Risk factors for atrial fibrillation incidence and progression

During atrial fibrillation (AF) irregular activation of the hearts atria occur, causing an irregular heart rate and altered blood flow. AF is the most common heart rhythm disorder, causing stroke, heart failure, dementia, reduced quality of life and high health care expences. AF is diagnosed increasingly frequent, at increasingly young age. Treatment requires knowledge on factors that may cause AF, which may help prevent occurence of AF and AF progression. AF progression is the proces by which scar tissue forms in the atria, which goes hand-in-hand with increased episodes of AF and AF-related complications. Examples of traditional risk factors for AF are hypertension, heart infarction and heart failure. However risk factors are changing because of improved treatment, increasing age of the population and changing lifestyle. We investigated risk factors for AF incidence and progression. We found that obesity nowadays has become an important risk factor for atrial fibrillation occurrence, at both younger age (<60 years) and older age. At younger age heritable factors seem to be more important than at older age, conversely, some traditional risk factors are less important at younger age. Furthermore, presence of AF related symtoms (e.g. shortness of breath) may be a sign of present risk factors, more AF related complications and therefore AF progression. Finally, we found that even in young patients with AF and obesity, atrial function is reduced, which is an early sign of scar tissue formation. This again underlines that AF treatment should embrace lifestyle change and weightloss

Let's stop dumping cookstoves in local communities. It's time to get implementation right

We most welcome the comment by Thakur, van Schayck and Boudewijns on our article on the effects and acceptability of implementing improved cookstoves. Adoption rates of improved cookstoves by local communities are often strikingly low. The authors underline the urge to advance cookstove implementation strategies, and reinforce the approach used in the FRESH AIR project. They highlight several important factors to increase adoption success and call for further research on the topic. We want to build on this comment by reflecting on decades of substantial discrepancies between the disappointing adoption rates of improved cookstoves, and the subsequent failure to adapt implementation strategies accordingly. We argue that it is not necessarily the lack of evidence that impedes the success of implementation strategies for improved cookstoves. Moreover, it is the lack of use of the evidence by implementors. We propose several ideas for overcoming this evidence-to-practice gap

Impact of allosteric modulation: exploring the binding kinetics of glutamate and other orthosteric ligands of the metabotropic glutamate receptor 2

While many orthosteric ligands have been developed for the mGlu2 receptor, little is known about their target binding kinetics and how these relate to those of the endogenous agonist glutamate. Here, the kinetic rate constants, i.e. kon and koff, of glutamate were determined for the first time followed by those of the synthetic agonist LY354740 and antagonist LY341495. To increase the understanding of the binding mechanism and impact of allosteric modulation thereon, kinetic experiments were repeated in the presence of allosteric modulators. Functional assays were performed to further study the interplay between the orthosteric and allosteric binding sites, including an impedance-based morphology assay. We found that dissociation rate constants of orthosteric mGlu2 ligands were all within a small 6-fold range, whereas association rate constants were ranging over more than three orders of magnitude and correlated to both affinity and potency. The latter showed that target engagement of orthosteric mGlu2 ligands is kon-driven in vitro. Moreover, only the off-rates of the two agonists were decreased by a positive allosteric modulator (PAM), thereby increasing their affinity. Interestingly, a PAM increased the duration of a glutamate-induced cellular response. A negative allosteric modulator (NAM) increased both on- and off-rate of glutamate without changing its affinity, while it did not affect these parameters for LY354740, indicating probe-dependency. In conclusion, we found that affinity- or potency-based orthosteric ligand optimization primarily results in ligands with high kon values. Moreover, positive allosteric modulators alter the binding kinetics of orthosteric agonists mainly by decreasing koff, which we were able to correlate to a lengthened cellular response. Together, this study shows the importance of studying binding kinetics in early drug discovery, as this may provide important insights towards improved efficacy in vivo.Medicinal Chemistr