Selection of endurance capabilities and the trade-off between pressure and volume in the evolution of the human heart.

Chimpanzees and gorillas, when not inactive, engage primarily in short bursts of resistance physical activity (RPA), such as climbing and fighting, that creates pressure stress on the cardiovascular system. In contrast, to initially hunt and gather and later to farm, it is thought that preindustrial human survival was dependent on lifelong moderate-intensity endurance physical activity (EPA), which creates a cardiovascular volume stress. Although derived musculoskeletal and thermoregulatory adaptations for EPA in humans have been documented, it is unknown if selection acted similarly on the heart. To test this hypothesis, we compared left ventricular (LV) structure and function across semiwild sanctuary chimpanzees, gorillas, and a sample of humans exposed to markedly different physical activity patterns. We show the human LV possesses derived features that help augment cardiac output (CO) thereby enabling EPA. However, the human LV also demonstrates phenotypic plasticity and, hence, variability, across a wide range of habitual physical activity. We show that the human LV's propensity to remodel differentially in response to chronic pressure or volume stimuli associated with intense RPA and EPA as well as physical inactivity represents an evolutionary trade-off with potential implications for contemporary cardiovascular health. Specifically, the human LV trades off pressure adaptations for volume capabilities and converges on a chimpanzee-like phenotype in response to physical inactivity or sustained pressure loading. Consequently, the derived LV and lifelong low blood pressure (BP) appear to be partly sustained by regular moderate-intensity EPA whose decline in postindustrial societies likely contributes to the modern epidemic of hypertensive heart disease.

Analgesic Efficacy of "Burst" and Tonic (500 Hz) Spinal Cord Stimulation Patterns: A Randomized Placebo-Controlled Crossover Study.

OBJECTIVES: The aim of this study was to compare the efficacy in reducing pain intensity in adult subjects suffering from chronic back and leg pain of burst (BST) and tonic sub-threshold stimulation at 500 Hz (T500) vs. sham stimulation delivered by a spinal cord stimulation (SCS) device capable of automated postural adjustment of current intensity. MATERIALS AND METHODS: A multicentre randomized double-blind, three-period, three-treatment, crossover study was undertaken at two centers in the United Kingdom. Patients who had achieved stable pain relief with a conventional SCS capable of automated postural adjustment of current intensity were randomized to sequences of BST, T500, and sham SCS with treatment order balanced across the six possible sequences. A current leakage was programmed into the implantable pulse generator (IPG) in the sham period. The primary outcome was patient reported pain intensity using a visual analog scale (VAS). RESULTS: Nineteen patients were enrolled and randomized. The mean reduction in pain with T500 was statistically significantly greater than that observed with either sham (25%; 95% CI, 8%-38%; p = 0.008) or BST (28%; 95% CI, 13%-41%; p = 0.002). There were no statistically significant differences in pain VAS for BST versus Sham (5%; 95% CI, -13% to 27%; p = 0.59). Exploratory sub-group analyses by study site and sex were also conducted for the T500 vs. sham and BST versus sham comparisons. CONCLUSIONS: The findings suggest a superior outcome versus sham from T500 stimulation over BST stimulation and a practical equivalence between BST and sham in a group of subjects with leg and back pain habituated to tonic SCS and having achieved a stable status with stimulation.

Effect of novel technology-enabled multidimensional physical activity feedback in primary care patients at risk of chronic disease - the MIPACT study: a randomised controlled trial.

BACKGROUND: Technological progress has enabled the provision of personalised feedback across multiple dimensions of physical activity that are important for health. Whether this multidimensional approach supports physical activity behaviour change has not yet been examined. Our objective was to examine the effectiveness of a novel digital system and app that provided multidimensional physical activity feedback combined with health trainer support in primary care patients identified as at risk of chronic disease. METHODS: MIPACT was a parallel-group, randomised controlled trial that recruited patients at medium (≥10 and < 20%) or high (≥20%) risk of cardiovascular disease and/or type II diabetes from six primary care practices in the United Kingdom. Intervention group participants (n = 120) received personal multidimensional physical activity feedback using a customised digital system and web-app for 3 months plus five health trainer-led sessions. All participants received standardised information regarding physical activity. Control group participants (n = 84) received no further intervention. The primary outcome was device-based assessment of physical activity at 12 months. RESULTS: Mean intervention effects were: moderate-vigorous physical activity: -1.1 (95% CI, - 17.9 to 15.7) min/day; moderate-vigorous physical activity in ≥10-min bouts: 0.2 (- 14.2 to 14.6) min/day; Physical Activity Level (PAL): 0.00 (- 0.036 to 0.054); vigorous physical activity: 1.8 (- 0.8 to 4.2) min/day; and sedentary time: 10 (- 19.3 to 39.3) min/day. For all of these outcomes, the results showed that the groups were practically equivalent and statistically ruled out meaningful positive or negative effects (>minimum clinically important difference, MCID). However, there was profound physical activity multidimensionality, and only a small proportion (5%) of patients had consistently low physical activity across all dimensions. CONCLUSION: In patients at risk of cardiovascular disease and/or type II diabetes, MIPACT did not increase mean physical activity. Using a sophisticated multidimensional digital approach revealed enormous heterogeneity in baseline physical activity in primary care patients, and practitioners may need to screen for low physical activity across dimensions rather than rely on disease-risk algorithms that are heavily influenced by age. TRIAL REGISTRATION: This trial is registered with the ISRCTN registry ( ISRCTN18008011 ; registration date 31 July 2013).

Issues in the determination of 'responders' and 'non-responders' in physiological research.

NEW FINDINGS: What is the topic for this review? We discuss the dichotomization of continuous-level physiological measurements into 'responders' and 'non-responders' when interventions/treatments are examined in robust parallel-group studies. What advances does it highlight? Sample responder counts are biased by pre-to-post within-subject variability. Sample differences in counts may be explained wholly by differences in mean response, even without individual response heterogeneity and even if test-retest measurement error informs the choice of response threshold. A less biased and more informative approach uses the SD of individual responses to estimate the chance a new person from the population of interest will be a responder. ABSTRACT: As a follow-up to our 2015 review, we cover more issues on the topic of 'response heterogeneity', which we define as clinically important individual differences in the physiological responses to the same treatment/intervention that cannot be attributed to random within-subject variability. We highlight various pitfalls with the common practice of counting the number of 'responders', 'non-responders' and 'adverse responders' in samples that have been given certain treatments or interventions for research purposes. We focus on the classical parallel-group randomized controlled trial and assume typical good practice in trial design. We show that sample responder counts are biased because individuals differ in terms of pre-to-post within-subject random variability in the study outcome(s) and not necessarily treatment response. Ironically, sample differences in responder counts may be explained wholly by sample differences in mean response, even if there is no response heterogeneity at all. Sample comparisons of responder counts also have relatively low statistical precision. These problems do not depend on how the response threshold has been selected, e.g. on the basis of a measurement error statistic, and are not rectified fully by the use of confidence intervals for individual responses in the sample. The dichotomization of individual responses in a research sample is fraught with pitfalls. Less biased approaches for estimating the proportion of responders in a population of interest are now available. Importantly, these approaches are based on the SD for true individual responses, directly incorporating information from the control group.

Peak Oxygen Uptake in Chronic Fatigue Syndrome/Myalgic Encephalomyelitis: A Meta-Analysis.

To evaluate the magnitude of the difference in VO2peak between patients with Chronic Fatigue Syndrome/ Myalgic Encephalomyelitis (CFS/ME) and apparently healthy controls, 7 databases (Cochrane, PubMed, PsycINFO, Web of Knowledge, Embase, Scopus, Medline) were searched for articles published up to March 2018. Search terms included "chronic fatigue syndrom*"AND ("peak" OR "maxim*" OR "max") AND ("oxygen uptake" OR "oxygen consumption" OR "VO2peak" or "VO2max". Eligibility criteria were adults>18 y with clinically diagnosed CFS/ME, with VO2peak measured in a maximal test and compared against an apparently healthy control group. The methodological quality of included studies was assessed using a modified Systematic Appraisal of Quality for Observational Research critical appraisal framework. A random effects meta-analysis was conducted on 32 cross-sectional studies (effects). Pooled mean VO2peak was 5.2 (95% CI: 3.8-6.6) ml.kg-1min-1 lower in CFS/ME patients vs. healthy controls. Between-study variability (Tau) was 3.4 (1.5-4.5) ml.kg-1min-1 indicating substantial heterogeneity. The 95% prediction interval was -1.9 to 12.2 ml.kg-1min-1. The probability that the effect in a future study would be>the minimum clinically important difference of 1.1 ml.kg-1min-1 (in favour of controls) was 0.88 - likely to be clinically relevant. Synthesis of the available evidence indicates that CFS/ME patients have a substantially reduced VO2peak compared to controls.

Association of psychological flexibility with engagement in pulmonary rehabilitation following an acute exacerbation of chronic obstructive pulmonary disease.

This study aimed to investigate (a) the association between psychological flexibility and engagement in pulmonary rehabilitation within 8 weeks following hospitalisation for an acute exacerbation of chronic obstructive pulmonary disease (AECOPD) and (b) how psychological (in)flexibility presents in this context. A mixed-methods study was conducted. Psychological flexibility during an AECOPD was assessed using The Acceptance and Action Questionnaire-II (AAQ-II) (n = 41) and the Engaged Living Scale (ELS) (n = 40). Engagement in post-AECOPD pulmonary rehabilitation was then recorded. Twenty-three patients also participated in cognitive interviews. Psychological flexibility was associated with a greater chance of accepting a pulmonary rehabilitation referral following an AECOPD. Small numbers prohibited analysis on attendance or completion. An AAQ-II score of 11 translated to a 60 (37-82)% probability of accepting a referral to pulmonary rehabilitation and an ELS score of 73 was associated with a 68 (46-91)% probability of accepting. Four themes were extracted from interviews: (1) family values, (2) self as abnormal, (3) 'can't do anything' versus 'I do what I can' and (4) disability, and related emotions, as barriers to action. Randomised clinical trials are needed to evaluate interventions designed to increase psychological flexibility (i.e. acceptance and commitment therapy) to support acceptance of pulmonary rehabilitation post-AECOPD.

Short- and long-term reliability of leg extensor power measurement in middle-aged and older adults.

Muscular power is important for maintaining physical functioning with aging. Proper quantification of the reliability of muscular power tests is crucial to inform monitoring of individuals and sample size planning for interventional studies. This study evaluated short- and long-term reliability of leg extensor power measurement in 72 adults (age 62.7 ± 8.6 years). Participants completed four repeat trials on the Nottingham leg extensor power rig, with a further trial twelve weeks later. Mean change, typical error, and intraclass correlation coefficients (ICC) were calculated. For short-term reliability, mean change in power output was trivial after two trials (1.2-4.8%). Typical errors were small following four trials in the dominant leg of males (10.9-5.8%), three in the non-dominant leg of males (9.9-6.2%) and the dominant leg of females (10.0-9.6%) and two in the non-dominant leg in females (8.3%). Intraclass correlation coefficients (ICCs) were very high (0.88-0.96). For long-term reliability, mean change remained trivial (1.0-2.5%), typical errors remained small (5.8-8.6%), and ICCs very high (0.94-0.96). The leg extensor power rig is a reliable method for assessing lower body muscular power, both short- and long-term, with only minimal habituation effects.

A comprehensive allometric analysis of 2nd digit length to 4th digit length in humans.

It has been widely reported that men have a lower ratio of the 2nd and 4th human finger lengths (2D : 4D). Size-scaling ratios, however, have the seldom-appreciated potential for providing biased estimates. Using an information-theoretic approach, we compared 12 candidate models, with different assumptions and error structures, for scaling untransformed 2D to 4D lengths from 154 men and 262 women. In each hand, the two-parameter power function and the straight line with intercept models, both with normal, homoscedastic error, were superior to the other models and essentially equivalent to each other for normalizing 2D to 4D lengths. The conventional 2D : 4D ratio biased relative 2D length low for the generally bigger hands of men, and vice versa for women, thereby leading to an artefactual indication that mean relative 2D length is lower in men than women. Conversely, use of the more appropriate allometric or linear regression models revealed that mean relative 2D length was, in fact, greater in men than women. We conclude that 2D does not vary in direct proportion to 4D for both men and women, rendering the use of the simple 2D : 4D ratio inappropriate for size-scaling purposes and intergroup comparisons.

Comparison of the Effects of Intermittent Boluses to Simple Continuous Infusion on Patients' Global Perceived Effect in Intrathecal Therapy for Pain: A Randomized Double-Blind Crossover Study.

Objective: Intrathecal drug delivery (ITDD) is commonly used for intractable pain management. A paucity of good-quality studies in chronic noncancer patients and concerns over increased dosages have focused interest on different modes of administration. The aim of this international multicenter randomized double-blind crossover trial was to compare the efficacy of the same daily dose of drugs administered by intermittent boluses vs simple continuous infusion. Methods: Eligible patients implanted with a programmable ITDD device were randomized to receive two weeks of either intermittent boluses or a simple continuous flow in period 1, followed by a crossover to the alternative mode of administration. The primary outcome measure was the Patients' Global Impression of Change (PGIC) scale. Results: The mean proportion of positive responders (at least "minimally improved") was 38.4% in the continuous condition vs 37.3% in the bolus (difference in proportions = 1.1%, 95% confidence interval [CI] = -21.8-24.0%, P = 0.93). The mean PGIC in the continuous condition was 3.8 vs 3.9 in the bolus (mean difference = -0.1, -0.6-0.4, P = 0.72). Exploratory analyses revealed a tendency for the mean proportion of positive responders to be higher at low vs high flow rates for both bolus and continuous administrations. Two patients were withdrawn from the study due to adverse events during the bolus phase, both with symptoms of increased pain, and one patient with additional symptoms of numbness and urinary retention. Conclusion: The mean PGIC and proportion of positive responders was not substantially different after intermittent bolus vs continuous administration.

A higher effort-based paradigm in physical activity and exercise for public health: making the case for a greater emphasis on resistance training.

It is well known that physical activity and exercise is associated with a lower risk of a range of morbidities and all-cause mortality. Further, it appears that risk reductions are greater when physical activity and/or exercise is performed at a higher intensity of effort. Why this may be the case is perhaps explained by the accumulating evidence linking physical fitness and performance outcomes (e.g. cardiorespiratory fitness, strength, and muscle mass) also to morbidity and mortality risk. Current guidelines about the performance of moderate/vigorous physical activity using aerobic exercise modes focuses upon the accumulation of a minimum volume of physical activity and/or exercise, and have thus far produced disappointing outcomes. As such there has been increased interest in the use of higher effort physical activity and exercise as being potentially more efficacious. Though there is currently debate as to the effectiveness of public health prescription based around higher effort physical activity and exercise, most discussion around this has focused upon modes considered to be traditionally 'aerobic' (e.g. running, cycling, rowing, swimming etc.). A mode customarily performed to a relatively high intensity of effort that we believe has been overlooked is resistance training. Current guidelines do include recommendations to engage in 'muscle strengthening activities' though there has been very little emphasis upon these modes in either research or public health effort. As such the purpose of this debate article is to discuss the emerging higher effort paradigm in physical activity and exercise for public health and to make a case for why there should be a greater emphasis placed upon resistance training as a mode in this paradigm shift.

Feedback from physical activity monitors is not compatible with current recommendations: A recalibration study.

Wearable devices to self-monitor physical activity have become popular with individuals and healthcare practitioners as a route to the prevention of chronic disease. It is not currently possible to reconcile feedback from these devices with activity recommendations because the guidelines refer to the amount of activity required on top of normal lifestyle activities (e.g., 150 minutes of moderate-to-vigorous intensity activity per week over-and-above normal moderate-to-vigorous lifestyle activities). The aim of this study was to recalibrate the feedback from self-monitoring. We pooled data from four studies conducted between 2006 and 2014 in patients and volunteers from the community that included both sophisticated measures of physical activity and 10-year risk for cardiovascular disease and type 2 diabetes (n=305). We determined the amount of moderate-to-vigorous intensity activity that corresponded to FAO/WHO/UNU guidance for a required PAL of 1.75 (Total Energy Expenditure/Basal Metabolic Rate). Our results show that, at the UK median PAL, total moderate-to-vigorous intensity physical activity will be around 735 minutes per week (~11% of waking time). We estimate that a 4% increase in moderate-to-vigorous intensity activity will achieve standardised guidance from FAO/WHO/UNU and will require ~1000 minutes of moderate-to-vigorous intensity activity per week. This study demonstrates that feedback from sophisticated wearable devices is incompatible with current physical activity recommendations. Without adjustment, people will erroneously form the view that they are exceeding recommendations by several fold. A more appropriate target from self-monitoring that accounts for normal moderate-to-vigorous lifestyle activities is ~1000 minutes per week, which represents ~15% of waking time.

True and false interindividual differences in the physiological response to an intervention.

NEW FINDINGS: What is the topic of this review? In 'personalized medicine', various plots and analyses are purported to quantify individual differences in intervention response, identify responders/non-responders and explore response moderators or mediators. What advances does it highlight? We highlight the impact of within-subject random variation, which is inevitable even with 'gold-standard' measurement tools/protocols and sometimes so substantial that it explains all apparent individual response differences. True individual response differences are quantified only by comparing the SDs of changes between intervention and comparator arms. When these SDs are similar, true individual response differences are clinically unimportant and further analysis unwarranted. Within the 'hot topic' of personalized medicine, we scrutinize common approaches for presenting and quantifying individual differences in the physiological response to an intervention. First, we explain how popular plots used to present individual differences in response are contaminated by random within-subject variation and the regression to the mean artefact. Using a simulated data set of blood pressure measurements, we show that large individual differences in physiological response can be suggested by some plots and analyses, even when the true magnitude of response is exactly the same in all individuals. Second, we present the appropriate designs and analysis approaches for quantifying the true interindividual variation in physiological response. It is imperative to include a comparator arm/condition (or derive information from a prior relevant repeatability study) to quantify true interindividual differences in response. The most important statistic is the SD of changes in the intervention arm, which should be compared with the same SD in the comparator arm or from a prior repeatability study in the same population conducted over the same duration as the particular intervention. Only if the difference between these SDs is clinically relevant is it logical to go on to explore any moderators or mediators of the intervention effect that might explain the individual response. To date, very few researchers have compared these SDs before making claims about individual differences in physiological response and their importance to personalized medicine.

Multidimensional physical activity: an opportunity, not a problem.

Our research shows that no single metric will reflect an individual's physical activity adequately because multiple biologically important dimensions are independent and unrelated. We propose that there is an opportunity to exploit this multidimensional characteristic of physical activity to improve personalized feedback and offer physical activity options and choices that are tailored to an individual's needs and preferences.

High-intensity interval exercise training for public health: a big HIT or shall we HIT it on the head?

BACKGROUND: The efficacy of high-intensity interval training for a broad spectrum of cardio-metabolic health outcomes is not in question. Rather, the effectiveness of this form of exercise is at stake. In this paper we debate the issues concerning the likely success or failure of high-intensity interval training interventions for population-level health promotion. DISCUSSION: Biddle maintains that high-intensity interval training cannot be a viable public health strategy as it will not be adopted or maintained by many people. This conclusion is based on an analysis of perceptions of competence, the psychologically aversive nature of high-intensity exercise, the affective component of attitudes, the less conscious elements of motivated behaviour that reflect our likes and dislikes, and analysis using the RE-AIM framework. Batterham argues that this appraisal is based on a constrained and outmoded definition of high-intensity interval training and that truly practical and scalable protocols have been - and continue to be - developed. He contends that the purported displeasure associated with this type of exercise has been overstated. Biddle suggests that the way forward is to help the least active become more active rather than the already active to do more. Batterham claims that traditional physical activity promotion has been a spectacular failure. He proposes that, within an evolutionary health promotion framework, high-intensity interval training could be a successful population strategy for producing rapid physiological adaptations benefiting public health, independent of changes in total physical activity energy expenditure. SUMMARY: Biddle recommends that we focus our attention elsewhere if we want population-level gains in physical activity impacting public health. His conclusion is based on his belief that high-intensity interval training interventions will have limited reach, effectiveness, and adoption, and poor implementation and maintenance. In contrast, Batterham maintains that there is genuine potential for scalable, enjoyable high-intensity interval exercise interventions to contribute substantially to addressing areas of public health priority, including prevention and treatment of Type 2 diabetes and cardiovascular disease.

The clinical relevance of the percentage flow-mediated dilation index.

In 2010, the American College of Cardiology Foundation and American Heart Association could not recommend brachial artery percentage flow-mediated dilation (FMD%) for risk assessment of coronary artery disease (CAD) in asymptomatic adults. We aimed to scrutinise past and recently published findings regarding FMD% in this same context of clinical utility and conclude that (1) the question of whether brachial FMD% is a suitable substitute for coronary vasodilation is addressed by method agreement statistics rather than the correlation coefficients that have been reported in past studies. Also, the much-repeated view that brachial FMD% and coronary vasodilation are "closely related" is not entirely justified, even before the influence of baseline lumen diameters on this relationship is accounted for; (2) along with the specialist training and the considerable time (≥1 h) that is required for the FMD% protocol, the error in individual measurements and population reference ranges is too large for clinical decisions to be robust on individual patients; (3) many interventions that are proposed to change FMD% also change baseline artery diameter, which can bias estimates of any intervention effects on the flow-mediated response per se, and (4) the FMD% index generates spurious correlations between shear rate, artery diameter and endothelial function, which may help to explain the apparent paradoxes of FMD% being higher in obese people and lower in athletes. In conclusion, the clinical relevance of brachial artery flow-mediated dilation is unclear at present. The dependence of the chosen index, FMD%, on initial artery size has contributed to this lack of clarity.

From animal cage to aircraft cabin: an overview of evidence translation in jet lag research.

Recent laboratory experiments on rodents have increased our understanding of circadian rhythm mechanisms. Typically, circadian biologists attempt to translate their laboratory-based findings to treatment of jet lag symptoms in humans. We aimed to scrutinise the strength of the various links in the translational pathway from animal model to human traveller. First, we argue that the translation of findings from pre-clinical studies to effective jet lag treatments and knowledge regarding longer-term population health is not robust, e.g. the association between circadian disruption and cancer found in animal models does not translate well to cabin crew and pilots, who have a lower risk of most cancers. Jet lag symptoms are heterogeneous, making the true prevalence and the effects of any intervention difficult to quantify precisely. The mechanistic chain between in vitro and in vivo treatment effects has weak links, especially between circadian rhythm disruption in animals and the improvement of jet lag symptoms in humans. While the number of animal studies has increased exponentially between 1990 and 2014, only 1-2 randomised controlled trials on jet lag treatments are published every year. There is one relevant Cochrane review, in which only 2-4 studies on melatonin, without baseline measures, were meta-analysed. Study effect sizes reduced substantially between 1987, when the first paper on melatonin was published, and 2000. We suggest that knowledge derived from a greater number of human randomised controlled trials would provide a firmer platform for circadian biologists to cite jet lag treatment as an important application of their findings.

Blood pressure regulation VII. The "morning surge" in blood pressure: measurement issues and clinical significance.

In keeping with this review-series theme, we question whether the morning surge in blood pressure (MSBP) is a benign response to the physiological challenges during the first 3 h after waking, or is it clinically important? Therefore, we scrutinise the circadian-related mechanisms, the measurement methods and the prognostic value of the MSBP. The MSBP is relatively small (<2 mmHg) under constant routine conditions. Nevertheless, the blood pressure response to exercise can be 8-14 mm Hg greater in the morning vs. afternoon, even when prior sleep is controlled. Systematic bias between MSBP methods can be >10 mmHg. The "sleep-trough" method provides the largest MSBP (≈25 mmHg), but the sensitivity of MSBP to a treatment/intervention depends largely on its repeatability. The repeatability standard deviation (SD) for most MSBP methods is ≈8 mm Hg. While the magnitude of this SD precludes the use of MSBP for diagnostic decisions on individual patients, sample sizes for future intervention studies may be feasible, depending on the minimal clinically important difference in MSBP. This difference is somewhat unclear given that a large MSBP has recently been reported to predict a reduced, rather than a higher, risk of cardiovascular disease, although this particular study has been criticised. The MSBP is also naturally correlated to changes in physical activity and nocturnal "dipping" status. Therefore, it is important to account for these potential confounders of the MSBP, so that more precise knowledge about its clinical significance is gained, thereby providing a sound rationale for physiological investigation and translational research.