Deaths due to pneumonia, bronchitis and influenza reported to ONS by week of notification in .NET framework

Generator QR Code JIS X 0510 in .NET framework Deaths due to pneumonia, bronchitis and influenza reported to ONS by week of notification
Deaths due to pneumonia, bronchitis and influenza reported to ONS by week of notification
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5000 4500 4000 Number of deaths 3500 3000 2500 2000 1500 1000 500 0 40
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99/00 98/99 96/97 89/90
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12 16 20 Week number
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FIGURE 13.1 Excess mortality in the United Kingdom from in uenza and bronchitis 1999 2000 reported by the Of ce of National Statistics (ONS).
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THE EMERGENCE OF PANDEMIC INFLUENZA A
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United States19 has shown some validity of this approach. But, in practical terms, could modern parents be persuaded of this bene t and agree to have their child immunized with yet another vaccine It is possible that an intranasally delivered spray of live-attenuated vaccine17 or one of the new inactivated vaccines given intranasally20 could have a comparable effect and at the same time avert parental concerns about conventional vaccines. This could be a public health tactic during a pandemic or threat situation. Meanwhile, we are left with the clear observation that the 85% or so of the population, which is outside the classical at risk group, remain vulnerable to in uenza infection each year. Most of these persons will be ill for 5 7 days but there are still many deaths in persons outside the at risk groups. It has been estimated that 40 50% of the 20,000 deaths in the United Kingdom at the time of the millennium were in the non- at risk groups. Therefore, there is a clear need for an extra intervention with vaccines or antivirals in the wider community. Such increased targeting would simultaneously build up vaccine production capacity and the quantities of antivirals available for an emerging pandemic or threat use. We will return to a discussion of applicability of a new generation of in uenza vaccines later. Thus, although the scienti c community along with pharmaceutical companies have developed vaccines and antiviral drugs over the last half century, the production and surge capacity to deal with a sudden outbreak could not be coped with.
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13.2 X-RAY CRYSTALLOGRAPHY OF THE INFLUENZA VIRUS NA AND THE DEVELOPMENT OF A NEW RANGE OF ANTIVIRAL DRUGS: THE NIs Concern about the next pandemic has pushed research toward the discovery of new anti-in uenza drugs. An anomaly now, however, is how to use these drugs to best advantage. One cannot develop antivirals solely for use in the infrequent pandemics. Conversely, they will be essential at this time to save lives and protect essential workers in the community, particularly during the rst wave of the outbreak. A quarter of a century ago a group of scientists began to explore the much understudied NA protein of in uenza. The NA had already been identi ed as a separate gene product21 and antibodies to NA were known to reduce viral spread in cell culture.22 X-ray crystallography revealed the positions of enzyme active sites and the antigenic epitopes of NA.23,24 The neuraminidase molecule is oriented rather usually for a glycoprotein, its N terminus being anchored in the viral membrane. After the three-dimensional structure of the in uenza neuraminidase was established, the positions on the molecule of the catalytic site of the enzyme could be identi ed and the binding of inhibitory chemicals visualized. But this was not the initial objective of these studies. The NA molecule has a box-shaped head, with a unique folding pattern. Each monomer has six b-sheets and contains four polypeptide strands. Viewed from above, each monomer has the appearance of a ower with the petals somewhat twisted to resemble a pinwheel. The stem is
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X-RAY CRYSTALLOGRAPHY OF THE INFLUENZA VIRUS NA
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considered to span the lipid bilayer of the virus with a hydrophobic stretch of amino acids. The catalytic site of NA was located by difference Fourier analysis of crystals soaked in sialic acid, which is the substrate for the NA enzyme. The site is surrounded by 14 conserved charged residues and contains three hydrophobic residues Tyr, Trp, and Leu. The new anti-NA drugs bind to 11 of these critical amino acids and knowledge of the crystal structure allowed a design strategy involving the addition of side groups to a core inhibitor structure, which would interact with the crucial amino acids in the NA active site (Figure 13.2). Palese and Schulman25 were among the rst virologists to exploit neuraminidase and its sialic acid (neuraminic acid) substrate as a target for chemical inhibitors. The original neuraminic acid analogues, which had been synthesized a decade before,26 were carefully reinvestigated for anti-in uenza effects on viral replication in mammalian cells. These drugs are transition state analogues active at micromolar levels. They were shown to reduce viral plaque size and cause virus to aggregate at the cell membrane after budding and, therefore, prevent ef cient release of progeny virions. Disappointingly, however, the early studies using mouse models of viral infection found the neuraminic acid analogues to have no effect on lung in uenza titers after administration via intraperitoneal injection. Essentially, the key molecule, Neu5Ac2en, was a dehydrated neuraminic acid derivative that mimicked the geometry of the transition state during the enzymatic reaction. In retrospect, intranasal or aerosol administration of the drug may have given positive virus
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