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In this randomized, double-blind trial in 1062 adults hospitalized with Covid-19, remdesivir was superior to placebo in shortening the time to recovery (10 days, vs. 15 days with placebo). The estimates of mortality by day 29 were 11.4% with remdesivir and 15.2% with placebo. The benefit of remdesivir was most apparent in patients who were receiving low-flow oxygen at baseline.

Microglia, the brain’s resident macrophages, help to regulate brain function by removing dying neurons, pruning non-functional synapses, and producing ligands that support neuronal survival 1 . Here we show that microglia are also critical modulators of neuronal activity and associated behavioural responses in mice. Microglia respond to neuronal activation by suppressing neuronal activity, and ablation of microglia amplifies and synchronizes the activity of neurons, leading to seizures. Suppression of neuronal activation by microglia occurs in a highly region-specific fashion and depends on the ability of microglia to sense and catabolize extracellular ATP, which is released upon neuronal activation by neurons and astrocytes. ATP triggers the recruitment of microglial protrusions and is converted by the microglial ATP/ADP hydrolysing ectoenzyme CD39 into AMP; AMP is then converted into adenosine by CD73, which is expressed on microglia as well as other brain cells. Microglial sensing of ATP, the ensuing microglia-dependent production of adenosine, and the adenosine-mediated suppression of neuronal responses via the adenosine receptor A 1 R are essential for the regulation of neuronal activity and animal behaviour. Our findings suggest that this microglia-driven negative feedback mechanism operates similarly to inhibitory neurons and is essential for protecting the brain from excessive activation in health and disease. Microglia, the brain’s immune cells, suppress neuronal activity in response to synaptic ATP release and alter behavioural responses in mice.

Adenosine is a potent anticonvulsant acting on excitatory synapses through A1 receptors. Cellular release of ATP, and its subsequent extracellular enzymatic degradation to adenosine, could provide a powerful mechanism for astrocytes to control the activity of neural networks during high-intensity activity. Despite adenosine's importance, the cellular source of adenosine remains unclear. We report here that multiple enzymes degrade extracellular ATP in brain tissue, whereas only Nt5e degrades AMP to adenosine. However, endogenous A1 receptor activation during cortical seizures in vivo or heterosynaptic depression in situ is independent of Nt5e activity, and activation of astrocytic ATP release via Ca2+ photolysis does not trigger synaptic depression. In contrast, selective activation of postsynaptic CA1 neurons leads to release of adenosine and synaptic depression. This study shows that adenosine-mediated synaptic depression is not a consequence of astrocytic ATP release, but is instead an autonomic feedback mechanism that suppresses excitatory transmission during prolonged activity.

Adenosine is a constituent of many molecules of life; increased free extracellular adenosine indicates cell damage or metabolic stress. The importance of adenosine signaling in basal physiology, as opposed to adaptive responses to danger/damage situations, is unclear. We generated mice lacking all four adenosine receptors (ARs), Adora1-/-;Adora2a-/-;Adora2b-/-;Adora3-/- (quad knockout [QKO]), to enable investigation of the AR dependence of physiologic processes, focusing on body temperature. The QKO mice demonstrate that ARs are not required for growth, metabolism, breeding, and body temperature regulation (diurnal variation, response to stress, and torpor). However, the mice showed decreased survival starting at about 15 weeks of age. While adenosine agonists cause profound hypothermia via each AR, adenosine did not cause hypothermia (or bradycardia or hypotension) in QKO mice, indicating that AR-independent signals do not contribute to adenosine-induced hypothermia. The hypothermia elicited by adenosine kinase inhibition (with A134974), inosine, or uridine also required ARs, as each was abolished in the QKO mice. The proposed mechanism for uridine-induced hypothermia is inhibition of adenosine transport by uridine, increasing local extracellular adenosine levels. In contrast, adenosine 5'-monophosphate (AMP)-induced hypothermia was attenuated in QKO mice, demonstrating roles for both AR-dependent and AR-independent mechanisms in this process. The physiology of the QKO mice appears to be the sum of the individual knockout mice, without clear evidence for synergy, indicating that the actions of the four ARs are generally complementary. The phenotype of the QKO mice suggests that, while extracellular adenosine is a signal of stress, damage, and/or danger, it is less important for baseline regulation of body temperature.

Cold exposure activates brown adipose tissue (BAT) through the sympathetic nervous system, and previous studies have reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat; here adenosine/A 2A signalling is shown to be involved in sympathetic activation of human and murine brown adipocytes to allow protection of mice from diet-induced obesity. A novel brown-fat activation pathway Following cold-exposure, brown adipose tissue (BAT, the energy-burning fat tissue that is a possible anti-obesity target) is activated by the sympathetic nervous system, releasing noradrenaline and stimulating β-adrenergic receptors. Previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat. Here, treatment of mice with adenosine A 2A receptor agonists is shown to stimulate energy dissipation via brown fat and to protect mice from diet-induced obesity. This work suggests that the previously overlooked adenosine/A 2A signalling pathway have a fundamental role in energy homeostasis and could provide a target for anti-obesity therapeutics. Brown adipose tissue (BAT) is specialized in energy expenditure, making it a potential target for anti-obesity therapies 1 , 2 , 3 , 4 , 5 . Following exposure to cold, BAT is activated by the sympathetic nervous system with concomitant release of catecholamines and activation of β-adrenergic receptors 1 , 2 , 3 , 4 , 5 . Because BAT therapies based on cold exposure or β-adrenergic agonists are clinically not feasible, alternative strategies must be explored. Purinergic co-transmission might be involved in sympathetic control of BAT and previous studies reported inhibitory effects of the purinergic transmitter adenosine in BAT from hamster or rat 6 , 7 , 8 . However, the role of adenosine in human BAT is unknown. Here we show that adenosine activates human and murine brown adipocytes at low nanomolar concentrations. Adenosine is released in BAT during stimulation of sympathetic nerves as well as from brown adipocytes. The adenosine A 2A receptor is the most abundant adenosine receptor in human and murine BAT. Pharmacological blockade or genetic loss of A 2A receptors in mice causes a decrease in BAT-dependent thermogenesis, whereas treatment with A 2A agonists significantly increases energy expenditure. Moreover, pharmacological stimulation of A 2A receptors or injection of lentiviral vectors expressing the A 2A receptor into white fat induces brown-like cells—so-called beige adipocytes. Importantly, mice fed a high-fat diet and treated with an A 2A agonist are leaner with improved glucose tolerance. Taken together, our results demonstrate that adenosine–A 2A signalling plays an unexpected physiological role in sympathetic BAT activation and protects mice from diet-induced obesity. Those findings reveal new possibilities for developing novel obesity therapies.

Remdesivir is a nucleotide analog prodrug approved for the treatment of COVID-19. This study evaluated the pharmacokinetics and safety of remdesivir and its metabolites (GS-704277 and GS-441524) in participants with varying degrees of renal impairment. Results of this phase I study, along with those of a phase III study, contributed to an extension of indication for remdesivir in the USA and Europe for use in patients with COVID-19 with all stages of renal impairment, including those on dialysis, with no dose adjustment. This phase I, open-label, parallel-group study enrolled participants who had mild (n = 12), moderate (n = 11), or severe (n = 10) renal impairment or kidney failure (n = 6 with dialysis, n = 4 without dialysis). Healthy matched controls were enrolled as reference. Remdesivir was given as single intravenous doses of 100 mg (mild and moderate renal impairment), 40 mg (severe renal impairment, kidney failure predialysis), and 20 mg (kidney failure postdialysis and without dialysis). Plasma pharmacokinetics of remdesivir were not affected by mild, moderate, or severe renal impairment or kidney failure. Geometric least squares mean ratios ranged from 0.8 to 1.2 for remdesivir area under the plasma concentration-time curve (AUC). GS-704277 AUC was up to 2.8-fold higher and GS-441524 AUC up to 7.9-fold higher in participants with renal impairment. Adverse events and laboratory abnormalities were consistent with the existing safety profile for remdesivir. Observed pharmacokinetics for remdesivir and its metabolites in participants with renal impairment aligned with expected changes based on known routes of elimination. Remdesivir was generally safe and well tolerated in participants with renal impairment, and no new safety concerns were identified. These results, along with those from the phase III study in patients with COVID-19 with severely reduced kidney function, support the use of remdesivir in patients with any degree of renal impairment with no dose adjustments. EudraCT no. 2020-003441-10; 9 July 2020.

Brain computation performed by billions of nerve cells relies on a sufficient and uninterrupted nutrient and oxygen supply 1 , 2 . Astrocytes, the ubiquitous glial neighbours of neurons, govern brain glucose uptake and metabolism 3 , 4 , but the exact mechanisms of metabolic coupling between neurons and astrocytes that ensure on-demand support of neuronal energy needs are not fully understood 5 , 6 . Here we show, using experimental in vitro and in vivo animal models, that neuronal activity-dependent metabolic activation of astrocytes is mediated by neuromodulator adenosine acting on astrocytic A2B receptors. Stimulation of A2B receptors recruits the canonical cyclic adenosine 3′,5′-monophosphate–protein kinase A signalling pathway, leading to rapid activation of astrocyte glucose metabolism and the release of lactate, which supplements the extracellular pool of readily available energy substrates. Experimental mouse models involving conditional deletion of the gene encoding A2B receptors in astrocytes showed that adenosine-mediated metabolic signalling is essential for maintaining synaptic function, especially under conditions of high energy demand or reduced energy supply. Knockdown of A2B receptor expression in astrocytes led to a major reprogramming of brain energy metabolism, prevented synaptic plasticity in the hippocampus, severely impaired recognition memory and disrupted sleep. These data identify the adenosine A2B receptor as an astrocytic sensor of neuronal activity and show that cAMP signalling in astrocytes tunes brain energy metabolism to support its fundamental functions such as sleep and memory. This study explores how adenosine A2B receptors can act as astrocytic sensors of brain metabolic activity and how cAMP signalling in astrocytes may support core brain functions such as sleep and memory.

Among nonhospitalized patients with Covid-19–related symptoms that began less than a week previously, a 3-day course of remdesivir resulted in an 87% lower risk of hospitalization or death than placebo. Adverse effects in the remdesivir group were similar to those in the placebo group.

In a trial involving 1033 patients hospitalized with Covid-19, the addition of baricitinib to remdesivir was associated with shorter recovery time, particularly among patients receiving high-flow oxygen, and with a 30% higher odds of improvement at day 15 than remdesivir alone. Adverse events were less frequent with the combination therapy.

Patients with myocardial infarction 1 to 3 years previously were assigned to ticagrelor, 90 or 60 mg twice daily, or to placebo, in addition to low-dose aspirin. At 3 years, ticagrelor reduced the risk of cardiovascular death, MI, or stroke but increased the risk of major bleeding. Myocardial infarction is a global problem. 1 In the United States alone, nearly 8 million people have a history of myocardial infarction. 2 Patients who have had a myocardial infarction are at heightened risk for recurrent ischemic events, 3 – 5 which suggests that this population may derive particular benefit from intensive secondary prevention. A key element in the pathobiology of cardiovascular ischemic events is the activated platelet. 6 Aspirin reduces the risk of ischemic events both among patients who present with an acute coronary syndrome and in secondary prevention for patients with a history of myocardial infarction. 7 The addition of a P2Y 12 receptor . . .