No abstract

The intestinal microbiota is a complex community of bacteria, archaea, viruses, protists and fungi 1,2 . While the composition of bacterial constituents has been linked to immune homeostasis and to infectious susceptibility [3][4][5][6][7] , the role of non-bacterial constituents and of cross-kingdom microbial interactions in these processes is poorly understood 2,8 . Fungi represent a major cause of infectious morbidity and mortality in immune-compromised individuals, though the relationship of intestinal fungi (i.e., the mycobiota) with fungal bloodstream infections (BSI) remains undefined 9 .Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:

Pan-African Clinical Trials Registry: PACTR201102000277177 (www.pactr.org).

High virulence of influenza virus A/Puerto Rico/8/34 in mice carrying the Mx1 resistance gene was recently shown to be determined by the viral surface proteins and the viral polymerase. Here, we demonstrated high-level polymerase activity in mammalian host cells but not avian host cells and investigated which mutations in the polymerase subunits PB1, PB2, and PA are critical for increased polymerase activity and high virus virulence. Mutational analyses demonstrated that an isoleucine-to-valine change at position 504 in PB2 was the most critical and strongly enhanced the activity of the reconstituted polymerase complex. An isoleucine-to-leucine change at position 550 in PA further contributed to increased polymerase activity and high virulence, whereas all other mutations in PB1, PB2, and PA were irrelevant. To determine whether this pattern of acquired mutations represents a preferred viral strategy to gain virulence, two independent new virus adaptation experiments were performed. Surprisingly, the conservative I504V change in PB2 evolved again and was the only mutation present in an aggressive virus variant selected during the first adaptation experiment. In contrast, the virulent virus selected in the second adaptation experiment had a lysine-to-arginine change at position 208 in PB1 and a glutamate-to-glycine change at position 349 in PA. These results demonstrate that a variety of minor amino acid changes in the viral polymerase can contribute to enhanced virulence of influenza A virus. Interestingly, all virulence-enhancing mutations that we identified in this study resulted in substantially increased viral polymerase activity.

New York State had 180,458 cases of SARS-CoV-2 and 9385 reported deaths as of April 10th, 2020. Patients with cancer comprised 8.4% of deceased individuals1. Population-based studies from China and Italy suggested a higher COVID-19 death rate in patients with cancer2,3, although there is a knowledge gap as to which aspects of cancer and its treatment confer risk of severe COVID-19 disease4. This information is critical to balance the competing safety considerations of reducing SARS-CoV-2 exposure and cancer treatment continuation. Since March 10th, 2020 Memorial Sloan Kettering Cancer Center performed diagnostic testing for SARS-CoV-2 in symptomatic patients. Overall, 40% out of 423 patients with cancer were hospitalized for COVID-19 illness, 20% developed severe respiratory illness, including 9% that required mechanical ventilation, and 9% that died. On multivariate analysis, age ≥ 65 years and treatment with immune checkpoint inhibitors (ICI) within 90 days were predictors for hospitalization and severe disease, while receipt of chemotherapy within 30 days and major surgery were not. Overall, COVID-19 illness is associated with higher rates of hospitalization and severe outcomes in patients with cancer. Association between ICI and COVID-19 outcomes will need interrogation in tumor-specific cohorts.

Anemia is a common complication of malaria that is characterized by the loss of infected and uninfected erythrocytes. In mouse malaria models, clearance of uninfected erythrocytes is promoted by autoimmune anti-phosphatidylserine (PS) antibodies produced by T-bet+B-cells, which bind to exposed PS in erythrocytes, but the mechanism in patients is still unclear. In Plasmodium falciparum patients with anemia, we show that atypical memory FcRL5+T-bet+ B-cells are expanded and associate both with higher levels of anti-PS antibodies in plasma and with the development of anemia in these patients. No association of anti-PS antibodies or anemia with other B-cell subsets and no association of other antibody specificities with FcRL5+T-bet+ B-cells is observed, revealing high specificity in this response. We also identify FcRL5+T-bet+ B-cells as producers of anti-PS antibodies in ex vivo cultures of naïve human peripheral blood mononuclear cells (PBMC) stimulated with P.-falciparum-infected erythrocyte lysates. These data define a crucial role for atypical memory B-cells and anti-PS autoantibodies in human malarial anemia.

BackgroundSevere malaria is a potentially life-threatening infectious disease. It has been conclusively shown that artesunate compared to quinine is superior in antiparasitic efficacy and in lowering mortality showing a better short-term safety profile. Regarding longer-term effects, reports of delayed haemolysis after parenteral artesunate for severe malaria in returning travellers have been published recently. So far, delayed haemolysis has not been described after the use of parenteral quinine.MethodsIn this retrospective study, all patients treated for severe malaria at the University Medical Centre Hamburg-Eppendorf were included between 2006 and 2012. The primary endpoint was the proportion of delayed haemolysis in patients treated with quinine versus those who received artesunate. As secondary endpoint, the proportion of any adverse event was assessed.ResultsA total of 36 patients with severe malaria were included in the analysis. Of these, 16 patients contributed sufficient data to assess the endpoint delayed haemolysis. Twelve were treated primarily with intravenous quinine – with four patients having received intrarectal artesunate as an adjunct treatment – and five patients were treated primarily with artesunate. Five cases of delayed haemolysis could be detected – two in patients treated with quinine and intrarectal artesunate and three in patients treated with artesunate. No case of delayed haemolysis was detected in patients treated with quinine alone.While adverse events observed in patients treated with artesunate were limited to delayed haemolysis (three patients, 60%) and temporary deterioration in renal function (three patients, 60%), patients treated with quinine showed a more diverse picture of side effects with 22 patients (71%) experiencing at least one adverse event. The most common adverse events after quinine were hearing disturbances (12 patients, 37%), hypoglycaemia (10 patients, 32%) and cardiotoxicity (three patients, 14%).ConclusionsThis study provides further evidence on delayed haemolysis after artesunate and underlines the importance of a standardized follow-up of patients treated with artesunate for severe malaria.

BackgroundMalaria remains one of the most serious infections for travellers to tropical countries. Due to the lack of harmonized guidelines a large variety of treatment regimens is used in Europe to treat severe malaria.MethodsThe European Network for Tropical Medicine and Travel Health (TropNet) conducted an 8-year, multicentre, observational study to analyse epidemiology, treatment practices and outcomes of severe malaria in its member sites across Europe. Physicians at participating TropNet centres were asked to report pseudonymized retrospective data from all patients treated at their centre for microscopically confirmed severe Plasmodium falciparum malaria according to the 2006 WHO criteria.ResultsFrom 2006 to 2014 a total of 185 patients with severe malaria treated in 12 European countries were included. Three patients died, resulting in a 28-day survival rate of 98.4%. The majority of infections were acquired in West Africa (109/185, 59%). The proportion of patients treated with intravenous artesunate increased from 27% in 2006 to 60% in 2013. Altogether, 56 different combinations of intravenous and oral drugs were used across 28 study centres. The risk of acute renal failure (36 vs 17% p = 0.04) or cerebral malaria (54 vs 20%, p = 0.001) was significantly higher in patients ≥60 years than in younger patients. Respiratory distress with the need for mechanical ventilation was significantly associated with the risk of death in the study population (13 vs 0%, p = 0.001). Post-artemisinin delayed haemolysis was reported in 19/70 (27%) patients treated with intravenous artesunate.ConclusionThe majority of patients with severe malaria in this study were tourists or migrants acquiring the infection in West Africa. Intravenous artesunate is increasingly used for treatment of severe malaria in many European treatment centres and can be given safely to European patients with severe malaria. Patients treated with intravenous artesunate should be followed up to detect and manage late haemolytic events.