Breast-feeding and childhood-onset type 1 diabetes:A pooled analysis of individual participant data from 43 observational studies

OBJECTIVE: To investigate if there is a reduced risk of type 1 diabetes in children breastfed or exclusively breastfed by performing a pooled analysis with adjustment for recognized confounders.
RESEARCH DESIGN AND METHODS: Relevant studies were identified from literature searches using MEDLINE, Web of Science, and EMBASE. Authors of relevant studies were asked to provide individual participant data or conduct prespecified analyses. Meta-analysis techniques were used to combine odds ratios (ORs) and investigate heterogeneity between studies.
RESULTS: Data were available from 43 studies including 9,874 patients with type 1 diabetes. Overall, there was a reduction in the risk of diabetes after exclusive breast-feeding for >2 weeks (20 studies; OR = 0.75, 95% CI 0.64-0.88), the association after exclusive breast-feeding for >3 months was weaker (30 studies; OR = 0.87, 95% CI 0.75-1.00), and no association was observed after (nonexclusive) breast-feeding for >2 weeks (28 studies; OR = 0.93, 95% CI 0.81-1.07) or >3 months (29 studies; OR = 0.88, 95% CI 0.78-1.00). These associations were all subject to marked heterogeneity (I(2) = 58, 76, 54, and 68%, respectively). In studies with lower risk of bias, the reduced risk after exclusive breast-feeding for >2 weeks remained (12 studies; OR = 0.86, 95% CI 0.75-0.99), and heterogeneity was reduced (I(2) = 0%). Adjustments for potential confounders altered these estimates very little.
CONCLUSIONS: The pooled analysis suggests weak protective associations between exclusive breast-feeding and type 1 diabetes risk. However, these findings are difficult to interpret because of the marked variation in effect and possible biases (particularly recall bias) inherent in the included studies.

Plasma HDL cholesterol and risk of myocardial infarction: A mendelian randomisation study

Background: High plasma HDL cholesterol is associated with reduced risk of myocardial infarction, but whether this association is causal is unclear. Exploiting the fact that genotypes are randomly assigned at meiosis, are independent of non-genetic confounding, and are unmodified by disease processes, mendelian random isation can be used to test the hypothesis that the association of a plasma biomarker with disease is causal.
Methods: We performed two mendelian randomisation analyses. First, we used as an instrument a single nucleotide polymorphism (SNP) in the endothelial lipase gene (LIPG Asn396Ser) and tested this SNP in 20 studies (20 913 myocardial infarction cases, 95 407 controls). Second, we used as an instrument a genetic score consisting of 14 common SNPs that exclusively associate with HDL cholesterol and tested this score in up to 12 482 cases of myocardial infarction and 41 331 controls. As a positive control, we also tested a genetic score of 13 common SNPs exclusively associated with LDL cholesterol.
Findings: Carriers of the LIPG 396Ser allele (2·6% frequency) had higher HDL cholesterol (0·14 mmol/L higher p=8×10-13) but similar levels of other lipid and non-lipid risk factors for myocardial infarction compared with noncarriers. This difference in HDL cholesterol is expected to decrease risk of myocardial infarction by 13% (odds ratio [OR] 0·87, 95% CI 0·84-0·91). However, we noted that the 396Ser allele was not associated with risk of myocardial infarction (OR 0·99, 95% CI 0·88-1·11, p=0·85). From observational epidemiology, an increase of 1 SD in HDL cholesterol was associated with reduced risk of myocardial infarction (OR 0·62, 95% CI 0·58-0·66). However, a 1 SD increase in HDL cholesterol due to genetic score was not associated with risk of myocardial infarction (OR 0·93 95% CI 0·68-1·26, p=0·63). For LDL cholesterol, the estimate from observational epidemiology (a 1 SD increase in LDL cholesterol associated with OR 1·54, 95% CI 1·45-1·63) was concordant with that from genetic score (OR 2·13 95% CI 1·69-2·69, p=2×10 -10).
Interpretation: Some genetic mechanisms that raise plasma HDL cholesterol do not seem to lower risk of myocardial infarction. These data challenge the concept that raising of plasma HDL cholesterol will uniformly translate into reductions in risk of myocardial infarction.

Opening the Frontier: The Gubbio-Perugia Frontier in the Course of History.

The frontier between Gubbio (ancient Umbria) and Perugia (ancient Etruria), in the northeast part of the modern region of Umbria, was founded in the late sixth century BC. The frontier endured in different forms, most notably in the late antique and medieval periods, as well as fleetingly in 1944, and is fossilized today in the local government boundaries. Archaeological, documentary and
philological evidence are brought together to investigate different scales of time that vary from millennia to single days in the representation of a frontier that captured a watershed of geological origins. The foundation of the frontier appears to have been a product of the active agency of the Etruscans, who projected new settlements across the Tiber in the course of the sixth century BC,
protected at the outer limit of their territory by the naturally defended farmstead of Col di Marzo. The immediate environs of the ancient abbey of Montelabate have been studied intensively by targeted, systematic and geophysical survey in conjunction with excavation, work that is still in progress. An overview of the development of the frontier is presented here, employing the data currently available.

Cannibale, Frigidaire, and the Multitude: Post-1977 Italian Comics through Radical Theory

A direct connection between comics and contemporary critical theory is to be found in the activity of the collective of artists who created "Cannibale" and "Frigidaire", the two most innovative Italian comics magazines of the late 1970s and early 1980s. The work of Andrea Pazienza, Filippo Scòzzari, Stefano Tamburini, Tanino Liberatore and Massimo Mattioli should be regarded as an expression of the radical movements from which Marxist Autonomist thinkers such as Antonio Negri, Franco ‘Bifo’ Berardi and Paolo Virno also emerged in the same period. As a consequence, the writings of the latter can be used to analyse the narrative and visual style, the recurring themes, and the editorial characteristics of the comics of the former. Moreover, an interesting parallel can also be drawn between the work of the most influential of these artists, Andrea Pazienza, and the thought of another prominent Italian philosopher, Giorgio Agamben, whose earliest books were published at that time too. The aim of this article is to show that the ideas of a number of the thinkers who have recently become internationally known as representatives of radical Italian theory, are useful to understand the work of this group of comics authors.

Food of the Blue

An episode of BBC Radio 4's detective series 'Baldi'. Paolo Baldi finds himself in a world of superstar academics, but why are their bloodless corpses littering the college? And what is that thing they drink to rejuvenate the venerable institution?

Intercepting the First Pass:Rapid Categorization is Suppressed for Unseen Stimuli

The operations and processes that the human brain employs to achieve fast visual categorization remain a matter of debate. A first issue concerns the timing and place of rapid visual categorization and to what extent it can be performed with an early feed-forward pass of information through the visual system. A second issue involves the categorization of stimuli that do not reach visual awareness. There is disagreement over the degree to which these stimuli activate the same early mechanisms as stimuli that are consciously perceived. We employed continuous flash suppression (CFS), EEG recordings, and machine learning techniques to study visual categorization of seen and unseen stimuli. Our classifiers were able to predict from the EEG recordings the category of stimuli on seen trials but not on unseen trials. Rapid categorization of conscious images could be detected around 100?ms on the occipital electrodes, consistent with a fast, feed-forward mechanism of target detection. For the invisible stimuli, however, CFS eliminated all traces of early processing. Our results support the idea of a fast mechanism of categorization and suggest that this early categorization process plays an important role in later, more subtle categorizations, and perceptual processes.

Linear Optics Simulation of Quantum Non-Markovian Dynamics

The simulation of open quantum dynamics has recently allowed the direct investigation of the features of system-environment interaction and of their consequences on the evolution of a quantum system. Such interaction threatens the quantum properties of the system, spoiling them and causing the phenomenon of decoherence. Sometimes however a coherent exchange of information takes place between system and environment, memory effects arise and the dynamics of the system becomes non-Markovian. Here we report the experimental realisation of a non-Markovian process where system and environment are coupled through a simulated transverse Ising model. By engineering the evolution in a photonic quantum simulator, we demonstrate the role played by system-environment correlations in the emergence of memory effects.

The Type IIb Supernova 2011dh from a Supergiant Progenitor

A set of hydrodynamical models based on stellar evolutionary progenitors is used to study the nature of SN 2011dh. Our modeling suggests that a large progenitor star ---with R ~200 Rsun---, is needed to reproduce the early light curve of SN 2011dh. This is consistent with the suggestion that the yellow super-giant star detected at the location of the SN in deep pre-explosion images is the progenitor star. From the main peak of the bolometric light curve and expansion velocities we constrain the mass of the ejecta to be ~2 Msun, the explosion energy to be E= 6-10 x 10^50 erg, and the 56Ni mass to be approximately 0.06 Msun. The progenitor star was composed of a helium core of 3 to 4 Msun and a thin hydrogen-rich envelope of ~0.1 M_sun with a main sequence mass estimated to be in the range of 12--15 Msun. Our models rule out progenitors with helium-core masses larger than 8 Msun, which correspond to M_ZAMS > 25 Msun. This suggests that a single star evolutionary scenario for SN 2011dh is unlikely.

SN 2009ip á la PESSTO:No evidence for core-collapse yet

We present observations of the interacting transient SN 2009ip, from the start of the outburst in October 2012 until the end of the 2012 observing season. The transient reached a peak of $M_V$=-17.7 mag before fading rapidly, with a total integrated luminosity of 1.9$\times10^{49}$ erg over the period of August-December 2012. The optical and near infrared spectra are dominated by narrow emission lines, signaling a dense circumstellar environment, together with multiple components of broad emission and absorption in H and He at velocities between 0.5-1.2$\times10^4$ km s$^{-1}$\. We see no evidence for nucleosynthesized material in SN 2009ip, even in late-time pseudo-nebular spectra. We set a limit of $

Genome-wide association meta-analysis of human longevity identifies a novel locus conferring survival beyond 90 years of age

The genetic contribution to the variation in human lifespan is approximately 25%.  Despite the large number of identified disease-susceptibility loci, it is not known which loci influence population mortality.  We performed a genome-wide association meta-analysis of 7729 long-lived individuals of European descent (≥ 85 years) and 16121 younger controls (< 65 years) followed by replication in an additional set of 13060 long-lived individuals and 61156 controls. In addition, we performed a subset analysis in cases ≥ 90 years. We observed genome-wide significant association with longevity, as reflected by survival to ages beyond 90 years, at a novel locus, rs2149954, on chromosome 5q33.3 (OR = 1.10, P =1.74 x 10-8). We also confirmed association of rs4420638 on chromosome 19q13.32 (OR = 0.72, P = 3.40 x 10-36), representing the TOMM40/APOE/APOC1 locus. In a prospective meta-analysis (n = 34103) the minor allele of rs2149954 (T) on chromosome 5q33.3 associates with increased survival (HR = 0.95, P = 0.003). This allele has previously been reported to associate with low blood pressure in middle age. Interestingly, the minor allele (T) associates with decreased cardiovascular mortality risk, independent of blood pressure. We report on the first GWAS-identified longevity locus on chromosome 5q33.3 influencing survival in the general European population. The minor allele of this locus associates with low blood pressure in middle age, although the contribution of this allele to survival may be less dependent on blood pressure. Hence, the pleiotropic mechanisms by which this intragenic variation contributes to lifespan regulation have to be elucidated.

ADAM17-Dependent c-MET-STAT3 Signaling Mediates Resistance to MEK Inhibitors in KRAS Mutant Colorectal Cancer

There are currently no approved targeted therapies for advanced KRAS mutant (KRASMT) colorectal cancer (CRC). Using a unique systems biology approach, we identified JAK1/2-dependent activation of STAT3 as the key mediator of resistance to MEK inhibitors in KRASMT CRC in vitro and in vivo. Further analyses identified acute increases in c-MET activity following treatment with MEK inhibitors in KRASMT CRC models, which was demonstrated to promote JAK1/2-STAT3-mediated resistance. Furthermore, activation of c-MET following MEK inhibition was found to be due to inhibition of the ERK-dependent metalloprotease ADAM17, which normally inhibits c-MET signaling by promoting shedding of its endogenous antagonist, soluble "decoy" MET. Most importantly, pharmacological blockade of this resistance pathway with either c-MET or JAK1/2 inhibitors synergistically increased MEK-inhibitor-induced apoptosis and growth inhibition in vitro and in vivo in KRASMT models, providing clear rationales for the clinical assessment of these combinations in KRASMT CRC patients.