Cardiovascular risk reduction with liraglutide: An exploratory mediation analysis of the leader trial

OBJECTIVE The Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial (ClinicalTrials.gov reg. no. NCT01179048) demonstrated a reduced risk of cardiovascular (CV) events for patients with type 2 diabetes who received the glucagon-like peptide 1 receptor agonist liraglutide versus placebo. The mechanisms behind this CV benefit remain unclear. We aimed to identify potential mediators for the CV benefit observed with liraglutide in the LEADER trial. RESEARCH DESIGN AND METHODS We performed exploratory analyses to identify potential mediators of the effect of liraglutide on major adverse CV events (MACE; composite of CV death, nonfatal myocardial infarction, or nonfatal stroke) from the following candidates: Glycated hemoglobin (HbA1c), body weight, urinary albumin-to-creatinine ratio (UACR), confirmed hypoglycemia, sulfonylurea use, insulin use, systolic blood pressure, and LDL cholesterol. These candidates were selected as CV risk factors on which liraglutide had an effect in LEADER such that a reduction in CV risk might result. We used two methods based on a Cox proportional hazards model and the new Vansteelandt method designed to use all available information from the mediator and to control for confounding factors. RESULTS Analyses using the Cox methods and Vansteelandt method indicated potential mediation by HbA1c (up to 41% and 83% mediation, respectively) and UACR (up to 29% and 33% mediation, respectively) on the effect of liraglutide on MACE. Mediation effects were small for other candidates. CONCLUSIONS These analyses identify HbA1c and, to a lesser extent, UACR as potential mediators of the CV effects of liraglutide. Whether either is a marker of an unmeasured factor or a true mediator remains a key question that invites further investigation

Constraining the dark energy dynamics with the cosmic microwave background bispectrum

We consider the influence of the dark energy dynamics at the onset of cosmic acceleration on the Cosmic Microwave Background (CMB) bispectrum, through the weak lensing effect induced by structure formation. We study the line of sight behavior of the contribution to the bispectrum signal at a given angular multipole $l$: we show that it is non-zero in a narrow interval centered at a redshift $z$ satisfying the relation $l/r(z)\simeq k_{NL}(z)$, where the wavenumber corresponds to the scale entering the non-linear phase, and $r$ is the cosmological comoving distance. The relevant redshift interval is in the range 0.1\lsim z\lsim 2 for multipoles 1000\gsim\ell\gsim 100; the signal amplitude, reflecting the perturbation dynamics, is a function of the cosmological expansion rate at those epochs, probing the dark energy equation of state redshift dependence independently on its present value. We provide a worked example by considering tracking inverse power law and SUGRA Quintessence scenarios, having sensibly different redshift dynamics and respecting all the present observational constraints. For scenarios having the same present equation of state, we find that the effect described above induces a projection feature which makes the bispectra shifted by several tens of multipoles, about 10 times more than the corresponding effect on the ordinary CMB angular power spectrum.Comment: 15 pages, 7 figures, matching version accepted by Physical Review D, one figure improve

Cargo-specific recruitment in clathrin and dynamin-independent endocytosis

Spatially controlled, cargo-specific endocytosis is essential for development, tissue homeostasis, and cancer invasion and is often hijacked by viral infections. Unlike clathrin-mediated endocytosis, which exploits cargo-specific adaptors for selective protein internalization, the clathrin and dynamin-independent endocytic pathway (CLIC-GEEC, CG-pathway) has until now been considered a bulk internalization route for the fluid phase, glycosylated membrane proteins and lipids. Although the core molecular players of CG endocytosis have been recently defined, no cargo-specific adaptors are known and evidence of selective protein uptake into the pathway is lacking. Here, we identify the first cargo-specific adaptor for CG-endocytosis and demonstrate its clinical relevance in breast cancer progression. By combining unbiased molecular characterization and super-resolution imaging, we identified the actin-binding protein swiprosin-1 (EFHD2) as a cargo-specific adaptor regulating integrin internalization via the CG-pathway. Swiprosin-1 couples active Rab21-associated integrins with key components of the CG-endocytic machinery, IRSp53 and actin. Swiprosin-1 is critical for integrin endocytosis, but not for other CG-cargo and supports integrin-dependent cancer cell migration and invasion, with clinically relevant implications for breast cancer. Our results demonstrate a previously unknown cargo selectivity for the CG-pathway and opens the possibility to discover more adaptors regulating it

Constraints on cosmological models from strong gravitational lensing systems

Strong lensing has developed into an important astrophysical tool for probing both cosmology and galaxies (their structure, formation, and evolution). Using the gravitational lensing theory and cluster mass distribution model, we try to collect a relatively complete observational data concerning the Hubble constant independent ratio between two angular diameter distances $D_{ds}/D_s$ from various large systematic gravitational lens surveys and lensing by galaxy clusters combined with X-ray observations, and check the possibility to use it in the future as complementary to other cosmological probes. On one hand, strongly gravitationally lensed quasar-galaxy systems create such a new opportunity by combining stellar kinematics (central velocity dispersion measurements) with lensing geometry (Einstein radius determination from position of images). We apply such a method to a combined gravitational lens data set including 70 data points from Sloan Lens ACS (SLACS) and Lens Structure and Dynamics survey (LSD). On the other hand, a new sample of 10 lensing galaxy clusters with redshifts ranging from 0.1 to 0.6 carefully selected from strong gravitational lensing systems with both X-ray satellite observations and optical giant luminous arcs, is also used to constrain three dark energy models ($\Lambda$CDM, constant $w$ and CPL) under a flat universe assumption. For the full sample ($n=80$) and the restricted sample ($n=46$) including 36 two-image lenses and 10 strong lensing arcs, we obtain relatively good fitting values of basic cosmological parameters, which generally agree with the results already known in the literature. This results encourages further development of this method and its use on larger samples obtained in the future.Comment: 22 pages, 5 figures, 2 tables; accepted by JCA

The Business Model: Recent Developments and Future Research

This article provides a broad and multifaceted review of the received literature on business models in which the authors examine the business model concept through multiple subject-matter lenses. The review reveals that scholars do not agree on what a business model is and that the literature is developing largely in silos, according to the phenomena of interest of the respective researchers. However, the authors also found emerging common themes among scholars of business models. Specifically, (1) the business model is emerging as a new unit of analysis; (2) business models emphasize a system-level, holistic approach to explaining how firms “do business”; (3) firm activities play an important role in the various conceptualizations of business models that have been proposed; and (4) business models seek to explain how value is created, not just how it is captured. These emerging themes could serve as catalysts for a more unified study of business models

The Reproductive Revolution

Este texto fue publicado en 2009 por The Sociological Review. Rogamos que, a efectos de divulgación, docencia y cita bibliográfica se acuda a la publicación impresa (u online de la propia revista) y la cita sea esta: MacInnes, J., Pérez Díaz, J. (2009), "The reproductive revolution" The Sociological Review 57 (2): 262-284. Su versión html puede encontrarse en esta dirección:http://www3.interscience.wiley.com/cgi-bin/fulltext/122368561/HTMLSTART Quienes estén interesados en ampliar la información sobre nuestra Teoría de la Revolución Reproductiva pueden visitar la página web siguiente: http://www.ieg.csic.es/jperez/pags/RRweb/RRweb.htm También encontrarán en este mismo repositorio otra publicación con unaexposición en castellano de las mismas ideas y publicada en la REIS bajo el título “La tercera revolución de la modernidad: la reproductiva”.We suggest that a third revolution alongside the better known economic and political ones has been vital to the rise of modernity: the reproductive revolution, comprising a historically unrepeatable shift in the efficiency of human reproduction which for the first time brought demographic security.As well as highlighting the contribution of demographic change to the rise of modernity and addressing the limitations of orthodox theories of the demographic transition, the concept of the reproductive revolution offers a better way to integrate sociology and demography. The former has tended to pay insufficient heed to sexual reproduction, individual mortality and the generational replacement of population, while the latter has undervalued its own distinctive theoretical contribution, portraying demographic change as the effect of causes lying elsewhere. We outline a theory of the reproductive revolution, review some relevant supporting empirical evidence and briefly discuss its implications both for demographic transition theory itself, and for a range of key social changes that we suggest it made possible: the decline of patriarchy and feminisation of the public sphere, the deregulation and privatisation of sexuality, family change, the rise of identity, ‘low’ fertility and ‘population ageing’.Peer reviewe