Patterns of energy allocation during energetic scarcity; evolutionary insights from ultra-endurance events

Exercise physiologists and evolutionary biologists share a research interest in determining patterns of energy allocation during times of acute or chronic energetic scarcity. Within sport and exercise science, this information has important implications for athlete health and performance. For evolutionary biologists, this would shed new light on our adaptive capabilities as a phenotypically plastic species. In recent years, evolutionary biologists have begun recruiting athletes as study participants and using contemporary sports as a model for studying evolution. This approach, known as human athletic palaeobiology, has identified ultra-endurance events as a valuable experimental model to investigate patterns of energy allocation during conditions of elevated energy demand, which are generally accompanied by an energy deficit. This energetic stress provokes detectable functional trade-offs in energy allocation between physiological processes. Early results from this modelsuggest thatlimited resources are preferentially allocated to processes which could be considered to confer the greatest immediate survival advantage (including immune and cognitive function). This aligns with evolutionary perspectives regarding energetic trade-offs during periods of acute and chronic energetic scarcity. Here, we discuss energy allocation patterns during periods of energetic stress as an area of shared interest between exercise physiology and evolutionary biology. We propose that, by addressing the ultimate “why” questions, namely why certain traits were selected for during the human evolutionary journey, an evolutionary perspective can complement the exercise physiology literature and provide a deeper insight of the reasons underpinning the body's physiological response to conditions of energetic stress

Anomalous Dimensions of Non-Chiral Operators from AdS/CFT

Non-chiral operators with positive anomalous dimensions can have interesting applications to supersymmetric model building. Motivated by this, we develop a new method for obtaining the anomalous dimensions of non-chiral double-trace operators in N=1 superconformal field theories (SCFTs) with weakly-coupled AdS duals. Via the Hamiltonian formulation of AdS/CFT, we show how to directly compute the anomalous dimension as a bound state energy in the gravity dual. This simplifies previous approaches based on the four-point function and the OPE. We apply our method to a class of effective AdS5 supergravity models, and we find that the binding energy can have either sign. If such models can be UV completed, they will provide the first calculable examples of SCFTs with positive anomalous dimensions.Comment: 38 pages, 2 figures, refs adde

Mavacamten for treatment of symptomatic obstructive hypertrophic cardiomyopathy (EXPLORER-HCM): health status analysis of a randomised, double-blind, placebo-controlled, phase 3 trial

BACKGROUND: Improving symptoms is a primary treatment goal in patients with obstructive hypertrophic cardiomyopathy. Currently available pharmacological options for hypertrophic cardiomyopathy are not disease-specific and are often inadequate or poorly tolerated. We aimed to assess the effect of mavacamten, a first-in-class cardiac myosin inhibitor, on patients' health status-ie, symptoms, physical and social function, and quality of life. METHODS: We did a health status analysis of EXPLORER-HCM, a phase 3, double-blind, randomised, placebo-controlled trial. The study took place at 68 clinical cardiovascular centres in 13 countries. Adult patients (≥18 years) with symptomatic obstructive hypertrophic cardiomyopathy (gradient ≥50 mm Hg and New York Heart Association class II-III) were randomly assigned (1:1) to mavacamten or placebo for 30 weeks, followed by an 8-week washout period. Both patients and staff were masked to study treatment. The primary outcome for this secondary analysis was the Kansas City Cardiomyopathy Questionnaire (KCCQ), a well validated disease-specific measure of patients' health status. It was administered at baseline and weeks 6, 12, 18, 30 (end of treatment), and 38 (end of study). Changes from baseline to week 30 in KCCQ overall summary (OS) score and all subscales were analysed using mixed model repeated measures. This study is registered with ClinicalTrials.gov, NCT03470545. FINDINGS: Between May 30, 2018, and July 12, 2019, 429 adults were assessed for eligibility, of whom 251 (59%) were enrolled and randomly assigned. Of 123 patients randomly assigned to mavacamten, 92 (75%) completed the KCCQ at baseline and week 30 and of the 128 patients randomly assigned to placebo 88 (69%) completed the KCCQ at baseline and week 30. At 30 weeks, the change in KCCQ-OS score was greater with mavacamten than placebo (mean score 14·9 [SD 15·8] vs 5·4 [13·7]; difference +9·1 [95% CI 5·5-12·8]; p<0·0001), with similar benefits across all KCCQ subscales. The proportion of patients with a very large change (KCCQ-OS ≥20 points) was 36% (33 of 92) in the mavacamten group versus 15% (13 of 88) in the placebo group, with an estimated absolute difference of 21% (95% CI 8·8-33·4) and number needed to treat of five (95% CI 3-11). These gains returned to baseline after treatment was stopped. INTERPRETATION: Mavacamten markedly improved the health status of patients with symptomatic obstructive hypertrophic cardiomyopathy compared with placebo, with a low number needed to treat for marked improvement. Given that the primary goals of treatment are to improve symptoms, physical and social function, and quality of life, mavacamten represents a new potential strategy for achieving these goals. FUNDING: MyoKardia, a Bristol Myers Squibb company

A pilot Internet "Value of Health" Panel: recruitment, participation and compliance

Objectives To pilot using a panel of members of the public to provide preference data via the Internet Methods A stratified random sample of members of the general public was recruited and familiarised with the standard gamble procedure using an Internet based tool. Health states were perdiodically presented in "sets" corresponding to different conditions, during the study. The following were described: Recruitment (proportion of people approached who were trained); Participation (a) the proportion of people trained who provided any preferences and (b) the proportion of panel members who contributed to each "set" of values; and Compliance (the proportion, per participant, of preference tasks which were completed). The influence of covariates on these outcomes was investigated using univariate and multivariate analyses. Results A panel of 112 people was recruited. 23% of those approached (n = 5,320) responded to the invitation, and 24% of respondents (n = 1,215) were willing to participate (net = 5.5%). However, eventual recruitment rates, following training, were low (2.1% of those approached). Recruitment from areas of high socioeconomic deprivation and among ethnic minority communities was low. Eighteen sets of health state descriptions were considered over 14 months. 74% of panel members carried out at least one valuation task. People from areas of higher socioeconomic deprivation and unmarried people were less likely to participate. An average of 41% of panel members expressed preferences on each set of descriptions. Compliance ranged from 3% to 100%. Conclusion It is feasible to establish a panel of members of the general public to express preferences on a wide range of health state descriptions using the Internet, although differential recruitment and attrition are important challenges. Particular attention to recruitment and retention in areas of high socioeconomic deprivation and among ethnic minority communities is necessary. Nevertheless, the panel approach to preference measurement using the Internet offers the potential to provide specific utility data in a responsive manner for use in economic evaluations and to address some of the outstanding methodological uncertainties in this field

Genomes as geography: using GIS technology to build interactive genome feature maps

BACKGROUND: Many commonly used genome browsers display sequence annotations and related attributes as horizontal data tracks that can be toggled on and off according to user preferences. Most genome browsers use only simple keyword searches and limit the display of detailed annotations to one chromosomal region of the genome at a time. We have employed concepts, methodologies, and tools that were developed for the display of geographic data to develop a Genome Spatial Information System (GenoSIS) for displaying genomes spatially, and interacting with genome annotations and related attribute data. In contrast to the paradigm of horizontally stacked data tracks used by most genome browsers, GenoSIS uses the concept of registered spatial layers composed of spatial objects for integrated display of diverse data. In addition to basic keyword searches, GenoSIS supports complex queries, including spatial queries, and dynamically generates genome maps. Our adaptation of the geographic information system (GIS) model in a genome context supports spatial representation of genome features at multiple scales with a versatile and expressive query capability beyond that supported by existing genome browsers. RESULTS: We implemented an interactive genome sequence feature map for the mouse genome in GenoSIS, an application that uses ArcGIS, a commercially available GIS software system. The genome features and their attributes are represented as spatial objects and data layers that can be toggled on and off according to user preferences or displayed selectively in response to user queries. GenoSIS supports the generation of custom genome maps in response to complex queries about genome features based on both their attributes and locations. Our example application of GenoSIS to the mouse genome demonstrates the powerful visualization and query capability of mature GIS technology applied in a novel domain. CONCLUSION: Mapping tools developed specifically for geographic data can be exploited to display, explore and interact with genome data. The approach we describe here is organism independent and is equally useful for linear and circular chromosomes. One of the unique capabilities of GenoSIS compared to existing genome browsers is the capacity to generate genome feature maps dynamically in response to complex attribute and spatial queries

Impact of generic alendronate cost on the cost-effectiveness of osteoporosis screening and treatment

Introduction: Since alendronate became available in generic form in the Unites States in 2008, its price has been decreasing. The objective of this study was to investigate the impact of alendronate cost on the cost-effectiveness of osteoporosis screening and treatment in postmenopausal women. Methods: Microsimulation cost-effectiveness model of osteoporosis screening and treatment for U.S. women age 65 and older. We assumed screening initiation at age 65 with central dual-energy x-ray absorptiometry (DXA), and alendronate treatment for individuals with osteoporosis; with a comparator of "no screening" and treatment only after fracture occurrence. We evaluated annual alendronate costs of $20 through$800; outcome measures included fractures; nursing home admission; medication adverse events; death; costs; quality-adjusted life-years (QALYs); and incremental cost-effectiveness ratios (ICERs) in 2010 U.S. dollars per QALY gained. A lifetime time horizon was used, and direct costs were included. Base-case and sensitivity analyses were performed. Results: Base-case analysis results showed that at annual alendronate costs of $200 or less, osteoporosis screening followed by treatment was cost-saving, resulting in lower total costs than no screening as well as more QALYs (10.6 additional quality-adjusted life-days). When assuming alendronate costs of$400 through $800, screening and treatment resulted in greater lifetime costs than no screening but was highly cost-effective, with ICERs ranging from$714 per QALY gained through $13,902 per QALY gained. Probabilistic sensitivity analyses revealed that the cost-effectiveness of osteoporosis screening followed by alendronate treatment was robust to joint input parameter estimate variation at a willingness-to-pay threshold of$50,000/QALY at all alendronate costs evaluated. Conclusions: Osteoporosis screening followed by alendronate treatment is effective and highly cost-effective for postmenopausal women across a range of alendronate costs, and may be cost-saving at annual alendronate costs of $200 or less. © 2012 Nayak et al

The social value of a QALY : raising the bar or barring the raise?

Background: Since the inception of the National Institute for Health and Clinical Excellence (NICE) in England, there have been questions about the empirical basis for the cost-per-QALY threshold used by NICE and whether QALYs gained by different beneficiaries of health care should be weighted equally. The Social Value of a QALY (SVQ) project, reported in this paper, was commissioned to address these two questions. The results of SVQ were released during a time of considerable debate about the NICE threshold, and authors with differing perspectives have drawn on the SVQ results to support their cases. As these discussions continue, and given the selective use of results by those involved, it is important, therefore, not only to present a summary overview of SVQ, but also for those who conducted the research to contribute to the debate as to its implications for NICE. Discussion: The issue of the threshold was addressed in two ways: first, by combining, via a set of models, the current UK Value of a Prevented Fatality (used in transport policy) with data on fatality age, life expectancy and age-related quality of life; and, second, via a survey designed to test the feasibility of combining respondents’ answers to willingness to pay and health state utility questions to arrive at values of a QALY. Modelling resulted in values of £10,000-£70,000 per QALY. Via survey research, most methods of aggregating the data resulted in values of a QALY of £18,000-£40,000, although others resulted in implausibly high values. An additional survey, addressing the issue of weighting QALYs, used two methods, one indicating that QALYs should not be weighted and the other that greater weight could be given to QALYs gained by some groups. Summary: Although we conducted only a feasibility study and a modelling exercise, neither present compelling evidence for moving the NICE threshold up or down. Some preliminary evidence would indicate it could be moved up for some types of QALY and down for others. While many members of the public appear to be open to the possibility of using somewhat different QALY weights for different groups of beneficiaries, we do not yet have any secure evidence base for introducing such a system

Revealing the footprints of squark gluino production through Higgs search experiments at the Large Hadron Collider at 7 TeV and 14 TeV

The invariant mass distribution of the di-photons from the decay of the lighter scalar Higgs boson(h) to be carefully measured by dedicated h search experiments at the LHC may be distorted by the di-photons associated with the squark-gluino events with much larger cross sections in Gauge Mediated Supersymmetry Breaking (GMSB) models. This distortion if observed by the experiments at the Large Hadron Collider at 7 TeV or 14 TeV, would disfavour not only the standard model but various two Higgs doublet models with comparable h - masses and couplings but without a sector consisting of new heavy particles decaying into photons. The minimal GMSB (mGMSB) model constrained by the mass bound on h from LEP and that on the lightest neutralino from the Tevatron, produce negligible effects. But in the currently popular general GMSB(GGMSB) models the tail of the above distribution may show statistically significant excess of events even in the early stages of the LHC experiments with integrated luminosity insufficient for the discovery of h. We illustrate the above points by introducing several benchmark points in various GMSB models - minimal as well as non-minimal. The same conclusion follows from a detailed parameter scan in a simplified GGMSB model recently employed by the CMS collaboration to interpret their searches in the di-photon + \etslash channel. Other observables like the effective mass distribution of the di-photon + X events may also reveal the presence of new heavy particles beyond the Higgs sector. The contamination of the h mass peak and simple remedies are also discussed.Comment: 23 pages, 7 figures, title and organization of the paper is changed, detailed parameter scan in a simplified GGMSB model is added, conclusions and old numerical results remain unchange

Individual differences in the use of the response scale determine valuations of hypothetical health states: an empirical study

Background. The effects of socio-demographic characteristics of the respondent, including age, on valuation scores of hypothetical health states remain inconclusive. Therefore, we analyzed data from a study designed to discriminate between the effects of respondents' age and time preference on valuations of health states to gain insight in the contribution of individual response patterns to the variance in valuation scores. Methods. A total of 212 respondents from three age g