BackgroundRespiratory syncytial virus (RSV) is the major respiratory pathogen of infants and young children. During each seasonal epidemic, multiple strains of both subgroup A and B viruses circulate in the community. Like other RNA viruses, RSV genome replication is prone to errors that results in a heterogeneous population of viral strains some of which may possess differences in virulence. We sought to determine whether clinical isolates of RSV differ in their capacity to induce inflammatory cytokines IL-6 and CCL5 (previously known as RANTES [regulated upon activation, normal T-cell expressed and secreted protein]), which are known to be induced in vitro and in vivo in response to RSV, during infection of A549 cells.ResultsScreening of subgroup A and B isolates revealed heterogeneity among strains to induce IL-6 and CCL5. We chose two subgroup B strains, New Haven (NH)1067 and NH1125, for further analysis because of their marked differences in cytokine inducing properties and because subgroup B strains, in general, are less genetically heterogeneous as compared to subgroup A strains. At 12 and 24 hours post infection RSV strains, NH1067 and NH1125 differed in their capacity to induce IL-6 by an order of magnitude or more. The concentrations of IL-6 and CCL5 were dependent on the dose of infectious virus and the concentration of these cytokines induced by NH1125 was greater than that of those induced by NH1067 when the multiplicity of infection of NH1067 used was as much as 10-fold higher than that of NH1125. The induction of IL-6 was dependent on viable virus as infection with UV-inactivated virus did not induce IL-6. The difference in IL-6 induction most likely could not be explained by differences in viral replication kinetics. The intracellular level of RSV RNA, as determined by quantitative RT-PCR, was indistinguishable between the 2 strains though the titer of progeny virus produced by NH1125 was greater than that produced by NH1067 at 16, 24 and 36 hours but essentially equal at 48 and 72 hours. Full genome sequencing of the 2 strains revealed 193 polymorphisms and 4 insertions in NH1067when compared to NH1125 (2 single base insertions in non-coding regions and 2 duplications of 3 and 60 bases in the RSV G gene). Of the polymorphisms, 147 occurred in coding regions and only 30 resulted in amino acid changes in 7 of the RSV genes.ConclusionsThese data suggest that RSV strains may not be homogeneous with regard to pathogenesis or virulence. Identification of the genetic polymorphisms associated with variations in cytokine induction may lead to insights into RSV disease and to the development of effective antiviral agents and vaccines.
Radiologists' recommendations contained in written reports of noncritical findings may not be consistently followed or acknowledged in the medical records. Our study shows that a few report recommendations that were not consistently followed or acknowledged contained findings that referred to potentially harmful conditions. The results triggered an investment in systems improvement at the studied institution.
We consider the question of why (primarily) and how (secondarily) to perform scientific oversight of research performed by investigators with a financial conflict of interest (COI). One way to frame the trade-off of having investigators with financial COI participate in research is through a decision rule: "Our institution is willing for financially conflicted investigators to participate in research around their intellectual property if (a) the science is likely to be significantly better with their participation (or if other significant benefits accrue); and (b) the COI can be adequately managed".A key component of COI management is the demonstration that the underlying science is sufficiently rigorous and transparent, and in turn, a scientific oversight plan is a key element of that demonstration. Scientific oversight plans should be proactively generated, by individuals (i.e., scientific reviewers) who are independent and expert, and they should assess the rigor and transparency of the research, in a fashion which is fair and efficient.Abbreviations: COI: conflict of interest; SOP: scientific oversight plan KEYWORDS Conflict of interest; reproducibility; scientific oversightCONTACT Gregory Samsa
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