Deactivation of the lipopolysaccharide antagonist eritoran (E5564) by high-density lipoprotein-associated apolipoproteins

Lipid A, the active moiety of LPS, exerts its effects through interaction with TLR4, triggering a signalling cascade that results in the release of pro-inflammatory cytokines. Eritoran is a lipid A analogue that competes with LPS for binding to TLR4; however, after intravenous administration, it undergoes a time-dependent deactivation as a consequence of binding to high-density lipoproteins (HDLs). The site of eritoran association with HDL remains unknown. Therefore the aim of this study was to determine if HDL-associated apolipoproteins A1, A2, serum amyloid A (SAA) and C1, inhibit the ability of eritoran to block LPS-induced TNF-α release from whole blood. Eritoran activity after LPS stimulation in human whole blood was assessed in the presence of reconstituted HDL (rHDL) containing different apos. In rHDL, the major apolipoproteins in both the healthy and septic state, A1 and SAA, caused a significant reduction in eritoran antagonistic activity and had a greater effect than minor apolipoproteins A2 and C1. Apolipoproteins associated with HDL are likely to facilitate eritoran deactivation. Apolipoproteins A1 and SAA should be of particular focus as they are the major apos found on HDL in both the healthy and septic state. Further evaluation of the physical association between apolipoproteins and eritoran should be explored.     

Anesthesiologists' and surgeons' perceptions about routine pre-operative testing in low-risk patients: application of the Theoretical Domains Framework (TDF) to identify factors that influence physicians' decisions to order pre-operative tests

ABSTRACT: BACKGROUND: Routine pre-operative tests for anesthesia management are often ordered by bothanesthesiologists and surgeons for healthy patients undergoing low-risk surgery. TheTheoretical Domains Framework (TDF) was developed to investigate determinants ofbehaviour and identify potential behaviour change interventions. In this study, the TDF is used to explore anaesthesiologists' and surgeons' perceptions of ordering routine tests forhealthy patients undergoing low-risk surgery. METHODS: Sixteen clinicians (eleven anesthesiologists and five surgeons) throughout Ontario wererecruited. An interview guide based on the TDF was developed to identify beliefs about preoperativetesting practices. Content analysis of physicians' statements into the relevanttheoretical domains was performed. Specific beliefs were identified by grouping similarutterances of the interview participants. Relevant domains were identified by noting thefrequencies of the beliefs reported, presence of conflicting beliefs, and perceived influence onthe performance of the behaviour under investigation. RESULTS: Seven of the twelve domains were identified as likely relevant to changing clinicians'behaviour about pre-operative test ordering for anesthesia management. Key beliefs wereidentified within these domains including: conflicting comments about who was responsiblefor the test-ordering (Social/professional role and identity); inability to cancel tests orderedby fellow physicians (Beliefs about capabilities and social influences); and the problem withtests being completed before the anesthesiologists see the patient (Beliefs about capabilitiesand Environmental context and resources). Often, tests were ordered by an anesthesiologistbased on who may be the attending anesthesiologist on the day of surgery while surgeonsordered tests they thought anesthesiologists may need (Social influences). There were alsoconflicting comments about the potential consequences associated with reducing testing,from negative (delay or cancel patients' surgeries), to indifference (little or no change inpatient outcomes), to positive (save money, avoid unnecessary investigations) (Beliefs aboutconsequences). Further, while most agreed that they are motivated to reduce orderingunnecessary tests (Motivation and goals), there was still a report of a gap between theirmotivation and practice (Behavioural regulation). CONCLUSION: We identified key factors that anesthesiologists and surgeons believe influence whether theyorder pre-operative tests routinely for anesthesia management for a healthy adults undergoinglow-risk surgery. These beliefs identify potential individual, team, and organisation targetsfor behaviour change interventions to reduce unnecessary routine test ordering.     

Learning curves, taking instructions, and patient safety: using a theoretical domains framework in an interview study to investigate prescribing errors among trainee doctors

ABSTRACT: BACKGROUND: Prescribing errors are a major source of morbidity and mortality and represent a significant patient safety concern. Evidence suggests that trainee doctors are responsible for most prescribing errors. Understanding the factors that influence prescribing behavior may lead to effective interventions to reduce errors. Existing investigations of prescribing errors have been based on Human Error Theory but not on other relevant behavioral theories. The aim of this study was to apply a broad theory-based approach using the Theoretical Domains Framework (TDF) to investigate prescribing in the hospital context among a sample of trainee doctors. METHOD: Semistructured interviews, based on 12 theoretical domains, were conducted with 22 trainee doctors to explore views, opinions, and experiences of prescribing and prescribing errors. Content analysis was conducted, followed by applying relevance criteria and a novel stage of critical appraisal, to identify which theoretical domains could be targeted in interventions to improve prescribing. RESULTS: Seven theoretical domains met the criteria of relevance: "social professional role and identity," "environmental context and resources," "social influences," "knowledge," "skills," "memory, attention, and decision making," and "behavioral regulation." From critical appraisal of the interview data, "beliefs about consequences" and "beliefs about capabilities" were also identified as potentially important domains. Interrelationships between domains were evident. Additionally, the data supported theoretical elaboration of the domain behavioral regulation. CONCLUSIONS: In this investigation of hospital-based prescribing, participants' attributions about causes of errors were used to identify domains that could be targeted in interventions to improve prescribing. In a departure from previous TDF practice, critical appraisal was used to identify additional domains that should also be targeted, despite participants' perceptions that they were not relevant to prescribing errors. These were beliefs about consequences and beliefs about capabilities. Specifically, in the light of the documented high error rate, beliefs that prescribing errors were not likely to have consequences for patients and that trainee doctors are capable of prescribing without error should also be targeted in an intervention. This study is the first to suggest critical appraisal for domain identification and to use interview data to propose theoretical elaborations and interrelationships between domains.     

Optimal strategy for controlling the spread of HIV/AIDS disease: a case study of South Africa

HIV/AIDS disease continues to spread alarmingly despite the huge amounts of resources invested in fighting it. There is a need to integrate the series of control measures available to ensure a consistent reduction in the incidence of the disease pending the discovery of its cure. We present a deterministic model for controlling the spread of the disease using change in sexual habits and antiretroviral (ARV) therapy as control measures. We formulate a fixed time optimal control problem subject to the model dynamics with the goal of finding the optimal combination of the two control measures that will minimize the cost of the control efforts as well as the incidence of the disease. We estimate the model state initial conditions and parameter values from the demographic and HIV/AIDS data of South Africa. We use Pontryagin's maximum principle to derive the optimality system and solve the system numerically. Compared with the practice in most resource-limited settings where ARV treatment is given only to patients with full-blown AIDS, our simulation results suggest that starting the treatment as soon as the patients progress to the pre-AIDS stage of the disease coupled with appreciable change in the susceptible individuals' sexual habits reduces both the incidence and prevalence of the disease faster. In fact, the results predict that the implementation of the proposed strategy would drive new cases of the disease towards eradication in 10 years.     

Vaccination of a melanoma patient with mature dendritic cells pulsed with MAGE-3 peptides triggers the activity of nonvaccine anti-tumor cells

We previously characterized the CTL response of a melanoma patient who experienced tumor regression following vaccination with an ALVAC virus coding for a MAGE-A3 Ag. Whereas anti-vaccine CTL were rare in the blood and inside metastases of this patient, anti-tumor CTL recognizing other tumor Ags, mainly MAGE-C2, were 100 times more frequent in the blood and considerably enriched in metastases following vaccination. In this study we report the analysis of the CTL response of a second melanoma patient who showed a mixed tumor response after vaccination with dendritic cells pulsed with two MAGE-A3 antigenic peptides presented, respectively, by HLA-A1 and HLA-DP4. Anti-MAGE-3.A1 CD8 and anti-MAGE-3.DP4 CD4 T cells became detectable in the blood after vaccination at a frequency of approximately 10(-5) among the CD8 or CD4 T cells, respectively, and they were slightly enriched in slowly progressing metastases. Additional anti-tumor CTL were present in the blood at a frequency of 2x10(-4) among the CD8 T cells and, among these, an anti-MAGE-C2 CTL clone was detected only following vaccination and was enriched by >1,000-fold in metastases relative to the blood. The striking similarity of these results with our previous observations further supports the hypothesis that the induction of a few anti-vaccine T cells may prime or restimulate additional anti-tumor T cell clones that are mainly responsible for the tumor regression.     

Reproductive success in varying light environments: direct and indirect effects of light on plants and pollinators

Plant populations often exist in spatially heterogeneous environments. Light level can directly affect plant reproductive success through resource availability or by altering pollinator behavior. It can also indirectly influence reproductive success by determining floral display size which may in turn influence pollinator attraction. We evaluated direct and indirect effects of light availability and measured phenotypic selection on phenological traits that may enhance pollen receipt in the insect-pollinated herb Campanulastrum americanum. In a natural population, plants in the sun had larger displays and received 7 times more visits than plants in the shade. Using experimental arrays to separate the direct effects of irradiance on insects from their response to display size, we found more visits to plants in the sun than in the shade, but no association between number of visits each flower received and display size. Plants in the sun were not pollen limited but pollen-augmented shade flowers produced 50% more seeds than open-pollinated flowers. Phenological traits, which may influence pollen receipt, were not under direct selection in the sun. However, earlier initiation and a longer duration of flowering were favored in the shade, which may enhance visitation in this pollen-limited habitat.     

Superior wood for violins--wood decay fungi as a substitute for cold climate

Violins produced by Antonio Stradivari during the late 17th and early 18th centuries are reputed to have superior tonal qualities. Dendrochronological studies show that Stradivari used Norway spruce that had grown mostly during the Maunder Minimum, a period of reduced solar activity when relatively low temperatures caused trees to lay down wood with narrow annual rings, resulting in a high modulus of elasticity and low density. The main objective was to determine whether wood can be processed using selected decay fungi so that it becomes acoustically similar to the wood of trees that have grown in a cold climate (i.e. reduced density and unchanged modulus of elasticity). This was investigated by incubating resonance wood specimens of Norway spruce (Picea abies) and sycamore (Acer pseudoplatanus) with fungal species that can reduce wood density, but lack the ability to degrade the compound middle lamellae, at least in the earlier stages of decay. Microscopic assessment of the incubated specimens and measurement of five physical properties (density, modulus of elasticity, speed of sound, radiation ratio, and the damping factor) using resonance frequency revealed that in the wood of both species there was a reduction in density, accompanied by relatively little change in the speed of sound. Thus, radiation ratio was increased from 'poor' to 'good', on a par with 'superior' resonance wood grown in a cold climate.