Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): a double-blind, randomised placebo-controlled trial

Background: Glucagon-like peptide 1 receptor agonists differ in chemical structure, duration of action, and in their effects on clinical outcomes. The cardiovascular effects of once-weekly albiglutide in type 2 diabetes are unknown. We aimed to determine the safety and efficacy of albiglutide in preventing cardiovascular death, myocardial infarction, or stroke. Methods: We did a double-blind, randomised, placebo-controlled trial in 610 sites across 28 countries. We randomly assigned patients aged 40 years and older with type 2 diabetes and cardiovascular disease (at a 1:1 ratio) to groups that either received a subcutaneous injection of albiglutide (30–50 mg, based on glycaemic response and tolerability) or of a matched volume of placebo once a week, in addition to their standard care. Investigators used an interactive voice or web response system to obtain treatment assignment, and patients and all study investigators were masked to their treatment allocation. We hypothesised that albiglutide would be non-inferior to placebo for the primary outcome of the first occurrence of cardiovascular death, myocardial infarction, or stroke, which was assessed in the intention-to-treat population. If non-inferiority was confirmed by an upper limit of the 95% CI for a hazard ratio of less than 1·30, closed testing for superiority was prespecified. This study is registered with ClinicalTrials.gov, number NCT02465515. Findings: Patients were screened between July 1, 2015, and Nov 24, 2016. 10 793 patients were screened and 9463 participants were enrolled and randomly assigned to groups: 4731 patients were assigned to receive albiglutide and 4732 patients to receive placebo. On Nov 8, 2017, it was determined that 611 primary endpoints and a median follow-up of at least 1·5 years had accrued, and participants returned for a final visit and discontinuation from study treatment; the last patient visit was on March 12, 2018. These 9463 patients, the intention-to-treat population, were evaluated for a median duration of 1·6 years and were assessed for the primary outcome. The primary composite outcome occurred in 338 (7%) of 4731 patients at an incidence rate of 4·6 events per 100 person-years in the albiglutide group and in 428 (9%) of 4732 patients at an incidence rate of 5·9 events per 100 person-years in the placebo group (hazard ratio 0·78, 95% CI 0·68–0·90), which indicated that albiglutide was superior to placebo (p<0·0001 for non-inferiority; p=0·0006 for superiority). The incidence of acute pancreatitis (ten patients in the albiglutide group and seven patients in the placebo group), pancreatic cancer (six patients in the albiglutide group and five patients in the placebo group), medullary thyroid carcinoma (zero patients in both groups), and other serious adverse events did not differ between the two groups. There were three (<1%) deaths in the placebo group that were assessed by investigators, who were masked to study drug assignment, to be treatment-related and two (<1%) deaths in the albiglutide group. Interpretation: In patients with type 2 diabetes and cardiovascular disease, albiglutide was superior to placebo with respect to major adverse cardiovascular events. Evidence-based glucagon-like peptide 1 receptor agonists should therefore be considered as part of a comprehensive strategy to reduce the risk of cardiovascular events in patients with type 2 diabetes. Funding: GlaxoSmithKline

Cabbage and fermented vegetables : From death rate heterogeneity in countries to candidates for mitigation strategies of severe COVID-19

Large differences in COVID-19 death rates exist between countries and between regions of the same country. Some very low death rate countries such as Eastern Asia, Central Europe, or the Balkans have a common feature of eating large quantities of fermented foods. Although biases exist when examining ecological studies, fermented vegetables or cabbage have been associated with low death rates in European countries. SARS-CoV-2 binds to its receptor, the angiotensin-converting enzyme 2 (ACE2). As a result of SARS-CoV-2 binding, ACE2 downregulation enhances the angiotensin II receptor type 1 (AT(1)R) axis associated with oxidative stress. This leads to insulin resistance as well as lung and endothelial damage, two severe outcomes of COVID-19. The nuclear factor (erythroid-derived 2)-like 2 (Nrf2) is the most potent antioxidant in humans and can block in particular the AT(1)R axis. Cabbage contains precursors of sulforaphane, the most active natural activator of Nrf2. Fermented vegetables contain many lactobacilli, which are also potent Nrf2 activators. Three examples are: kimchi in Korea, westernized foods, and the slum paradox. It is proposed that fermented cabbage is a proof-of-concept of dietary manipulations that may enhance Nrf2-associated antioxidant effects, helpful in mitigating COVID-19 severity.Peer reviewe

Nrf2-interacting nutrients and COVID-19 : time for research to develop adaptation strategies

There are large between- and within-country variations in COVID-19 death rates. Some very low death rate settings such as Eastern Asia, Central Europe, the Balkans and Africa have a common feature of eating large quantities of fermented foods whose intake is associated with the activation of the Nrf2 (Nuclear factor (erythroid-derived 2)-like 2) anti-oxidant transcription factor. There are many Nrf2-interacting nutrients (berberine, curcumin, epigallocatechin gallate, genistein, quercetin, resveratrol, sulforaphane) that all act similarly to reduce insulin resistance, endothelial damage, lung injury and cytokine storm. They also act on the same mechanisms (mTOR: Mammalian target of rapamycin, PPAR gamma:Peroxisome proliferator-activated receptor, NF kappa B: Nuclear factor kappa B, ERK: Extracellular signal-regulated kinases and eIF2 alpha:Elongation initiation factor 2 alpha). They may as a result be important in mitigating the severity of COVID-19, acting through the endoplasmic reticulum stress or ACE-Angiotensin-II-AT(1)R axis (AT(1)R) pathway. Many Nrf2-interacting nutrients are also interacting with TRPA1 and/or TRPV1. Interestingly, geographical areas with very low COVID-19 mortality are those with the lowest prevalence of obesity (Sub-Saharan Africa and Asia). It is tempting to propose that Nrf2-interacting foods and nutrients can re-balance insulin resistance and have a significant effect on COVID-19 severity. It is therefore possible that the intake of these foods may restore an optimal natural balance for the Nrf2 pathway and may be of interest in the mitigation of COVID-19 severity

Caractérisation des propriétés thermomécaniques des enrobés bitumineux pour infrastructure ferroviaire

The research presented in this document was carried out in collaboration between the National School of Public Works (Ecole Nationale des Travaux Publics de l’Etat – ENTPE) of the University of Lyon and the French National Railway Company (Société Nationale des Chemins de Fer français – SNCF). The objective of this study is the characterisation of the thermomechanical properties of road base-course bituminous mixtures commonly used in France for their use in railway track structures. Linear Viscoelastic (LVE) and fatigue resistance properties have been investigated. The influence of moisture damage including freeze-thaw cycles on the properties of the studied mixtures was also studied. LVE and fatigue resistance properties were obtained by means of sinusoidal tension-compression tests on cylindrical samples at the ENTPE/LTDS laboratory. A protocol for moisture conditioning of bituminous mixtures samples was developed based on the French and American standard test methods for moisture susceptibility and on the literature review on the subject. Moisture damage was assessed using complex modulus and fatigue tests. The LVE behaviour of the materials was described using the 2S2P1D (2 Springs, 2 Parabolic elements and 1 Dashpot) model developed at the ENTPE/LTDS laboratory. Three road base-course mixtures available in the French market were studied: a GB3, a GB4 and a mixture called GB PMB (for Polymer-Modified Bitumen). The GB3 mixture stands as the reference material since it is commonly used for the base-courses of conventional roads in France. The GB4 mixture stands as a better performing material than the GB3. The specific studied GB4 formulation corresponds to that used as sub-ballast of the Brittany-Loire high-speed line (HSL) in western France. The GB PMB stands as an improved version of the GB3 in which the base bitumen is replaced by polymer-modified bitumen. The interest of the study of this third mixture is to assess the relevance of using PMB’s in bituminous mixtures intended for railway platforms. The test zone of the East-European HSL served as case study to identify the loading conditions and the behaviour of a bituminous sub-ballast layer in a French track. The several advantages of using bituminous mixtures as sub-ballast material identified in the literature are confirmed by the feedback from this test zone. The results obtained show that the studied bituminous mixtures present excellent bearing capacities (stiffness) for their use as sub-ballast layers in France. The used moisture conditioning protocol did not alter the LVE behaviour of the materials. The good performance of the materials is then expected to be perennial regarding the effect of moisture on the LVE behaviour. With respect to fatigue resistance, the results show that the use of a PMB provides an important increase of the fatigue life as well as a reduction of the susceptibility to moisture damage. However, given the identified loading levels of the bituminous sub-ballast in a common French track structure, all three mixtures present adequate fatigue resistance properties.Le travail de recherche présenté dans ce document a été réalisé dans le cadre d’une collaboration entre l’ENTPE/ niversité de Lyon et la SNCF. L’objectif de l’étude est la caractérisation des propriétés thermomécaniques des enrobés bitumineux à être utilisés dans la construction de voies ferrées. Le comportement viscoélastique linéaire (VEL) et la résistance à la fatigue d’enrobés pour couche de base couramment utilisés en France ont été étudiés. L’influence de l’eau sur ces propriétés a été aussi étudiée du fait que l’exposition à l’eau des couches bitumineuses en structure ferroviaire peut les altérer et réduire la durée de vie de l’ouvrage. La caractérisation du comportement VEL et de la résistance à la fatigue des matériaux a été faite en réalisant des essais mécaniques en traction-compression sur des éprouvettes cylindriques au laboratoire LTDS/ENTPE. Une nouvelle procédure de conditionnement à l’eau et au gel a été proposée sur la base des méthodes d’essai normalisées française et américaine. La susceptibilité à l’eau des matériaux a été obtenue par comparaison des résultats des essais mécaniques entre éprouvettes conditionnées et non conditionnées. Le comportement VEL des matériaux a été simulé avec le modèle 2S2P1D, développée à l’ENTPE. Trois formules pour couche de base ont été testées : une GB3, une GB4 et une formule appelée GB PMB. Cette dernière est la même formule GB3 mais avec un bitume modifié aux polymères SBS. La GB3 sert comme matériau de référence. La GB4 est un matériau de meilleures performances que la GB3. La formule GB4 étudiée correspond à celle mise en place dans la couche sous-ballast de la Ligne à Grande Vitesse (LGV) Bretagne-Pays de Loire. L’intérêt d’étudier la GB PMB est de savoir si l’utilisation de bitumes modifiés aux polymères est pertinente dans un contexte ferroviaire ou pas. 2 La zone test construite dans la LGV Est-Européenne près de la ville de Reims avec une couche sous-ballast en enrobé bitumineux a servi comme cas d’étude pour cette thèse. Les différents avantages de l’utilisation de matériaux bitumineux en structure ferroviaire retrouvées dans la bibliographie ont été confirmés avec le retour sur l’expérience de cette zone test. Les résultats obtenus des travaux expérimentaux montrent que les trois formules étudiées présentent des capacités portantes (rigidité) suffisantes pour leur utilisation comme couche sous-ballast. La méthode de conditionnement à l’eau et au gel utilisée n’a pas altéré le comportement VEL des matériaux. En ce qui concerne les essais de fatigue, les résultats ont montré que l’utilisation d’un bitume modifié aux polymères augmente sensiblement la résistance à la fatigue de la GB3. La GB PMB a aussi montré une plus faible susceptibilité de la résistance à la fatigue à l’eau et au gel que la GB3. Du fait que les niveaux de sollicitation de la base de la couche d’enrobé de la zone test LVG EE sont très faibles, tous les matériaux étudiés présentent des propriétés satisfaisantes de résistance à la fatigue en couche sous-ballast

Viscoelastic Behaviour Characterization of a Gap-graded Asphalt Mixture with SBS Polymer Modified Bitumen

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The database of the PREDICTS (Projecting Responses of Ecological Diversity In Changing Terrestrial Systems) project

The PREDICTS project—Projecting Responses of Ecological Diversity In Changing Terrestrial Systems (www.predicts.org.uk)—has collated from published studies a large, reasonably representative database of comparable samples of biodiversity from multiple sites that differ in the nature or intensity of human impacts relating to land use. We have used this evidence base to develop global and regional statistical models of how local biodiversity responds to these measures. We describe and make freely available this 2016 release of the database, containing more than 3.2 million records sampled at over 26,000 locations and representing over 47,000 species. We outline how the database can help in answering a range of questions in ecology and conservation biology. To our knowledge, this is the largest and most geographically and taxonomically representative database of spatial comparisons of biodiversity that has been collated to date; it will be useful to researchers and international efforts wishing to model and understand the global status of biodiversity