Background Neurological manifestations in coronavirus disease (COVID)‐2019 may adversely affect clinical outcomes. Severe COVID‐19 and uremia are risk factors for neurological complications. However, the lack of insight into their pathogenesis, particularly with respect to the role of the cytokine release syndrome (CRS), is currently hampering effective therapeutic interventions. Methods In this longitudinal study, we sought to describe the neurological manifestations of patients with COVID‐19 and gain pathophysiological insights especially with respect to the CRS. Extensive clinical, laboratory, and imaging phenotyping was performed in five patients admitted to our renal unit. Results Neurological presentation included confusion, tremor, cerebellar ataxia, behavioral alterations, aphasia, pyramidal syndrome, coma, cranial nerve palsy, dysautonomia, and central hypothyroidism. Neurological disturbances were remarkably accompanied by laboratory evidence of CRS. SARS‐CoV‐2 was undetectable in the cerebrospinal fluid (CSF). Hyperalbuminorrachia and increased levels of the astroglial protein S100B were suggestive of blood‐brain barrier (BBB) dysfunction. Brain MRI findings comprised evidence of acute leukoencephalitis (n = 3, of whom one with a hemorrhagic form), cytotoxic edema mimicking ischemic stroke (n = 1), or normal results (n = 2). Treatment with corticosteroids and/or intravenous immunoglobulins was attempted – resulting in rapid recovery from neurological disturbances in two cases. SARS‐CoV2 was undetectable in 88 of the 90 patients with COVID‐19 who underwent RT‐PCR testing of CSF. Conclusions Patients with COVID‐19 can develop neurological manifestations that share clinical, laboratory, and imaging similarities with those of chimeric antigen receptor‐T cell‐related encephalopathy. The pathophysiological underpinnings appear to involve CRS, endothelial activation, BBB dysfunction, and immune‐mediated mechanisms.

The aim of this study was to estimate the incidence of COVID-19 disease in the French national population of dialysis patients, their course of illness and to identify the risk factors associated with mortality. Our study included all patients on dialysis recorded in the French REIN Registry in April 2020. Clinical characteristics at last follow-up and the evolution of COVID-19 illness severity over time were recorded for diagnosed cases (either suspicious clinical symptoms, characteristic signs on the chest scan or a positive reverse transcription polymerase chain reaction) for SARS-CoV-2. A total of 1,621 infected patients were reported on the REIN registry from March 16th, 2020 to May 4th, 2020. Of these, 344 died. The prevalence of COVID-19 patients varied from less than 1% to 10% between regions. The probability of being a case was higher in males, patients with diabetes, those in need of assistance for transfer or treated at a self-care unit. Dialysis at home was associated with a lower probability of being infected as was being a smoker, a former smoker, having an active malignancy, or peripheral vascular disease. Mortality in diagnosed cases (21%) was associated with the same causes as in the general population. Higher age, hypoalbuminemia and the presence of an ischemic heart disease were statistically independently associated with a higher risk of death. Being treated at a selfcare unit was associated with a lower risk. Thus, our study showed a relatively low frequency of COVID-19 among dialysis patients contrary to what might have been assumed.

Serotonin (5-HT) exerts pleiotropic effects in the human cardiovascular system. Some of the effects are thought to be mediated via 5-HT4 receptors, which are expressed in the human atrium and in ventricular tissue. However, a true animal model to study these receptors in more detail has been hitherto lacking. Therefore, we generated, for the first time, a transgenic (TG) mouse with cardiac myocyte-specific expression of the human 5-HT4 receptor. RT-PCR and immunohistochemistry revealed expression of the receptor at the mRNA and protein levels. Stimulation of isolated cardiac preparations by isoproterenol increased phospholamban phosphorylation at Ser 16 and Thr 17 sites. 5-HT increased phosphorylation only in TG mice but not in wild-type (WT) mice. Furthermore, 5-HT increased contractility in isolated perfused hearts from TG mice but not WT mice. These effects of 5-HT could be blocked by the 5-HT 4 receptor-selective antagonist GR-125487. An intravenous infusion of 5-HT increased left ventricular contractility in TG mice but not in WT mice. Similarly, the increase in contractility by 5-HT in isolated cardiomyocytes from TG mice was accompanied by and probably mediated through an increase in L-type Ca 2ϩ channel current and in Ca 2ϩ transients. In intact animals, echocardiography revealed an inotropic and chronotropic effect of subcutaneously injected 5-HT in TG mice but not in WT mice. In isolated hearts from TG mice, spontaneous polymorphic atrial arrhythmias were noted. These findings demonstrate the functional expression of 5-HT4 receptors in the heart of TG mice, and a potential proarrhythmic effect in the atrium. Therefore, 5-HT4 receptorexpressing mice might be a useful model to mimic the human heart, where 5-HT 4 receptors are present and functional in the atrium and ventricle of the healthy and failing heart, and to investigate the influence of 5-HT in the development of cardiac arrhythmias and heart failure. serotonin; arrhythmia; transgenic mice; signal transduction MOST OF THE SEROTONIN (5-HT) in the blood originates from enterochromaffine cells of the gastrointestinal tract (53). 5-HT is released by these cells and is avidly taken up by platelets. Platelets seem to be the main source of 5-HT that influences the cardiovascular system. These influences include vasoconstriction, an increase in platelet aggregation, apoptosis of cardiac cells, augmentation in beating rate, the generation of arrhythmias (27), valvular heart disease (49), and positive inotropic and relaxant effects (for an overview, see Ref. 29).At present, seven groups of 5-HT-receptors have been distinguished (5-HT 1 -5-HT 7 ) (29). The 5-HT 4 receptor mediates the positive inotropic effect in humans (8,31,33,51). In the human atrium and ventricle, mRNAs of several splice variants of the 5-HT 4 receptor have been found (6, 2, 9).In isolated multicellular preparations from human atria, 5-HT exerts a positive inotropic effect and a relaxant (or lusitropic) effect (31, 33). These effects were accompanied by increases in cAMP content and ele...

The cilgavimab−tixagevimab combination retains a partial in vitro neutralizing activity against the current SARS‐CoV‐2 variants of concern (omicron BA.1, BA.1.1, and BA.2). Here, we examined whether preexposure prophylaxis with cilgavimab−tixagevimab can effectively protect kidney transplant recipients (KTRs) against the omicron variant. Of the 416 KTRs who received intramuscular prophylactic injections of 150 mg tixagevimab and 150 mg cilgavimab, 39 (9.4%) developed COVID‐19. With the exception of one case, all patients were symptomatic. Hospitalization and admission to an intensive care unit were required for 14 (35.9%) and three patients (7.7%), respectively. Two KTRs died of COVID‐19‐related acute respiratory distress syndrome. SARS‐CoV‐2 sequencing was carried out in 15 cases (BA.1, n = 5; BA.1.1, n = 9; BA.2, n = 1). Viral neutralizing activity of the serum against the BA.1 variant was negative in the 12 tested patients, suggesting that this prophylactic strategy does not provide sufficient protection against this variant of concern. In summary, preexposure prophylaxis with cilgavimab−tixagevimab at the dose of 150 mg of each antibody does not adequately protect KTRs against omicron. Further clarification of the optimal dosing can assist in our understanding of how best to harness its protective potential.

In human atrium, serotonin (5-HT) exerts pleiotropic effects, which are thought to be mediated via 5-HT4 receptors. Here, we used transgenic mice (TG) that overexpress the human 5-HT4(a) receptor under control of the heart-specific α-myosin heavy chain promoter in the atria (and ventricles). Contractile studies were performed in isolated electrically driven left atrial preparations and spontaneously beating right atrial preparation of TG and littermate control mice (wild type (WT)). 5-HT increased force of contraction and phospholamban phosphorylation on serine 16 only in left atrial preparations from TG but not from WT. In contrast, β-adrenoceptor stimulation of left atrial preparations by isoprenaline increased force of contraction with similar pEC50 values and to a similar maximum extent in both TG and WT. The contractile effects of 5-HT in left atrial preparations from TG could be blocked by the 5-HT4 receptor-specific antagonists GR125487 or GR113808. In right atrial preparations from WT and TG, the β-adrenoceptor agonist isoprenaline exerted a positive chronotropic effect with similar pEC50 values and similar maximum effects. Only in right atrial preparations from TG but not WT, 5-HT exerted a positive chronotropic effect that could be attenuated by 5-HT4 receptor-specific antagonists. Finally, in left atrial preparations of TG, a higher incidence of arrhythmias was noted compared to WT. The present data indicate that the human 5-HT4 receptors expressed in mouse atria are functional. This is the first transgenic model to study this human receptor in the atrium ex vivo or in vivo.