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Seventy six senior academics from 11 countries invite The BMJ ’s editors to reconsider their policy of rejecting qualitative research on the grounds of low priority. They challenge the journal to develop a proactive, scholarly, and pluralist approach to research that aligns with its stated mission

Introduction: Self-management interventions in patients with chronic conditions have received increasing attention over the past few years, yet the meta-analyses encountered considerable heterogeneity in results. This suggests that the effectiveness of self-management interventions must be assessed in the context of which components are responsible for eliciting the effect and in which subgroups of patients the intervention works best. The aim of the present study is to identify condition-transcending determinants of success of self-management interventions in two parallel individual patient data meta-analyses of self-management trials in patients with congestive heart failure (CHF) and in patients with chronic obstructive pulmonary disease (COPD). Methods and analysis: Investigators of 53 randomised trials (32 in CHF and 21 in COPD) will be requested to share their de-identified individual patient data. Data will be analysed using random effects models, taking clustering within studies into account. Effect modification by age, sex, disease severity, symptom status, comorbid conditions and level of education will be assessed. Sensitivity analyses will be conducted to assess the robustness of the findings. Ethics and dissemination: The de-identified individual patient data are used only for the purpose for which they were originally collected and for which ethical approval has been obtained by the original investigators. Knowledge on the effective ingredients of self-management programmes and identification of subgroups of patients in which those interventions are most effective will guide the development of evidence-based personalised self-management interventions for patients with CHF and COPD as well as with other chronic diseases. Trial registration number: PROSPERO: CRD42013004698.

The capacity to focus one's attention for an extended period of time can be increased through training in contemplative practices. However, the cognitive processes engaged during meditation that support trait changes in cognition are not well characterized. We conducted a longitudinal wait-list controlled study of intensive meditation training. Retreat participants practiced focused attention (FA) meditation techniques for three months during an initial retreat. Wait-list participants later undertook formally identical training during a second retreat. Dense-array scalp-recorded electroencephalogram (EEG) data were collected during 6 min of mindfulness of breathing meditation at three assessment points during each retreat. Second-order blind source separation, along with a novel semi-automatic artifact removal tool (SMART), was used for data preprocessing. We observed replicable reductions in meditative state-related beta-band power bilaterally over anteriocentral and posterior scalp regions. In addition, individual alpha frequency (IAF) decreased across both retreats and in direct relation to the amount of meditative practice. These findings provide evidence for replicable longitudinal changes in brain oscillatory activity during meditation and increase our understanding of the cortical processes engaged during meditation that may support long-term improvements in cognition.

Key points Ketone bodies are proposed to represent an alternative fuel source driving energy production, particularly during exercise. Biologically, the extent to which mitochondria utilize ketone bodies compared to other substrates remains unknown. We demonstratein vitrothat maximal mitochondrial respiration supported by ketone bodies is low when compared to carbohydrate-derived substrates in the left ventricle and red gastrocnemius muscle from rodents, and in human skeletal muscle. When considering intramuscular concentrations of ketone bodies and the presence of other carbohydrate and lipid substrates, biological rates of mitochondrial respiration supported by ketone bodies are predicted to be minimal. At the mitochondrial level, it is therefore unlikely that ketone bodies are an important source for energy production in cardiac and skeletal muscle, particularly when other substrates are readily available. Ketone bodies (KB) have recently gained popularity as an alternative fuel source to support mitochondrial oxidative phosphorylation and enhance exercise performance. However, given the low activity of ketolytic enzymes and potential inhibition from carbohydrate oxidation, it remains unknown if KBs can contribute to energy production. We therefore determined the ability of KBs (sodiumdl-beta-hydroxybutyrate, beta-HB; lithium acetoacetate, AcAc) to stimulatein vitromitochondrial respiration in the left ventricle (LV) and red gastrocnemius (RG) of rats, and in human vastus lateralis. Compared to pyruvate, the ability of KBs to maximally drive respiration was low in isolated mitochondria and permeabilized fibres (PmFb) from the LV (similar to 30-35% of pyruvate), RG (similar to 10-30%), and human vastus lateralis (similar to 2-10%). In PmFb, the concentration of KBs required to half-maximally drive respiration (LV: 889 mu m beta-HB, 801 mu mAcAc; RG: 782 mu m beta-HB, 267 mu mAcAc) were greater than KB content representative of the muscle microenvironment (similar to 100 mu m). This would predict low rates (similar to 1-4% of pyruvate) of biological KB-supported respiration in the LV (8-14 pmol s(-1) mg(-1)) and RG (3-6 pmol s(-1) mg(-1)) at rest and following exercise. Moreover, KBs did not increase respiration in the presence of saturating pyruvate, submaximal pyruvate (100 mu m) reduced the ability of physiological beta-HB to drive respiration, and addition of other intracellular substrates (succinate + palmitoylcarnitine) decreased maximal KB-supported respiration. As a result, product inhibition is likely to limit KB oxidation. Altogether, the ability of KBs to drive mitochondrial respiration is minimal and they are likely to be outcompeted by other substrates, compromising their use as an important energy source.

Aims Treatment of patients with heart failure (HF) relies on measurement of LVEF. However, the extent to which EF is recorded varies markedly. We sought to characterize the patient group that is missing a measure of EF, and to explore the association between missing EF and outcome. Methods and results Individual data on 30 445 patients from 28 observational studies in the Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) project were used to compare the prevalence of co-morbidities and outcome across three groups of HF patients: those with missing EF (HF-mEF), reduced EF (HF-REF), and preserved EF (HF-PEF). A total of 29% had HF-mEF, 52% HF-REF, and 19% HF-PEF. Compared with patients in whom EF was known, patients with HF-mEF were older, had a greater prevalence of COPD and previous stroke, and were smokers. Patients with HF-mEF were less likely to receive evidence-based treatment than those with HF-REF. Adjusted mortality in HF-mEF was similar to that in HF-REF and greater than that in HF-PEF at 3 years [HF-REF, hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.95–1.12); HF-PEF, HR 0.78, 95% CI 0.71–0.86]. Conclusion Missing EF is common. The short- and long-term outcome of patients with HF-mEF is poor and they exhibit different co-morbidity profiles and treatment patterns compared with patients with known EF. HF patients with missing EF represent a high risk group.

International audience; Fiber tractography (FT) using diffusion magnetic resonance imaging (dMRI) is widely used for investigating microstructural properties of white matter (WM) fiber-bundles and for mapping structural connections of the human brain. While studying the architectural configuration of the brain's circuitry with FT is not without controversy, recent progress in acquisition, processing, modeling, analysis, and visualization of dMRI data pushes forward the reliability in reconstructing WM pathways. Despite being aware of the well-known pitfalls in analyzing dMRI data and several other limitations of FT discussed in recent literature, we present the superoanterior fasciculus (SAF), a novel bilateral fiber tract in the frontal region of the human brain that-to the best of our knowledge-has not been documented. The SAF has a similar shape to the anterior part of the cingulum bundle, but it is located more frontally. To minimize the possibility that these FT findings are based on acquisition or processing artifacts, different dMRI data sets and processing pipelines have been used to describe the SAF. Furthermore, we evaluated the configuration of the SAF with complementary methods, such as polarized light imaging (PLI) and human brain dissections. The FT results of the SAF demonstrate a long pathway, consistent across individuals, while the human dissections indicate fiber pathways connecting the postero-dorsal with the antero-dorsal cortices of the frontal lobe.

Background: The contemporary prognostic value of the physical examination— beyond traditional risk factors including natriuretic peptides, risk scores, and symptoms—in heart failure (HF) with reduced ejection fraction is unknown. We aimed to determine the association between physical signs of congestion at baseline and during study follow-up with quality of life and clinical outcomes and to assess the treatment effects of sacubitril/valsartan on congestion. Methods: We analyzed participants from PARADIGM-HF (Prospective Comparison of Angiotensin Receptor-Neprilysin Inhibitor With Angiotensin Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in HF) with an available physical examination at baseline. We examined the association of the number of signs of congestion (jugular venous distention, edema, rales, and third heart sound) with the primary outcome (cardiovascular death or HF hospitalization), its individual components, and all-cause mortality using time-updated, multivariable-adjusted Cox regression. We further evaluated whether sacubitril/valsartan reduced congestion during follow-up and whether improvement in congestion is related to changes in clinical outcomes and quality of life, assessed by Kansas City Cardiomyopathy Questionnaire overall summary scores. Results: Among 8380 participants, 0, 1, 2, and 3+ signs of congestion were present in 70%, 21%, 7%, and 2% of patients, respectively. Patients with baseline congestion were older, more often female, had higher MAGGIC risk scores (Meta-Analysis Global Group in Chronic Heart Failure) and lower Kansas City Cardiomyopathy Questionnaire overall summary scores ( P <0.05). After adjusting for baseline natriuretic peptides, time-updated Meta-Analysis Global Group in Chronic Heart Failure score, and time-updated New York Heart Association class, increasing time-updated congestion was associated with all outcomes ( P <0.001). Sacubitril/valsartan reduced the risk of the primary outcome irrespective of clinical signs of congestion at baseline ( P =0.16 for interaction), and treatment with the drug improved congestion to a greater extent than did enalapril ( P =0.011). Each 1-sign reduction was independently associated with a 5.1 (95% CI, 4.7–5.5) point improvement in Kansas City Cardiomyopathy Questionnaire overall summary scores. Change in congestion strongly predicted outcomes even after adjusting for baseline congestion ( P <0.001). Conclusions: In HF with reduced ejection fraction, the physical exam continues to provide significant independent prognostic value even beyond symptoms, natriuretic peptides, and Meta-Analysis Global Group in Chronic Heart Failure risk score. Sacubitril/valsartan improved congestion to a greater extent than did enalapril. Reducing congestion in the outpatient setting is independently associated with improved quality of life and reduced cardiovascular events, including mortality. Clinical Trial Registration: https://www.clinicaltrials.gov . Unique identifier: NCT01035255.

Background: There are two approaches to the differential examination of school motivation. The first is to examine motivation towards specific school subjects (between school subject differentiation). The second is to examine school motivation as a multidimensional concept that varies in terms of not only intensity but also quality (within school subject differentiation). These two differential approaches have led to important discoveries and provided a better understanding of student motivational dynamics. However, little research has combined these two approaches. Aims: This study examines young elementary students' motivations across school subjects (writing, reading, and maths) from the stance of self-determination theory. First, we tested whether children self-report different levels of intrinsic, identified, and controlled motivation towards specific school subjects. Second, we verified whether children self-report differentiated types of motivation across school subjects. Sample: Participants were 425 French-Canadian children (225 girls, 200 boys) from three elementary schools. Children were in Grades 1 (N=121), 2 (N=126), and 3 (N=178). Results: Results show that, for a given school subject, young elementary students self-report different levels of intrinsic, identified, and controlled motivation. Results also indicate that children self-report different levels of motivation types across school subjects. Our findings also show that most differentiation effects increase across grades. Some gender effects were also observed. Conclusion: These results highlight the importance of distinguishing among types of school motivation towards specific school subjects in the early elementary years.

Although the role of IQ in developmental dyslexia remains ambiguous, the dominant clinical and research approaches rely on a definition of dyslexia that requires reading skill to be significantly below the level expected given an individual’s IQ. In the study reported here, we used functional MRI (fMRI) to examine whether differences in brain activation during phonological processing that are characteristic of dyslexia were similar or dissimilar in children with poor reading ability who had high IQ scores (discrepant readers) and in children with poor reading ability who had low IQ scores (nondiscrepant readers). In two independent samples including a total of 131 children, using univariate and multivariate pattern analyses, we found that discrepant and nondiscrepant poor readers exhibited similar patterns of reduced activation in brain areas such as left parietotemporal and occipitotemporal regions. These results converge with behavioral evidence indicating that, regardless of IQ, poor readers have similar kinds of reading difficulties in relation to phonological processing.

Thank you for the opportunity to respond to the letter submitted by Gayda and colleagues in response to our recent review published in The Journal of Physiology (Gibala et al. 2012). With regards to their first comment regarding our new ‘practical’ high-intensity interval exercise (HIIE) protocol, we disagree with the assertion that ‘exercise intensity at 60% of peak power cannot be considered high intensity.’ In our efforts to develop a low-volume HIIE protocol that can be applied across different cohorts including clinical populations, we devised a model comprising 10 × 60 s work bouts at an intensity eliciting ∼85–90% of maximal heart rate (HRmax; averaged over the 10 intervals), interspersed by 60 s of recovery. We have found that the percentage of peak power output (PPO; determined using a standard ramp test to volitional fatigue which does not always elicit peak O2 uptake) that approximates the desired target heart rate (i.e. the % of HRmax) varies considerably between subjects and is exercise-mode specific. For example, in the study by Hood et al. (2011) which was conducted on sedentary healthy adults, a workload equivalent to 60% of PPO during upright cycling was sufficient to elicit a training intensity of ∼90% HRmax. However, in our recent study conducted on patients with type 2 diabetes, the intensity required to elicit ∼90% HRmax was ∼95% of PPO determined during recumbent cycling (Little et al. 2011). We agree with the assertion by Gayda and colleagues that ‘acute physiological responses during different HIIE protocols as well as patient's safety, tolerance and comfort should be tested before their implementation into training programs’. Ongoing protocol optimization work in our laboratory reveal that when interval exercise was prescribed as 80% of PPO in coronary artery disease (CAD) patients – most of whom were taking beta-blocker medication – the 10 × 60 s protocol resulted in peak heart rates during the exercise that averaged ∼85% of age-predicted HRmax. Further, the 10 × 60 s protocol was best tolerated and rated as most preferred by CAD patients in comparison with a modified Wingate protocol (repeated 30 s efforts at 100% PPO with 4 min unloaded cycling for recovery), the standard aerobic interval training protocol used by Wisloff and colleagues (2007), or a moderate-intensity continuous exercise (MICE) protocol. It is likely that high-intensity interval training (HIT) does not conform to a ‘one size fits all’ approach and the interval training stimulus needs to be tailored to individuals depending on their initial level of fitness, exercise tolerance, use of prescription medications and other factors. We also concur with the other main comment by Gayda and colleagues that ‘the superiority of this HIIE protocol [our 10 × 60 s ‘hard’/60 s ‘easy’ model]… needs to be demonstrated.’ Indeed, our review concluded ‘One aspect that is unclear from the present literature is the precise intensity and minimal volume of training that is needed to potentiate the effect of the stimulus-adaptation on outcomes such as mitochondrial biogenesis and relevant health markers. To answer such questions, a complex series of studies needs to be undertaken that systematically ‘titrate’ levels of the ‘training impulse’ and determine subsequent cellular, performance and clinical responses after divergent training interventions.’ Specifically with respect to the use of HIIE in patients with cardiovascular risk or cardiovascular disease, the letter by Gayda and colleagues highlights four references from their laboratory that were not cited in our review. Given the relatively broad scope of our review and the fact that Journal guidelines restricted the number of references to 50, it was obviously not possible to cite all relevant work. Moreover, two of the citations listed by Gayda et al. were acute exercise studies (whereas the focus of our review was training adaptations) and the other two citations were a journal abstract and a recent paper published in February 2012 (neither of which we had access to at the time of submission of our original manuscript). We are also aware of the pioneering research conducted by Meyer and colleagues (e.g. Meyer et al. 1998) and have acknowledged this work in a previous commentary (MacDonald & Currie, 2009). We apologize to all authors whose work on interval training we could not cite due to the broad focus of our review and referencing limitations imposed by The Journal.