The conduct of an RCT during an evolving pandemic poses unique challenges not encountered during other forms of clinical research [40] . First, it is necessary to initiate studies quickly. The normal time interval from concept to first patient enrolment for a new RCT is typically of the order of two years or more. Second, the scope and duration of the pandemic is unknown and unpredictable. Third, the mitigating effects of large-scale vaccination programs and changes in H1N1 infectivity resulting from virus mutation are unknown. Fourth, the practicalities of conducting clinical research during a pandemic are unknown. For example, research personnel may be seconded to provide clinical care, pharmacists may face challenges in dispensing drug and placebo, REBs may not permit alternative consent models and it may be difficult to obtain consent from patients who may lack decision-making capacity and families, who may be unwell themselves, unable to visit the hospital or requested to stay away during the pandemic. Finally, faced with the clinical imperative of treating gravely ill and previously well, young patients, clinicians may opt to use open label treatment rather than permit enrolment into a blinded RCT. Because we believe that it is important to develop the capacity to initiate RCTs under pandemic conditions and to test study procedures prior to implementing a large scale RCT, we propose to conduct a multi-centre pilot trial to assess the feasibility of our clinical protocol and study procedures. Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway Influenza A virus (IAV) enters host cells upon binding of its hemagglutinin glycoprotein to sialylated host cell receptors. Whereas dynamin-dependent, clathrin-mediated endocytosis (CME) is generally considered as the IAV infection pathway, some observations suggest the occurrence of an as yet uncharacterized alternative entry route. By manipulating entry parameters we established experimental conditions that allow the separate analysis of dynamin-dependent and -independent entry of IAV. Whereas entry of IAV in phosphate-buffered saline could be completely inhibited by dynasore, a specific inhibitor of dynamin, a dynasore-insensitive entry pathway became functional in the presence of fetal calf serum. This finding was confirmed with the use of small interfering RNAs targeting dynamin-2. In the presence of serum, both IAV entry pathways were operational. Under these conditions entry could be fully blocked by combined treatment with dynasore and the amiloride derivative EIPA, the hallmark inhibitor of macropinocytosis, whereas either drug alone had no effect. The sensitivity of the dynamin-independent entry pathway to inhibitors or dominant-negative mutants affecting actomyosin dynamics as well as to a number of specific inhibitors of growth factor receptor tyrosine kinases and downstream effectors thereof all point to the involvement of macropinocytosis in IAV entry. Consistently, IAV particles and soluble FITC-dextran were shown to co-localize in cells in the same vesicles. Thus, in addition to the classical dynamin-dependent, clathrin-mediated endocytosis pathway, IAV enters host cells by a dynamin-independent route that has all the characteristics of macropinocytosis. Influenza A virus (IAV) is an enveloped, segmented negativestrand RNA virus infecting a wide variety of birds and mammals. As its first step in infection IAV attaches to host cells by the binding of its major surface protein, the hemagglutinin (HA), to sialic acids, which are omnipresent on the glycolipids and glycoproteins exposed on the surfaces of cells. Where the structural requirements for this interaction have been studied in great detail, much less is known about whether and how the attachment to specific sialylated receptors (e.g. to N-linked glycoproteins, Olinked glycoproteins or gangliosides or even to specific receptors within these groups) affects the subsequent endocytic steps. Obviously, knowledge about the repertoire of endocytic pathways that can successfully be used by IAV will increase our insights into cell and species tropism of IAV. In turn, this will contribute to our understanding of the requirements for the generation of novel viruses with pandemic potential that can arise by exchange of RNA segments between currently circulating human serotypes and an animal virus during occasional co-infection in a human or an animal host.