transit trapped between the leads of a permanent dual-chamber pacemaker: a case report

<p>Abstract</p> <p>Introduction</p> <p>Two-dimensional echocardiography is a useful tool in diagnosing cardiac masses. However, the three-dimensional offline reconstruction technique of transesophageal echocardiography might be superior to two-dimensional transesophageal echocardiography in providing additional information of structural details.</p> <p>Case presentation</p> <p>We report the case of a 76-year-old Caucasian man with a permanent dual-chamber pacemaker and a worm-like right-heart thrombus in transit. Two-dimensional transthoracic echocardiography and two-dimensional transesophageal echocardiography showed that it was debatable as to whether "the worm" was originating from the leads. Offline three-dimensional transesophageal echocardiography reconstruction technique proved superior in identifying the cardiac mass as a thrombus trapped between the leads of the pacemaker. The thrombus was successfully dissolved by systemic heparin therapy.</p> <p>Conclusions</p> <p>The three-dimensional transesophageal echocardiography is useful and effective in patients with implanted pacemakers or defibrillators when other closely competing imaging modalities are contraindicated, such as magnetic resonance imaging. In patients with pacemakers and trapped thrombus in transit for whom surgical therapy might be a high risk, medical therapy seems to offer a safer and convincing alternative. Whether the management of right-heart thrombi has to be modified due to the presence of pacemaker leads is controversial.</p

Pharmacokinetic and clinical profile of a novel formulation of bosentan in children with pulmonary arterial hypertension: the FUTURE-1 study

center dot Exposure to bosentan was lower in paediatric pulmonary arterial hypertension (PAH) patients treated with the marketed adult formulation at a dose of about 2 mg kg-1 when compared with adult PAH patients. center dot In healthy adult subjects, bosentan pharmacokinetics are less than dose-proportional at doses of >= 500 mg. WHAT THIS STUDY ADDS center dot The pharmacokinetics of a new paediatric bosentan formulation were characterized in paediatric PAH patients. center dot The level of exposure to bosentan as observed in adult PAH patients cannot be reached in paediatric patients with b.i.d. dosing. center dot In paediatric PAH patients, nondose-proportional pharmacokinetics of bosentan occur at lower doses when compared with healthy adult subjects. AIM To show equivalent bosentan exposure in paediatric patients with pulmonary arterial hypertension (PAH) when compared with a cohort of historical controls of adult PAH patients using a newly developed paediatric formulation. METHODS Thirty-six paediatric PAH patients were enrolled in this multicentre, prospective, open-label, noncontrolled study and treated for 4 weeks with bosentan 2 mg kg-1 b.i.d. and then for 8 weeks with 4 mg kg-1 b.i.d. Blood samples were taken for pharmacokinetic purposes. Exploratory efficacy measurements included World Health Organization (WHO) functional class and parent's and clinician's Global Clinical Impression scales. RESULTS Comparing children with a historical group of adults, the geometric mean ratio (90% confidence interval) of the area under the plasma concentration-time curve was 0.54 (0.37, 0.78), i.e. children had lower exposure to bosentan than adults. Bosentan concentrations following doses of 2 and 4 mg kg-1 were similar. Improvements in WHO functional class and the Global Clinical Impression scales occurred mainly in bosentan-naive patients, whereas the rare worsenings occurred in patients already on bosentan prior to study initiation. The paediatric formulation was well accepted and bosentan well tolerated in this study. No cases of elevated liver enzymes or anaemia were reported. CONCLUSIONS Exposure to bosentan, as shown comparing the results from this study with those from a study in adults, was different in paediatric and adult PAH patients. Since FUTURE-1 and past studies suggest a favourable benefit-risk profile for bosentan at 2 mg kg-1 b.i.d., this dose is recommended for children with PAH. The new paediatric formulation was well tolerate