Targeting the Virus Capsid as a Tool to Fight RNA Viruses

Several strategies have been developed to fight viral infections, not only in humans but also in animals and plants. Some of them are based on the development of efficient vaccines, to target the virus by developed antibodies, others focus on finding antiviral compounds with activities that inhibit selected virus replication steps. Currently, there is an increasing number of antiviral drugs on the market; however, some have unpleasant side effects, are toxic to cells, or the viruses quickly develop resistance to them. As the current situation shows, the combination of multiple antiviral strategies or the combination of the use of various compounds within one strategy is very important. The most desirable are combinations of drugs that inhibit different steps in the virus life cycle. This is an important issue especially for RNA viruses, which replicate their genomes using error-prone RNA polymerases and rapidly develop mutants resistant to applied antiviral compounds. Here, we focus on compounds targeting viral structural capsid proteins, thereby inhibiting virus assembly or disassembly, virus binding to cellular receptors, or acting by inhibiting other virus replication mechanisms. This review is an update of existing papers on a similar topic, by focusing on the most recent advances in the rapidly evolving research of compounds targeting capsid proteins of RNA viruses.     

Ca’ Granda,an avant-garde hospital between the Renaissance and Modern age: a unique scenario in European history

The Ospedale Maggiore, known as Ca’ Granda, was founded in 1456 by will of Francesco Sforza, Duke of Milan, and was considered for almost five centuries a model for Milanese, Italian and even European healthcare. Attracting patients from all over Europe, the Ca’ Granda distinguished itself for the introduction of new treatments and innovative health reforms. In the burial ground of the hospital still lie the bodies of the deceased patients, who came from the poorest strata of the population. The study of their remains aims to give back a general identity and a story to each of these persons as well as reconstruct a fraction of the sixteenth century population of Milano as concerns lifestyle and disease and examine practises and therapy of this exceptional hospital. It is estimated that about two million commingled bones and articulated skeletons rest in the crypt, together with other types of findings (e.g., ceramic, coins, clothing). These remains are the object of a large project involving various disciplines ranging from humanities to hard sciences. The aim of this paper is to bring this historical gem to the attention of scholars and provide a glimpse of what its contents have already revealed.     

The evolution of brain neuron numbers in amniotes

Reconstructing the evolution of brain information-processing capacity is paramount for understanding the rise of complex cognition. Comparative studies of brain evolution typically use brain size as a proxy. However, to get a less biased picture of the evolutionary paths leading to high cognitive power, we need to compare brains not by mass but by numbers of neurons, which are their basic computational units. This study reconstructs the evolution of brains across amniotes by directly analyzing neuron numbers by using the largest dataset of its kind and including essential data on reptiles. We show that reptiles have not only small brains relative to body size but also low neuronal densities, resulting in average neuron numbers over 20 times lower than those in birds and mammals of similar body size. Amniote brain evolution is characterized by the following four major shifts in neuron–brain scaling. The most dramatic increases in brain neurons occurred independently with the appearance of birds and mammals, resulting in convergent neuron scaling in the two endotherm lineages. The other two major increases in the number of neurons happened in core land birds and anthropoid primates, which are two groups known for their cognitive prowess. Interestingly, relative brain size is associated with relative neuronal cell density in reptiles, birds, and primates but not in other mammals. This has important implications for studies using relative brain size as a proxy when looking for evolutionary drivers of animal cognition.

The evolution of cognitive capacity or “intelligence” and its underlying neural substrate has been of long-standing interest to biologists. Great strides have been made in understanding the evolution of brain size in vertebrates, with studies analyzing data on thousands of species (1–3). Since larger animals have larger brains but are not necessarily smarter, most studies of cognitive evolution use relative brain size (corrected for body size), which is thought to reflect extra neurons beyond those needed for controlling the body (4). We now have a good idea where major changes in brain–body scaling happened within birds (2) and mammals (3), and it is also clear that both mammals and birds have relatively larger brains than nonavian sauropsids (hereafter referred to as reptiles), although this has been rarely formally quantified because data on reptilian brain sizes are scarce (5).However, we still lack a clear picture of the evolution of actual brain processing capacity. This is because the same increase in relative brain size can be reached by different evolutionary paths, not always involving actual brain enlargement, and might often result from selection on body size (3). Moreover, similarly sized brains of distantly related species can harbor substantially different numbers of neurons overall and in major brain parts (6, 7). These two caveats invalidate the very idea that we can estimate extra neurons and glean information about cognitive capacity from absolute or relative brain size alone.This capacity is better determined by the number of neurons in the brain or specific brain parts (although their relative importance is still debated), their connections, interneuronal distance, and axonal conduction velocity (8, 9). Unlike brain size, though, these measures are not readily available for a sufficient number of species to be of practical use. Nevertheless, thanks to methodological advances (10), neuronal scaling rules (the allometric relationship between brain mass and neuron numbers) have now been determined for eight high-level mammalian clades (6, 11–13) as well as for a limited sampling of birds (14, 15).To get the big picture of amniote brain evolution, we have to include data on nonavian reptiles. The deepest split in amniote evolution occurred between the synapsid lineage, leading to mammals, and the sauropsid lineage, including reptiles and birds. We cannot tell if similarities between birds and mammals are due to shared ancestry or convergent evolution without considering reptiles. Yet, the dearth of quantitative data on reptile brains is striking—brain mass is available for 183 species (5, 16), compared to thousands for birds and mammals, and neuron numbers are known for a mere 4 reptile species (17–19).Taken together, to understand the evolution of brain processing capacity in amniotes, we need to include nonavian reptiles, consider changes in both brain–body and neuron–brain scaling, and examine the allocation of neurons to different brain parts. In this study, we provide these much needed data and reconstruct the big picture of brain evolution in amniotes in terms of neuron numbers.     

Clinical validation of an audio-based uroflowmetry application in adult males

IntroductionUroflowmetry is a common test to evaluate lower urinary tract symptoms. Audio-based uroflowmetry is a novel, alternative approach that determines urine flow by measuring sound. Available as a smartphone application, it has potential for screening and monitoring common urological pathologies, particularly in out-of-office environments. This study is the first to evaluate audio-based uroflowmetry in a clinical setting against the gold standard.MethodsAdult male patients (n=44) attending a general urology clinic were recruited. Audio-based uroflowmetry and conventional uroflowmetry were performed concurrently. Pearson correlation and Bland-Altman analysis were used to compare performance with respect to max flow, time to max flow, and total voiding time. Symmetric mean absolute percentage error (SMAPE) was used to compare curve shapes. Repeatability was evaluated separately in three healthy volunteers using repeat measures correlation.ResultsAmong urology clinic patients, the correlation for max flow was 0.12. Correlation for time to max flow was 0.46, with limits of agreement of −120–165%. Correlation for total voiding time was 0.91, with limits of agreement of −41–38%. The SMAPE for curve shape was 32.6%, with corresponding accuracy of 67.4%. Among healthy volunteers, the repeat measures correlation for max flow was 0.72.ConclusionsAudio-based uroflowmetry was inconsistent in evaluating flow rate, attributable to high variability and difficult standardization for acoustic signals. Performance improved with respect to temporal variables, as well as flow curve shape. Further work evaluating intra-patient reliability and pathology-specific performance is required to fully evaluate audio-based uroflowmetry as a screening or monitoring tool.     

Major bleeding with antithrombotic agents: a 2012–2015 study using the French nationwide Health Insurance database linked to emergency department records within five areas – rationale and design of SACHA study

Bleeding represents the most recognized and feared complications of antithrombotic drugs including oral anticoagulants. Previous studies showed inconsistent results on the safety profile. Among explanations, bleeding definition could vary and classification bias exists related to the lack of medical evaluation. To quantify the risk of major haemorrhagic event and event‐free survival associated with antithrombotic drugs (vitamin K antagonist [VKA], non‐VKA anticoagulant [NOAC], antiplatelet agent, parenteral anticoagulant) in 2012–2015, we linked the French nationwide Health Insurance database (SNIIRAM) with a local ‘emergency database’ (clinical and biological data collected in clinical records). In the VKA‐NOAC comparison, a Cox regression analysis will be used to estimate the hazard ratio of major haemorrhagic event adjusted on gender, modified HAS‐BLED score and comorbidities. A distinction on the type of major haemorrhagic event (intracranial, gastrointestinal and other haemorrhagic events) was made. We present here the study protocol and the database linkage results. Using six linkage keys, among 3 837 557 hospital visits identified in SNIIRAM, 5264 have been matched with a major haemorrhagic event identified in the ‘emergency database’, thus clinically confirmed. The 1090 unmatched haemorrhagic events could be explained by the fact that patients were not extracted in the SNIIRAM database (patients living in accommodation establishment with internal use of pharmacy, military people with specific insurance…). We showed the value of SNIIRAM enrichment with a clinical database, a necessary step to categorize haemorrhagic events by a clinically relevant definition and medical validation; it will allow to estimate more accuracy each type of haemorrhagic event.