Immune-mediated competition in rodent malaria is most likely caused by induced changes in innate immune clearance of merozoites

Malarial infections are often genetically diverse, leading to competitive interactions between parasites. A quantitative understanding of the competition between strains is essential to understand a wide range of issues, including the evolution of virulence and drug resistance. In this study, we use dynamical-model based Bayesian inference to investigate the cause of competitive suppression of an avirulent clone of Plasmodium chabaudi (AS) by a virulent clone (AJ) in immuno-deficient and competent mice. We test whether competitive suppression is caused by clone-specific differences in one or more of the following processes: adaptive immune clearance of merozoites and parasitised red blood cells (RBCs), background loss of merozoites and parasitised RBCs, RBC age preference, RBC infection rate, burst size, and within-RBC interference. These processes were parameterised in dynamical mathematical models and fitted to experimental data. We found that just one parameter μ, the ratio of background loss rate of merozoites to invasion rate of mature RBCs, needed to be clone-specific to predict the data. Interestingly, μ was found to be the same for both clones in single-clone infections, but different between the clones in mixed infections. The size of this difference was largest in immuno-competent mice and smallest in immuno-deficient mice. This explains why competitive suppression was alleviated in immuno-deficient mice. We found that competitive suppression acts early in infection, even before the day of peak parasitaemia. These results lead us to argue that the innate immune response clearing merozoites is the most likely, but not necessarily the only, mediator of competitive interactions between virulent and avirulent clones. Moreover, in mixed infections we predict there to be an interaction between the clones and the innate immune response which induces changes in the strength of its clearance of merozoites. What this interaction is unknown, but future refinement of the model, challenged with other datasets, may lead to its discovery

The systematic guideline review: method, rationale, and test on chronic heart failure

Background: Evidence-based guidelines have the potential to improve healthcare. However, their de-novo-development requires substantial resources-especially for complex conditions, and adaptation may be biased by contextually influenced recommendations in source guidelines. In this paper we describe a new approach to guideline development-the systematic guideline review method (SGR), and its application in the development of an evidence-based guideline for family physicians on chronic heart failure (CHF). Methods: A systematic search for guidelines was carried out. Evidence-based guidelines on CHF management in adults in ambulatory care published in English or German between the years 2000 and 2004 were included. Guidelines on acute or right heart failure were excluded. Eligibility was assessed by two reviewers, methodological quality of selected guidelines was appraised using the AGREE instrument, and a framework of relevant clinical questions for diagnostics and treatment was derived. Data were extracted into evidence tables, systematically compared by means of a consistency analysis and synthesized in a preliminary draft. Most relevant primary sources were re-assessed to verify the cited evidence. Evidence and recommendations were summarized in a draft guideline. Results: Of 16 included guidelines five were of good quality. A total of 35 recommendations were systematically compared: 25/35 were consistent, 9/35 inconsistent, and 1/35 un-rateable (derived from a single guideline). Of the 25 consistencies, 14 were based on consensus, seven on evidence and four differed in grading. Major inconsistencies were found in 3/9 of the inconsistent recommendations. We re-evaluated the evidence for 17 recommendations (evidence-based, differing evidence levels and minor inconsistencies) - the majority was congruent. Incongruity was found where the stated evidence could not be verified in the cited primary sources, or where the evaluation in the source guidelines focused on treatment benefits and underestimated the risks. The draft guideline was completed in 8.5 man-months. The main limitation to this study was the lack of a second reviewer. Conclusion: The systematic guideline review including framework development, consistency analysis and validation is an effective, valid, and resource saving-approach to the development of evidence-based guidelines

Smoking and Risk of Kidney Failure in the Singapore Chinese Health Study

Background:The relationship between smoking and risk of kidney failure, especially in people of Chinese origin, is not clear. We analyzed data from the Singapore Chinese Health Study to investigate whether smoking increases the risk of kidney failure.Methods:The Singapore Chinese Health Study is a population-based cohort of 63,257 Chinese adults enrolled between 1993 and 1998. Information on smoking status was collected at baseline. Incidence of kidney failure was identified via record linkage with the nationwide Singapore Renal Registry until 2008. Kidney failure was defined by one of the following: 1) serum creatinine level of more than or equal to 500 μmol/l (5.7 mg/dl), 2) estimated glomerular filtration rate of less than 15 ml/min/1.73 m2, 3) undergoing hemodialysis or peritoneal dialysis, 4) undergone kidney transplantation. Cox proportional hazard regression analysis was performed for the outcome of kidney failure after adjusting for age, education, dialect, herbal medications, body mass index, sex, physician-diagnosed hypertension and diabetes mellitus.Results:The mean age of subjects was 55.6 years at baseline, and 44% were men. Overall 30.6% were ever smokers (current or former) at baseline. A total of 674 incident cases of kidney failure occurred during a median follow-up of 13.3 years. Among men, smokers had a significant increase in the adjusted risk of kidney failure [hazard ratio (HR): 1.29; 95% CI: 1.02-1.64] compared to never smokers. There was a strong dose-dependent association between number of years of smoking and kidney failure, (p for trend = 0.011). The risk decreased with prolonged cessation (quitting ≥10 years since baseline). The number of women smokers was too few for conclusive relationship.Limitation:Information on baseline kidney function was not available.Conclusions:Cigarette smoking is associated with increased risk of kidney failure among Chinese men. The risk appears to be dose- and duration-dependent and modifiable after long duration of cessation. © 2013 Jin et al

Asteroseismology and Interferometry

Asteroseismology provides us with a unique opportunity to improve our understanding of stellar structure and evolution. Recent developments, including the first systematic studies of solar-like pulsators, have boosted the impact of this field of research within Astrophysics and have led to a significant increase in the size of the research community. In the present paper we start by reviewing the basic observational and theoretical properties of classical and solar-like pulsators and present results from some of the most recent and outstanding studies of these stars. We centre our review on those classes of pulsators for which interferometric studies are expected to provide a significant input. We discuss current limitations to asteroseismic studies, including difficulties in mode identification and in the accurate determination of global parameters of pulsating stars, and, after a brief review of those aspects of interferometry that are most relevant in this context, anticipate how interferometric observations may contribute to overcome these limitations. Moreover, we present results of recent pilot studies of pulsating stars involving both asteroseismic and interferometric constraints and look into the future, summarizing ongoing efforts concerning the development of future instruments and satellite missions which are expected to have an impact in this field of research.Comment: Version as published in The Astronomy and Astrophysics Review, Volume 14, Issue 3-4, pp. 217-36

Evaluating the role of quality assessment of primary studies in systematic reviews of cancer practice guidelines

BACKGROUND: The purpose of this study was to evaluate the role of study quality assessment of primary studies in cancer practice guidelines. METHODS: Reliable and valid study quality assessment scales were sought and applied to published reports of trials included in systematic reviews of cancer guidelines. Sensitivity analyses were performed to evaluate the relationship between quality scores and pooled odds ratios (OR) for mortality and need for blood transfusion. RESULTS: Results found that that whether trials were classified as high or low quality depended on the scale used to assess them. Although the results of the sensitivity analyses found some variation in the ORs observed, the confidence intervals (CIs) of the pooled effects from each of the analyses of high quality trials overlapped with the CI of the pooled odds of all trials. Quality score was not predictive of pooled ORs studied here. CONCLUSIONS: Had sensitivity analyses based on study quality been conducted prospectively, it is highly unlikely that different conclusions would have been found or that different clinical recommendations would have emerged in the guidelines

Randomised controlled trial of a secondary prevention program for myocardial infarction patients ('ProActive Heart'): study protocol. Secondary prevention program for myocardial infarction patients

Background: \ud Coronary heart disease (CHD) is a significant cause of health and economic burden. Secondary prevention programs play a pivotal role in the treatment and management of those affected by CHD although participation rates are poor due to patient, provider, health system and societal-level barriers. As such, there is a need to develop innovative secondary prevention programs to address the treatment gap. Telephone-delivered care is convenient, flexible and has been shown to improve behavioural and clinical outcomes following myocardial infarction (MI). This paper presents the design of a randomised controlled trial to evaluate the efficacy of a six-month telephone-delivered secondary prevention program for MI patients (ProActive Heart).\ud \ud Methods:\ud 550 adult MI patients have been recruited over a 14 month period (December 2007 to January 2009) through two Brisbane metropolitan hospitals, and randomised to an intervention or control group (n = 225 per group). The intervention commences within two weeks of hospital discharge delivered by study-trained health professionals ('health coaches') during up to 10 × 30 minute scripted telephone health coaching sessions. Participants also receive a ProActive Heart handbook and an educational resource to use during the health coaching sessions. The intervention focuses on appropriate modification of CHD risk factors, compliance with pharmacological management, and management of psychosocial issues. Data collection occurs at baseline or prior to commencement of the intervention (Time 1), six months follow-up or the completion of the intervention (Time 2), and at 12 months follow-up for longer term outcomes (Time 3). Primary outcome measures include quality of life (Short Form-36) and physical activity (Active Australia Survey). A cost-effective analysis of the costs and outcomes for patients in the intervention and control groups is being conducted from the perspective of health care costs to the government.\ud \ud Discussion: The results of this study will provide valuable new information about an innovative telephone-delivered cost-effective secondary prevention program for MI patients

Interval exercise versus continuous exercise in patients with moderate to severe chronic obstructive pulmonary disease – study protocol for a randomised controlled trial [ISRCTN11611768]

BACKGROUND: Physical exercise has become a cornerstone of management of chronic obstructive pulmonary disease (COPD) because it leads to clinically relevant improvements of exercise capacity and health-related quality of life (HRQL). Despite the scarcity of randomised trials directly comparing exercise protocols, current guidelines recommend high intensity continuous exercise for lower extremities as the probably most effective exercise modality. However, for patients admitted to inpatient respiratory rehabilitation programmes, it is often difficult to initiate such an exercise programme because they are severely limited by dyspnoea and leg fatigue and therefore unable to perform continuous exercise at higher intensities and for periods longer than 30 minutes. Interval exercise may be an attractive alternative for these COPD patients because it allows high intensity exercise with recovery periods. The aim of this study is to assess if interval exercise compared to high intensity continuous exercise is not of inferior effectiveness in terms of HRQL and exercise capacity improvements but associated with better exercise tolerance in patients with moderate to severe COPD at the beginning of a respiratory rehabilitation. METHODS/DESIGN: We will assign patients with moderately severe to severe COPD to either continuous exercise or interval exercise using a stratified randomisation. Patients will follow 12–15 exercise sessions during a comprehensive inpatient respiratory rehabilitation. Primary end point for effectiveness is HRQL as measured by the Chronic Respiratory Questionnaire (CRQ) two weeks after the end of rehabilitation and secondary endpoints include additional clinical outcomes such as functional exercise capacity, other HRQL measures, patients' experience of physical exercise as well as physiological measures of the effects of physical exercise such as cardiopulmonary exercise testing. Including expected drop-outs, we will need 52 patients per group to show differences corresponding to the minimal clinically important difference of the CRQ. Outcome assessors and investigators involved in data analysis will be blinded to group assignment until analyses have been carried out. DISCUSSION: Clinicians and the scientific community need evidence on the benefits and tolerance of exercise protocols available in clinical practice. The proposed trial will provide important and needed data on interval and continuous exercise for decision making in clinical practice