Systemic oxidative-nitrosative-inflammatory stress during acute exercise in hypoxia; implications for microvascular oxygenation and aerobic capacity

New Findings

What is the central question of this study?Exercise performance is limited during hypoxia by a critical reduction in cerebral and skeletal tissue oxygenation. To what extent an elevation in systemic free radical accumulation contributes to microvascular deoxygenation and the corresponding reduction in maximal aerobic capacity remains unknown.What is the main finding and its importance?We show that altered free radical metabolism is not a limiting factor for exercise performance in hypoxia, providing important insight into the fundamental mechanisms involved in the control of vascular oxygen transport.

Exercise performance in hypoxia may be limited by a critical reduction in cerebral and skeletal tissue oxygenation, although the underlying mechanisms remain unclear. We examined whether increased systemic free radical accumulation during hypoxia would be associated with elevated microvascular deoxygenation and reduced maximal aerobic capacity (). Eleven healthy men were randomly assigned single-blind to an incremental semi-recumbent cycling test to determine  in both normoxia (21% O_{2) and hypoxia (12% O2) separated by a week. Continuous-wave near-infrared spectroscopy was employed to monitor concentration changes in oxy- and deoxyhaemoglobin in the left vastus lateralis muscle and frontal cerebral cortex. Antecubital venous blood samples were obtained at rest and at  to determine oxidative (ascorbate radical by electron paramagnetic resonance spectroscopy), nitrosative (nitric oxide metabolites by ozone-based chemiluminescence and 3-nitrotyrosine by enzyme-linked immunosorbent assay) and inflammatory stress biomarkers (soluble intercellular/vascular cell adhesion 1 molecules by enzyme-linked immunosorbent assay). Hypoxia was associated with increased cerebral and muscle tissue deoxygenation and lower  (P < 0.05 versus normoxia). Despite an exercise-induced increase in oxidative–nitrosative–inflammatory stress, hypoxia per se did not have an additive effect (P > 0.05 versus normoxia). Consequently, we failed to observe correlations between any metabolic, haemodynamic and cardiorespiratory parameters (P > 0.05). Collectively, these findings suggest that altered free radical metabolism cannot explain the elevated microvascular deoxygenation and corresponding lower  in hypoxia. Further research is required to determine whether free radicals when present in excess do indeed contribute to the premature termination of exercise in hypoxia.}

Genetic assessment of parentage in the caridean rock shrimp Rhynchocinetes typus based on microsatellite markers

Over the past decade, the common rock shrimp, Rhynchocinetes typus H. Milne Edwards, 1837, has been the focus of extensive investigations on mating behaviour. The species is now perceived as a model system for the study of reproductive strategies and sexual conflict in crustaceans displaying external fertilization. Using molecular markers, the current study assesses whether social mating behaviour in common rock shrimp translates into true genetic parentage. In a large mesocosm tank with >200 individuals of both sexes, the analysis of 15 families (22 eggs per female) for three informative microsatellites unambiguously confirmed multiple paternity in 11 instances (73%) involving, in each case, two to four males. Where more than one male was identified siring a particular brood, reproductive skew was apparent towards a single individual. Results suggest that multiple paternity in this species results from subordinate male coercive behaviour, female solicitation of multiple male matings or a combination of both.

A modified method for measuring antibiotic use in healthcare settings: implications for antibiotic stewardship and benchmarking

Objectives: To determine whether adjusting the denominator of the common hospital antibiotic use measurement unit (defined daily doses/100 bed-days) by including age-adjusted comorbidity score (100 bed-days/age-adjusted comorbidity score) would result in more accurate and meaningful assessment of hospital antibiotic use. 

Methods: The association between the monthly sum of age-adjusted comorbidity and monthly antibiotic use was measured using time-series analysis (January 2008 to June 2012). For the purposes of conducting internal benchmarking, two antibiotic usage datasets were constructed, i.e. 2004-07 (first study period) and 2008-11 (second study period). Monthly antibiotic use was normalized per 100 bed-days and per 100 bed-days/age-adjusted comorbidity score. 

Results: Results showed that antibiotic use had significant positive relationships with the sum of age-adjusted comorbidity score (P = 0.0004). The results also showed that there was a negative relationship between antibiotic use and (i) alcohol-based hand rub use (P = 0.0370) and (ii) clinical pharmacist activity (P = 0.0031). Normalizing antibiotic use per 100 bed-days contributed to a comparative usage rate of 1.31, i.e. the average antibiotic use during the second period was 31% higher than during the first period. However, normalizing antibiotic use per 100 bed-days per age-adjusted comorbidity score resulted in a comparative usage rate of 0.98, i.e. the average antibiotic use was 2% lower in the second study period. Importantly, the latter comparative usage rate is independent of differences in patient density and case mix characteristics between the two studied populations. 

Conclusions: The proposed modified antibiotic measure provides an innovative approach to compare variations in antibiotic prescribing while taking account of patient case mix effects. 

Per-Flow State Management Technique for High-Speed Networks

Flow processing is a fundamental element of stateful traffic classification and it has been recognized as an essential factor for delivering today’s application-aware network operations and security services. The basic function within a flow processing engine is to search and maintain a flow table, create new flow entries if no entry matches and associate each entry with flow states and actions for future queries. Network state information on a per-flow basis must be managed in an efficient way to enable Ethernet frame transmissions at 40 Gbit/s (Gbps) and 100 Gbps in the near future. This paper presents a hardware solution of flow state management for implementing large-scale flow tables on popular computer memories using DDR3 SDRAMs. Working with a dedicated flow lookup table at over 90 million lookups per second, the proposed system is able to manage 512-bit state information at run time.

Macroautophagic cargo sequestration assays

Macroautophagy, the process responsible for bulk sequestration and lysosomal degradation of cytoplasm, is often monitored by means of the autophagy-related marker protein LC3. This protein is linked to the phagophoric membrane by lipidation during the final steps of phagophore assembly, and it remains associated with autophagic organelles until it is degraded in the lysosomes. The transfer of LC3 from cytosol to membranes and organelles can be measured by immunoblotting or immunofluorescence microscopy, but these assays provide no information about functional macroautophagic activity, i.e., whether the phagophores are actually engaged in the sequestration of cytoplasmic cargo and enclosing this cargo into sealed autophagosomes. Moreover, accumulating evidence suggest that macroautophagy can proceed independently of LC3. There is therefore a need for alternative methods, preferably effective cargo sequestration assays, which can monitor actual macroautophagic activity. Here, we provide an overview of various approaches that have been used over the last four decades to measure macroautophagic sequestration activity in mammalian cells. Particular emphasis is given to the so-called "LDH sequestration assay", which measures the transfer of the autophagic cargo marker enzyme LDH (lactate dehydrogenase) from the cytosol to autophagic vacuoles. The LDH sequestration assay was originally developed to measure macroautophagic activity in primary rat hepatocytes. Subsequently, it has found use in several other cell types, and in this article we demonstrate a further validation and simplification of the method, and show that it is applicable to several cell lines that are commonly used to study autophagy.

Genetically Determined Height and Coronary Artery Disease

Background: The nature and underlying mechanisms of an inverse association between adult height and the risk of coronary artery disease (CAD) are unclear. 
Methods: We used a genetic approach to investigate the association between height and CAD, using 180 height-associated genetic variants. We tested the association between a change in genetically determined height of 1 SD (6.5 cm) with the risk of CAD in 65,066 cases and 128,383 controls. Using individual-level genotype data from 18,249 persons, we also examined the risk of CAD associated with the presence of various numbers of height-associated alleles. To identify putative mechanisms, we analyzed whether genetically determined height was associated with known cardiovascular risk factors and performed a pathway analysis of the height-associated genes. 
Results: We observed a relative increase of 13.5% (95% confidence interval [CI], 5.4 to 22.1; P<0.001) in the risk of CAD per 1-SD decrease in genetically determined height. There was a graded relationship between the presence of an increased number of height-raising variants and a reduced risk of CAD (odds ratio for height quartile 4 versus quartile 1, 0.74; 95% CI, 0.68 to 0.84; P<0.001). Of the 12 risk factors that we studied, we observed significant associations only with levels of low-density lipoprotein cholesterol and triglycerides (accounting for approximately 30% of the association). We identified several overlapping pathways involving genes associated with both development and atherosclerosis. 
Conclusions: There is a primary association between a genetically determined shorter height and an increased risk of CAD, a link that is partly explained by the association between shorter height and an adverse lipid profile. Shared biologic processes that determine achieved height and the development of atherosclerosis may explain some of the association. (Funded by the British Heart Foundation and others.)

Effectiveness of a biomarker-based exclusion of ventilator-acquired pneumonia to reduce antibiotic use: protocol for a randomised controlled trial (VAPrapid-2):Study protocol for a randomised controlled trial

Background Ventilator-acquired pneumonia (VAP) is a common reason for antimicrobial therapy in the intensive care unit (ICU). Biomarker-based diagnostics could improve antimicrobial stewardship through rapid exclusion of VAP. Bronchoalveloar lavage (BAL) fluid biomarkers have previously been shown to allow the exclusion of VAP with high confidence. Methods/Design This is a prospective, multi-centre, randomised, controlled trial to determine whether a rapid biomarker-based exclusion of VAP results in fewer antibiotics and improved antimicrobial management. Patients with clinically suspected VAP undergo BAL, and VAP is confirmed by growth of a potential pathogen at > 104 colony-forming units per millilitre (CFU/ml). Patients are randomised 1:1, to either a ‘biomarker-guided recommendation on antibiotics’ in which BAL fluid is tested for IL-1β and IL-8 in addition to routine microbiology testing, or to ‘routine use of antibiotics’ in which BAL undergoes routine microbiology testing only. Clinical teams are blinded to intervention until 6 hours after randomisation, when biomarker results are reported to the clinician. The primary outcome is a change in the frequency distribution of antibiotic-free days (AFD) in the 7 days following BAL. Secondary outcome measures include antibiotic use at 14 and 28 days; ventilator-free days; 28-day mortality and ICU mortality; sequential organ failure assessment (SOFA) at days 3, 7 and 14; duration of stay in critical care and the hospital; antibiotic-associated infections; and antibiotic-resistant pathogen cultures up to hospital discharge, death or 56 days. A healthcare-resource-utilisation analysis will be calculated from the duration of critical care and hospital stay. In addition, safety data will be collected with respect to performing BAL. A sample size of 210 will be required to detect a clinically significant shift in the distribution of AFD towards more patients having fewer antibiotics and therefore more AFD. Discussion This trial will test whether a rapid biomarker-based exclusion of VAP results in rapid discontinuation of antibiotics and therefore improves antibiotic management in patients with suspected VAP.

Breaking and Entering: Examining the role of stress and aerial exposure in predator-prey relationships between the common shore crab (Carcinus maenas) and cultivated blue mussels (Mytilus edulis).

During benthic cultivation Mytilus edulis (blue mussels) are subject to predation pressure from a number of predators including Carcinus maenas (shore crabs). This predator can be responsible for substantial losses of mussels from the fishery and a full understanding of the predator–prey relationship between M. edulis and C. maenas is required to ensure attempts that reduce predatory pressure and subsequent commercial loss are successful. Whilst much work has examined the prey–predator size relationships between C. maenas and M. edulis, far less research has investigated how stress, such as periods of extended aerial exposure, may affect these relationships. We tested whether profit in terms of calories gained by crabs consuming mussels stressed by aerial exposure for 48 h differed from that of mussels at ambient conditions and whether being stressed affected the mussel's likelihood of predation. We also tested whether the size relationship between predators and their prey differed when mussels were stressed. We found that the profitability of prey (calories gained per second of handling time) did not vary between stressed and unstressed mussels. Handling times for stressed and unstressed mussels were similar, even when crabs were presented with mussels of the maximum size that they are able to consume. Small crabs were more likely to reject a mussel of preferred size if it was unstressed, suggesting that crabs may be able to assess that these mussels would require extra effort to break into and consume. Our findings suggest that the predator–prey relationship between mussels and crabs is not altered when mussels are stressed. C. maenas remains a voracious predator and regardless of the condition of mussels laid on commercial beds there is a need to control this predator in attempt to reduce losses in the benthic fishery.

Social housing tenants, Climate Change and sustainable living: A study of awareness, behaviours and willingness to adapt

Despite a focus in the UK on providing sustainable housing in recent years, it is unlikely that targets set to reduce resource consumption in housing will be achieved without a greater focus on human behaviour. It is necessary to understand the actions of people occupying dwellings, as it is invariably the occupants rather than the buildings that decided whether or not to consume resources. In this paper the authors present a pilot study where 53 social housing tenant households in Northern Ireland were interviewed to ascertain their perceptions of Climate Change, their current behaviours and their willingness to reduce energy and water consumption in the home. The intention was to explore links between perceptions and reported behaviour as well as perceptions and willingness to reduce resource consumption. Results show that 77% of tenants believed Climate Change to be an important issue; 57% accepted that it is up to the individual to take responsibility for tackling Climate Change; and demonstrated a strong desire to make a difference to reduce their impact. The researchers identified both passive (devices) and active (behaviours) resource savings currently in place and established where further resource reduction was feasible based on tenants' willingness to alter their behaviours.

Computing probable maximum loss in catastrophe reinsurance portfolios on multi-core and many-core architectures

In the reinsurance market, the risks natural catastrophes pose to portfolios of properties must be quantified, so that they can be priced, and insurance offered. The analysis of such risks at a portfolio level requires a simulation of up to 800 000 trials with an average of 1000 catastrophic events per trial. This is sufficient to capture risk for a global multi-peril reinsurance portfolio covering a range of perils including earthquake, hurricane, tornado, hail, severe thunderstorm, wind storm, storm surge and riverine flooding, and wildfire. Such simulations are both computation and data intensive, making the application of high-performance computing techniques desirable.

In this paper, we explore the design and implementation of portfolio risk analysis on both multi-core and many-core computing platforms. Given a portfolio of property catastrophe insurance treaties, key risk measures, such as probable maximum loss, are computed by taking both primary and secondary uncertainties into account. Primary uncertainty is associated with whether or not an event occurs in a simulated year, while secondary uncertainty captures the uncertainty in the level of loss due to the use of simplified physical models and limitations in the available data. A combination of fast lookup structures, multi-threading and careful hand tuning of numerical operations is required to achieve good performance. Experimental results are reported for multi-core processors and systems using NVIDIA graphics processing unit and Intel Phi many-core accelerators.

Improving E-Assessment Systems With A focus On Adaptive Feedback And Marking

Institutions involved in the provision of tertiary education across Europe are feeling the pinch. European universities, and other higher education (HE) institutions, must operate in a climate where the pressure of government spending cuts (Garben, 2012) is in stark juxtaposition to the EU’s strategy to drive forward and maintain a growth of student numbers in the sector (eurostat, 2015).

In order to remain competitive, universities and HE institutions are making ever-greater use of electronic assessment (E-Assessment) systems (Chatzigavriil et all, 2015; Ferrell, 2012). These systems are attractive primarily because they offer a cost-effect and scalable approach for assessment. In addition to scalability, they also offer reliability, consistency and impartiality; furthermore, from the perspective of a student they are most popular because they can offer instant feedback (Walet, 2012).

There are disadvantages, though.

First, feedback is often returned to a student immediately on competition of their assessment. While it is possible to disable the instant feedback option (this is often the case during an end of semester exam period when assessment scores must be can be ratified before release), however, this option tends to be a global ‘all on’ or ‘all off’ configuration option which is controlled centrally rather than configurable on a per-assessment basis.

If a formative in-term assessment is to be taken by multiple groups of
students, each at different times, this restriction means that answers to each question will be disclosed to the first group of students undertaking the assessment. As soon as the answers are released “into the wild” the academic integrity of the assessment is lost for subsequent student groups.

Second, the style of feedback provided to a student for each question is often limited to a simple ‘correct’ or ‘incorrect’ indicator. While this type of feedback has its place, it often does not provide a student with enough insight to improve their understanding of a topic that they did not answer correctly.

Most E-Assessment systems boast a wide range of question types including Multiple Choice, Multiple Response, Free Text Entry/Text Matching and Numerical questions. The design of these types of questions is often quite restrictive and formulaic, which has a knock-on effect on the quality of feedback that can be provided in each case.

Multiple Choice Questions (MCQs) are most prevalent as they are the most prescriptive and therefore most the straightforward to mark consistently. They are also the most amenable question types, which allow easy provision of meaningful, relevant feedback to each possible outcome chosen.
Text matching questions tend to be more problematic due to their free text entry nature. Common misspellings or case-sensitivity errors can often be accounted for by the software but they are by no means fool proof, as it is very difficult to predict in advance the range of possible variations on an answer that would be considered worthy of marks by a manual marker of a paper based equivalent of the same question.

Numerical questions are similarly restricted. An answer can be checked for accuracy or whether it is within a certain range of the correct answer, but unless it is a special purpose-built mathematical E-Assessment system the system is unlikely to have computational capability and so cannot, for example, account for “method marks” which are commonly awarded in paper-based marking.

From a pedagogical perspective, the importance of providing useful formative feedback to students at a point in their learning when they can benefit from the feedback and put it to use must not be understated (Grieve et all, 2015; Ferrell, 2012).

In this work, we propose a number of software-based solutions, which will overcome the limitations and inflexibilities of existing E-Assessment systems.

Pharmacist-led feedback workshops increase appropriate prescribing of antimicrobials

Objectives To investigate whether and how structured feedback sessions can increase rates of appropriate antimicrobial prescribing by junior doctors.

Methods This was a mixed-methods study, with a conceptual orientation towards complexity and systems thinking. Fourteen junior doctors, in their first year of training, were randomized to intervention (feedback) and 21 to control (routine practice) groups in a single UK teaching hospital. Feedback on their antimicrobial prescribing was given, in writing and via group sessions. Pharmacists assessed the appropriateness of all new antimicrobial prescriptions 2 days per week for 6 months (46 days). The mean normalized prescribing rates of suboptimal to all prescribing were compared between groups using the t-test. Thematic analysis of qualitative interviews with 10 participants investigated whether and how the intervention had impact.

Results Data were collected on 204 prescriptions for 166 patients. For the intervention group, the mean normalized rate of suboptimal to all prescribing was 0.32 ± 0.36; for the control group, it was 0.68 ± 0.36. The normalized rates of suboptimal prescribing were significantly different between the groups (P = 0.0005). The qualitative data showed that individuals' prescribing behaviour was influenced by a complex series of dynamic interactions between individual and social variables, such as interplay between personal knowledge and the expectations of others.

Conclusions The feedback intervention increased appropriate prescribing by acting as a positive stimulus within a complex network of behavioural influences. Prescribing behaviour is adaptive and can be positively influenced by structured feedback. Changing doctors' perceptions of acceptable, typical and best practice could reduce suboptimal antimicrobial prescribing.