The muscle metabolome differs between healthy and frail older adults

Populations around the world are aging rapidly. Age-related loss of physiological functions negatively affects quality of life. A major contributor to the frailty syndrome of aging is loss of skeletal muscle. In this study we assessed the skeletal muscle biopsy metabolome of healthy young, healthy older and frail older subjects to determine the effect of age and frailty on the metabolic signature of skeletal muscle tissue. In addition, the effects of prolonged whole-body resistance-type exercise training on the muscle metabolome of older subjects were examined. The baseline metabolome was measured in muscle biopsies collected from 30 young, 66 healthy older subjects and 43 frail older subjects. Follow-up samples from frail older (24 samples) and healthy older subjects (38 samples) were collected after 6 months of prolonged resistance-type exercise training. Young subjects were included as a reference If thisgroup. Primary differences in skeletal muscle metabolite levels between young and healthy older subjects were related to mitochondrial function, muscle fiber type, and tissue turnover. Similar differences were observed when comparing frail older subjects with healthy older subjects at baseline. Prolonged resistance-type exercise training resulted in an adaptive response of amino acid metabolism, especially reflected in branched chain amino acids and genes related to tissue remodeling. The effect of exercise training on branched-chain amino acid-derived acylcarnitines in older subjects points to a downward shift in branched-chain amino acid catabolism upon training. We observed only modest correlations between muscle and plasma metabolite levels, which pleads against the use of plasma metabolites as a direct read-out of muscle metabolism and stresses the need for direct assessment of metabolites in muscle tissue biopsies

Simplivariate Models: Ideas and First Examples

One of the new expanding areas in functional genomics is metabolomics: measuring the metabolome of an organism. Data being generated in metabolomics studies are very diverse in nature depending on the design underlying the experiment. Traditionally, variation in measurements is conceptually broken down in systematic variation and noise where the latter contains, e.g. technical variation. There is increasing evidence that this distinction does not hold (or is too simple) for metabolomics data. A more useful distinction is in terms of informative and non-informative variation where informative relates to the problem being studied. In most common methods for analyzing metabolomics (or any other high-dimensional x-omics) data this distinction is ignored thereby severely hampering the results of the analysis. This leads to poorly interpretable models and may even obscure the relevant biological information. We developed a framework from first data analysis principles by explicitly formulating the problem of analyzing metabolomics data in terms of informative and non-informative parts. This framework allows for flexible interactions with the biologists involved in formulating prior knowledge of underlying structures. The basic idea is that the informative parts of the complex metabolomics data are approximated by simple components with a biological meaning, e.g. in terms of metabolic pathways or their regulation. Hence, we termed the framework ‘simplivariate models’ which constitutes a new way of looking at metabolomics data. The framework is given in its full generality and exemplified with two methods, IDR analysis and plaid modeling, that fit into the framework. Using this strategy of ‘divide and conquer’, we show that meaningful simplivariate models can be obtained using a real-life microbial metabolomics data set. For instance, one of the simple components contained all the measured intermediates of the Krebs cycle of E. coli. Moreover, these simplivariate models were able to uncover regulatory mechanisms present in the phenylalanine biosynthesis route of E. coli

Co-designing Urban Living Solutions to Improve Older People’s Mobility and Well-Being

Mobility is a key aspect of active ageing enabling participation and autonomy into later life. Remaining active brings multiple physical but also social benefits leading to higher levels of well-being. With globally increasing levels of urbanisation alongside demographic shifts meaning in many parts of the world this urban population will be older people, the challenge is how cities should evolve to enable so-called active ageing. This paper reports on a co-design study with 117 participants investigating the interaction of existing urban spaces and infrastructure on mobility and well-being for older residents (aged 55 + years) in three cities. A mixed method approach was trialled to identify locations beneficial to subjective well-being and participant-led solutions to urban mobility challenges. Spatial analysis was used to identify key underlying factors in locations and infrastructure that promoted or compromised mobility and well-being for participants. Co-designed solutions were assessed for acceptability or co-benefits amongst a wider cross-section of urban residents (n = 233) using online and face-to-face surveys in each conurbation. Our analysis identified three critical intersecting and interacting thematic problems for urban mobility amongst older people: The quality of physical infrastructure; issues around the delivery, governance and quality of urban systems and services; and the attitudes and behaviors of individuals that older people encounter. This identified complexity reinforces the need for policy responses that may not necessarily involve design or retrofit measures, but instead might challenge perceptions and behaviors of use and access to urban space. Our co-design results further highlight that solutions need to move beyond the generic and placeless, instead embedding specific locally relevant solutions in inherently geographical spaces, populations and processes to ensure they relate to the intricacies of place

Complementary feeding: a Global Network cluster randomized controlled trial

Background: Inadequate and inappropriate complementary feeding are major factors contributing to excess morbidity and mortality in young children in low resource settings. Animal source foods in particular are cited as essential to achieve micronutrient requirements. The efficacy of the recommendation for regular meat consumption, however, has not been systematically evaluated. Methods/Design: A cluster randomized efficacy trial was designed to test the hypothesis that 12 months of daily intake of beef added as a complementary food would result in greater linear growth velocity than a micronutrient fortified equi-caloric rice-soy cereal supplement. The study is being conducted in 4 sites of the Global Network for Women\u27s and Children\u27s Health Research located in Guatemala, Pakistan, Democratic Republic of the Congo (DRC) and Zambia in communities with toddler stunting rates of at least 20%. Five clusters per country were randomized to each of the food arms, with 30 infants in each cluster. The daily meat or cereal supplement was delivered to the home by community coordinators, starting when the infants were 6 months of age and continuing through 18 months. All participating mothers received nutrition education messages to enhance complementary feeding practices delivered by study coordinators and through posters at the local health center. Outcome measures, obtained at 6, 9, 12, and 18 months by a separate assessment team, included anthropometry, dietary variety and diversity scores, biomarkers of iron, zinc and Vitamin B(12) status (18 months), neurocognitive development (12 and 18 months), and incidence of infectious morbidity throughout the trial. The trial was supervised by a trial steering committee, and an independent data monitoring committee provided oversight for the safety and conduct of the trial. Discussion: Findings from this trial will test the efficacy of daily intake of meat commencing at age 6 months and, if beneficial, will provide a strong rationale for global efforts to enhance local supplies of meat as a complementary food for young children

Common variants near FRK/COL10A1 and VEGFA are associated with advanced age-related macular degeneration

Despite significant progress in the identification of genetic loci for age-related macular degeneration (AMD), not all of the heritability has been explained. To identify variants which contribute to the remaining genetic susceptibility, we performed the largest meta-analysis of genome-wide association studies to date for advanced AMD. We imputed 6 036 699 single-nucleotide polymorphisms with the 1000 Genomes Project reference genotypes on 2594 cases and 4134 controls with follow-up replication of top signals in 5640 cases and 52 174 controls. We identified two new common susceptibility alleles, rs1999930 on 6q21-q22.3 near FRK/COL10A1 [odds ratio (OR) 0.87; P = 1.1 × 10−8] and rs4711751 on 6p12 near VEGFA (OR 1.15; P = 8.7 × 10−9). In addition to the two novel loci, 10 previously reported loci in ARMS2/HTRA1 (rs10490924), CFH (rs1061170, and rs1410996), CFB (rs641153), C3 (rs2230199), C2 (rs9332739), CFI (rs10033900), LIPC (rs10468017), TIMP3 (rs9621532) and CETP (rs3764261) were confirmed with genome-wide significant signals in this large study. Loci in the recently reported genes ABCA1 and COL8A1 were also detected with suggestive evidence of association with advanced AMD. The novel variants identified in this study suggest that angiogenesis (VEGFA) and extracellular collagen matrix (FRK/COL10A1) pathways contribute to the development of advanced AMD

State of the art. Overview of concepts, indicators and methodologies used for analyzing the social OMC.

This paper is a detailed analysis about the literature on the Social OMC from 2006-2010, focusing on how OMC research has been carried out. It specifically points to which theoretical framework/concepts are used, and how change is conceptualised and measured. It is organised in five sections. The first concerns visibility and awareness about the OMC; the second analyses research on the EU level coordination process; the third scrutinizes how features of the OMC have been analysed. The fourth and fifth sections, addressing how national integration of the OMC has been researched, respectively address substantive policy change as well as national policy-making. Strikingly, virtually all OMC research adopts theoretical frameworks derived from literature on Europeanisation and/or institutionalisation. Also, as the OMC is voluntary and sanction-free, it depends heavily on how and the the extent to which actors use it (agenda-setting, conflict resolution, maintaining focus on a policy issue, developing a policy dialogue, etc). OMC research has become nuanced and does highlight how, for which purpose and with which outcome actors engage with the OMC. Another finding is that there is data on policy issues addressed through the OMC, learning does take place and there is knowledge about domestic policy problems. However, the linkage between knowledge of an issue and direct use of the OMC for policy change in social policy is weak, but that may change with EU2020, where social policy has received a higher profile. Most research covers the EU-15, much more research needs to be undertaken in newer EU member states

Modelling Data Environments WithinPROV to Assist AnonymisationDecision-making

The Anonymisation Decision-making Framework (ADF) operationalizes the risk management of data exchange between organizations, referred to as "data environments". The second edition of ADF has increased its emphasis on modeling data flows, highlighting a potential new use of provenance information to support anonymisation decision-making. In this paper, we provide a use case that showcases this functionality. Based on this use case, we identify how provenance information could be utilized within the ADF, and identify a currently un-met requirement which is the modeling of data environments. We show how data environments can be implemented within the W3C PROV in four different ways. We analyze the costs and benefits of each approach, and consider another use case as a partial check for completeness. We then summarize our findings and suggest ways forward

Non-parametric estimation of reference adjusted, standardised probabilities of all-cause death and death due to cancer for population group comparisons

Abstract Background Ensuring fair comparisons of cancer survival statistics across population groups requires careful consideration of differential competing mortality due to other causes, and adjusting for imbalances over groups in other prognostic covariates (e.g. age). This has typically been achieved using comparisons of age-standardised net survival, with age standardisation addressing covariate imbalance, and the net estimates removing differences in competing mortality from other causes. However, these estimates lack ease of interpretability. In this paper, we motivate an alternative non-parametric approach that uses a common rate of other cause mortality across groups to give reference-adjusted estimates of the all-cause and cause-specific crude probability of death in contrast to solely reporting net survival estimates. Methods We develop the methodology for a non-parametric equivalent of standardised and reference adjusted crude probabilities of death, building on the estimation of non-parametric crude probabilities of death. We illustrate the approach using regional comparisons of survival following a diagnosis of rectal cancer for men in England. We standardise to the covariate distribution and other cause mortality of England as a whole to offer comparability, but with close approximation to the observed all-cause region-specific mortality. Results The approach gives comparable estimates to observed crude probabilities of death, but allows direct comparison across population groups with different covariate profiles and competing mortality patterns. In our illustrative example, we show that regional variations in survival following a diagnosis of rectal cancer persist even after accounting for the variation in deprivation, age at diagnosis and other cause mortality. Conclusions The methodological approach of using standardised and reference adjusted metrics offers an appealing approach for future cancer survival comparison studies and routinely published cancer statistics. Our non-parametric estimation approach through the use of weighting offers the ability to estimate comparable survival estimates without the need for statistical modelling

Henry Purcell: Dido and Aeneas

This impressive performance by an extraordinary group of musicians makes for a significant addition to the catalogue. Sarah Connolly and the Orchestra of the Age of Enlightenment will perform Dido and Aeneas at the Royal Opera House, Covent Garden in March 2009