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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.

Patients often start treatment to reduce fracture risk because of a bone mineral density T-score consistent with osteoporosis (≤ −2.5). Others with a T-score above −2.5 may be treated when there is a history of fragility fracture or when a fracture risk algorithm categorizes them as having a high risk for fracture. It is common to initiate therapy with a generic oral bisphosphonate, unless contraindicated, and continue therapy if the patient is responding as assessed by stability or an increase in bone mineral density. However, some patients may respond well to an oral bisphosphonate, yet remain with an unacceptably high risk for fracture. Recognition of this occurrence has led to the development of an alternative strategy: treat-to-target. This involves identifying a biological marker (treatment target) that represents an acceptable fracture risk and then initiating treatment with an agent likely to reach this target. If the patient is on a path to reaching the target with initial therapy, treatment is continued. If it appears the target will not be reached with initial therapy, treatment is changed to an agent more likely to achieve the goal.

Key pointsKetone 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.

We made sex-based comparisons of rates of myofibrillar protein synthesis (MPS) and anabolic signaling after a single bout of high-intensity resistance exercise. Eight men (20 ± 10 yr, BMI = 24.3 ± 2.4) and eight women (22 ± 1.8 yr, BMI = 23.0 ± 1.9) underwent primed constant infusions of l-[ ring-13C6]phenylalanine on consecutive days with serial muscle biopsies. Biopsies were taken from the vastus lateralis at rest and 1, 3, 5, 24, 26, and 28 h after exercise. Twenty-five grams of whey protein was ingested immediately and 26 h after exercise. We also measured exercise-induced serum testosterone because it is purported to contribute to increases in myofibrillar protein synthesis (MPS) postexercise and its absence has been hypothesized to attenuate adaptative responses to resistance exercise in women. The exercise-induced area under the testosterone curve was 45-fold greater in men than women in the early (1 h) recovery period following exercise ( P < 0.001). MPS was elevated similarly in men and women (2.3- and 2.7-fold, respectively) 1–5 h postexercise and after protein ingestion following 24 h recovery. Phosphorylation of mTORSer2448 was elevated to a greater extent in men than women acutely after exercise ( P = 0.003), whereas increased phosphorylation of p70S6K1Thr389 was not different between sexes. Androgen receptor content was greater in men (main effect for sex, P = 0.049). Atrogin-1 mRNA abundance was decreased after 5 h recovery in both men and women ( P < 0.001), and MuRF-1 expression was elevated in men after protein ingestion following 24 h recovery ( P = 0.003). These results demonstrate minor sex-based differences in signaling responses and no difference in the MPS response to resistance exercise in the fed state. Interestingly, our data demonstrate that exercise-induced increases in MPS are dissociated from postexercise testosteronemia and that stimulation of MPS occurs effectively with low systemic testosterone concentrations in women.

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.

Abstract Understanding emotions in technology-based learning environments (TBLEs) has become a paramount goal across different research communities, but to date, these have operated in relative isolation. Based on control-value theory (Pekrun, 2006), we reviewed 186 studies examining emotions in TBLEs that were published between 1965 and 2018. We extracted effect sizes quantifying relations between emotions (enjoyment, curiosity/interest, anxiety, anger/frustration, confusion, boredom) and their antecedents (control-value appraisals, prior knowledge, gender, TBLE characteristics) and outcomes (engagement, learning strategies, achievement). Mean effects largely supported hypotheses (e.g., positive relations between enjoyment and appraisals, achievement, and cognitive support) and remained relatively stable across moderators. These findings imply that levels of emotions differ across TBLEs, but that their functional relations with appraisals and learning are equivalent across environments. Implications for research and designing emotionally sound TBLEs are discussed.

<b><i>Background:</i></b> An international expert panel convened by the Independent Scientific Committee on Drugs developed a multi-criteria decision analysis model of the relative importance of different types of harm related to the use of nicotine-containing products. <b><i>Method:</i></b> The group defined 12 products and 14 harm criteria. Seven criteria represented harms to the user, and the other seven indicated harms to others. The group scored all the products on each criterion for their average harm worldwide using a scale with 100 defined as the most harmful product on a given criterion, and a score of zero defined as no harm. The group also assessed relative weights for all the criteria to indicate their relative importance. <b><i>Findings:</i></b> Weighted averages of the scores provided a single, overall score for each product. Cigarettes (overall weighted score of 100) emerged as the most harmful product, with small cigars in second place (overall weighted score of 64). After a substantial gap to the third-place product, pipes (scoring 21), all remaining products scored 15 points or less. <b><i>Interpretation:</i></b> Cigarettes are the nicotine product causing by far the most harm to users and others in the world today. Attempts to switch to non-combusted sources of nicotine should be encouraged as the harms from these products are much lower.

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.

Background Multiple barriers may inhibit the adoption of clinical interventions and impede successful implementation. Use of standardised methods to prioritise barriers to target when selecting implementation interventions is an understudied area of implementation research. The aim of this study was to describe a method to identify and prioritise barriers to the implementation of clinical practice elements which were used to inform the development of the T3 trial implementation intervention (Triage, Treatment [thrombolysis administration; monitoring and management of temperature, blood glucose levels, and swallowing difficulties] and Transfer of stroke patients from Emergency Departments [ED]). Methods A survey was developed based on a literature review and data from a complementary trial to identify the commonly reported barriers for the nine T3 clinical care elements. This was administered via a web-based questionnaire to a purposive sample of Australian multidisciplinary clinicians and managers in acute stroke care. The questionnaire addressed barriers to each of the nine T3 trial clinical care elements. Participants produced two ranked lists: on their perception of: firstly, how influential each barrier was in preventing clinicians from performing the clinical care element (influence attribute); and secondly how difficult the barrier was to overcome (difficulty attribute). The rankings for both influence and difficulty were combined to classify the barriers according to three categories (‘least desirable’, desirable’ or ‘most desirable’ to target) to assist interpretation. Results All invited participants completed the survey; (n = 17; 35% medical, 35% nursing, 18% speech pathology, 12% bed managers). The barriers classified as most desirable to target and overcome were a ‘lack of protocols for the management of fever’ and ‘not enough blood glucose monitoring machines’. Conclusions A structured decision-support procedure has been illustrated and successfully applied to identify and prioritise barriers to target within an implementation intervention. This approach may prove to be a useful in other studies and as an adjunct to undertaking barrier assessments within individual sites when planning implementation interventions. Electronic supplementary material The online version of this article (doi:10.1186/s12874-017-0298-4) contains supplementary material, which is available to authorized users.

The purpose of this study was to identify factors that are associated with experiencing genetic discrimination (GD) among individuals at risk for Huntington disease (HD). Multivariable logistic regression analysis was used to examine factors associated with experiencing GD in data from a cross-sectional, self-report survey of 293 individuals at risk for HD. The study sample comprised 167 genetically tested respondents, and 66 who were not tested (80% response rate). Overall, individuals who learn they are at risk for HD at a younger age (OR = 3.1; 95% CI: 1.5–6.2; P = 0.002), are mutation-positive (OR = 2.8; 95% CI: 1.4–6.0; P = 0.006), or are highly educated (OR = 2.7; 95% CI: 1.4–5.1; P = 0.002) are more likely to experience GD, particularly in insurance, family, and social settings. Further, younger age was associated with discrimination in insurance (OR = 0.97; 95% CI: 0.94–1.00; P = 0.038). This study provides evidence that some people who are at risk for HD were more likely to experience GD than others. Individuals who learned they are at risk for HD at a younger age and those who are mutation-positive were more likely to experience GD, particularly in insurance, family, and social settings. Younger individuals were more likely to experience discrimination in the insurance setting. Overall, highly educated individuals were also more likely to report discrimination. These results provide direction for clinical and family discussions, counseling practice, and policy aimed at mitigating experiences of GD. © 2010 Wiley-Liss, Inc.