COVID-19: impact on Public Health and hypothesis-driven investigations on genetic susceptibility and severity.

COVID-19 is a new complex multisystem disease caused by the novel coronavirus SARS-CoV-2. In slightly over 2 years, it infected nearly 500 million and killed 6 million human beings worldwide, causing an unprecedented coronavirus pandemic. Currently, the international scientific community is engaged in elucidating the molecular mechanisms of the pathophysiology of SARS-CoV-2 infection as a basis of scientific developments for the future control of COVID-19. Global exome and genome analysis efforts work to define the human genetics of protective immunity to SARS-CoV-2 infection. Here, we review the current knowledge regarding the SARS-CoV-2 infection, the implications of COVID-19 to Public Health and discuss genotype to phenotype association approaches that could be exploited through the selection of candidate genes to identify the genetic determinants of severe COVID-19.

Clinical characteristics and outcome of elderly patients admitted in emergency department with an oxygen mismatch and type 2 myocardial infarction or myocardial injury.

BACKGROUND: Aging is a risk factor for type 2 myocardial infarction or myocardial injury, but few data are available on the elderly. We aimed to determine the factors associated with these pathologies and mortality in the elderly population and its age classes. METHODS: A retrospective cohort of all patients with oxygen mismatch (anemia, hypoxia, tachycardia, hypo/hypertension) for whom a troponin drawn was performed at admission in 2 emergency departments. Medical records were reviewed and classified as having type 2 myocardial infarction, acute or chronic myocardial injury, or no myocardial injury. RESULTS: Of the 824 patients who presented with oxygen mismatch, 675 (81.9%) were older than 65 years. Age over 85 years was a risk factor for acute non-ischemic myocardial injury (odds ratio, 95% confidence interval 2.23, 1.34-3.73). Non-ischemic myocardial injury was associated with hypoxemia, tachycardia, and acute renal failure in those older than 85 years, but only with acute infection in the 75-84-year-old group. Type 2 myocardial infarction was associated only with acute renal failure in the oldest group and, in the 75-84-year-old group, with acute heart failure and shock. Patients older than 85 years with acute myocardial injury, with or without infarction, had a higher in-hospital mortality, but subsequently, mortality depends more on the comorbidities than on age. CONCLUSION: Factors associated with type 2 myocardial infarction and acute non-ischemic myocardial injury in elderly admitted with oxygen mismatch vary notably between age classes. They are associated with in-hospital mortality but not with subsequent mortality when other cormorbities are taken into account.

Antimalarial screening via large-scale purification of Plasmodium falciparum Ca2+-ATPase 6 and in vitro studies.

The most severe form of human malaria is caused by the parasite Plasmodium falciparum. Despite the current need, there is no effective vaccine and parasites are becoming resistant to most of the antimalarials available. Therefore, there is an urgent need to discover new drugs from targets that have not yet suffered from drug pressure with the aim of overcoming the problem of new emerging resistance. Membrane transporters, such as P. falciparum Ca(2+)-ATPase 6 (PfATP6), the P. falciparum sarcoplasmic/endoplasmic reticulum Ca(2+)-ATPase (SERCA), have been proposed as potentially good antimalarial targets. The present investigation focuses on: (a) the large-scale purification of PfATP6 for maintenance of its enzymatic activity; (b) screening for PfATP6 inhibitors from a compound library; and (c) the selection of the best inhibitors for further tests on P. falciparum growth in vitro. We managed to heterologously express in yeast and purify an active form of PfATP6 as previously described, although in larger amounts. In addition to some classical SERCA inhibitors, a chemical library of 1680 molecules was screened. From these, we selected a pool of the 20 most potent inhibitors of PfATP6, presenting half maximal inhibitory concentration values in the range 1-9 µm. From these, eight were chosen for evaluation of their effect on P. falciparum growth in vitro, and the best compound presented a half maximal inhibitory concentration of ~ 2 µm. We verified the absence of an inhibitory effect of most of the compounds on mammalian SERCA1a, representing a potential advantage in terms of human toxicity. The present study describes a multidisciplinary approach allowing the selection of promising PfATP6-specific inhibitors with good antimalarial activity.