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To get the solution, we are looking for, we need to point out what we know. We assume, that x is the value we are looking for. Influenza viruses bind through hemagglutinin onto sialic acid sugars on the surfaces of epithelial cells , typically in the nose, throat, and lungs of mammals, and intestines of birds Stage 1 in infection figure.
The intracellular details are still being elucidated. It is known that virions converge to the microtubule organizing center, interact with acidic endosomes and finally enter the target endosomes for genome release.
Once inside the cell, the acidic conditions in the endosome cause two events to happen: First, part of the hemagglutinin protein fuses the viral envelope with the vacuole's membrane, then the M2 ion channel allows protons to move through the viral envelope and acidify the core of the virus, which causes the core to disassemble and release the viral RNA and core proteins.
Newly synthesized viral proteins are either secreted through the Golgi apparatus onto the cell surface in the case of neuraminidase and hemagglutinin, step 5b or transported back into the nucleus to bind vRNA and form new viral genome particles step 5a.
Other viral proteins have multiple actions in the host cell, including degrading cellular mRNA and using the released nucleotides for vRNA synthesis and also inhibiting translation of host-cell mRNAs.
Hemagglutinin and neuraminidase molecules cluster into a bulge in the cell membrane. The vRNA and viral core proteins leave the nucleus and enter this membrane protrusion step 6.
The mature virus buds off from the cell in a sphere of host phospholipid membrane , acquiring hemagglutinin and neuraminidase with this membrane coat step 7.
Because of the absence of RNA proofreading enzymes, the RNA-dependent RNA polymerase that copies the viral genome makes an error roughly every 10 thousand nucleotides, which is the approximate length of the influenza vRNA.
Hence, the majority of newly manufactured influenza viruses are mutants; this causes antigenic drift , which is a slow change in the antigens on the viral surface over time.
The resulting rapid change in viral genetics produces antigenic shifts , which are sudden changes from one antigen to another.
These sudden large changes allow the virus to infect new host species and quickly overcome protective immunity.
Also, when two or more viruses infect a cell, genetic variation may be generated by homologous recombination. When an infected person sneezes or coughs more than half a million virus particles can be spread to those close by.
Influenza can be spread in three main ways:   by direct transmission when an infected person sneezes mucus directly into the eyes, nose or mouth of another person ; the airborne route when someone inhales the aerosols produced by an infected person coughing, sneezing or spitting and through hand-to-eye, hand-to-nose, or hand-to-mouth transmission, either from contaminated surfaces or from direct personal contact such as a handshake.
The relative importance of these three modes of transmission is unclear, and they may all contribute to the spread of the virus. As the influenza virus can persist outside of the body, it can also be transmitted by contaminated surfaces such as banknotes ,  doorknobs, light switches and other household items.
The mechanisms by which influenza infection causes symptoms in humans have been studied intensively. One of the mechanisms is believed to be the inhibition of adrenocorticotropic hormone ACTH resulting in lowered cortisol levels.
For instance, part of the process that allows influenza viruses to invade cells is the cleavage of the viral hemagglutinin protein by any one of several human proteases.
However, in highly virulent strains, such as H5N1, the hemagglutinin can be cleaved by a wide variety of proteases, allowing the virus to spread throughout the body.
The viral hemagglutinin protein is responsible for determining both which species a strain can infect and where in the human respiratory tract a strain of influenza will bind.
In contrast, the highly lethal H5N1 strain binds to receptors that are mostly found deep in the lungs. Common symptoms of the flu such as fever, headaches, and fatigue are the result of the huge amounts of proinflammatory cytokines and chemokines such as interferon or tumor necrosis factor produced from influenza-infected cells.
This effect has been proposed to be the cause of the unusual lethality of both the H5N1 avian influenza,  and the pandemic strain. Due to the high mutation rate of the virus, a particular influenza vaccine usually confers protection for no more than a few years.
Each year, the World Health Organization predicts which strains of the virus are most likely to be circulating in the next year see Historical annual reformulations of the influenza vaccine , allowing pharmaceutical companies to develop vaccines that will provide the best immunity against these strains.
It takes about six months for the manufacturers to formulate and produce the millions of doses required to deal with the seasonal epidemics; occasionally, a new or overlooked strain becomes prominent during that time.
The most dangerous adverse effect is a severe allergic reaction to either the virus material itself or residues from the hen eggs used to grow the influenza; however, these reactions are extremely rare.
Not enough data was available to draw definite conclusions about serious complications such as pneumonia or hospitalization.
For healthy adults, a Cochrane review showed that vaccines reduced the incidence of lab-confirmed influenza from 2.
However, for influenza-like illness which is defined as the same symptoms of cough, fever, headache, runny nose, and bodily aches and pains, vaccine reduced the risk from The difference is most probably explained by the fact that over viruses cause the same or similar symptoms as the flu virus.
The cost-effectiveness of seasonal influenza vaccination has been widely evaluated for different groups and in different settings.
When vaccines and antiviral medications are limited, non-pharmaceutical interventions are essential to reduce transmission and spread.
The lack of controlled studies and rigorous evidence of the effectiveness of some measures has hampered planning decisions and recommendations.
Nevertheless, strategies endorsed by experts for all phases of flu outbreaks include hand and respiratory hygiene, self-isolation by symptomatic individuals and the use of face masks by them and their caregivers, surface disinfection, rapid testing and diagnosis, and contact tracing.
In some cases, other forms of social distancing including school closures and travel restrictions are recommended. Reasonably effective ways to reduce the transmission of influenza include good personal health and hygiene habits such as: not touching the eyes, nose or mouth;  frequent hand washing with soap and water, or with alcohol-based hand rubs ;  covering coughs and sneezes with a tissue or sleeve; avoiding close contact with sick people; and staying home when sick.
Avoiding spitting is also recommended. Since influenza spreads through both aerosols and contact with contaminated surfaces, surface sanitizing may help prevent some infections.
Social distancing strategies used during past pandemics, such as quarantines, travel restrictions, and the closing of schools, churches and theaters, have been employed to slow the spread of influenza viruses.
The more moderate effect on total deaths was attributed to the measures being employed too late, or lifted too early, most after six weeks or less.
For typical flu outbreaks, routine cancellation of large gatherings or mandatory travel restrictions have received little agreement, particularly as they may be disruptive and unpopular.
School closures have been found by most empirical studies to reduce community spread, but some findings have been contradictory.
Recommendations for these community restrictions are usually on a case-by-case basis. There are a number of rapid tests for the flu.
One is called a Rapid Molecular Assay, when an upper respiratory tract specimen mucus is taken using a nasal swab or a nasopharyngeal swab.
People with the flu are advised to get plenty of rest, drink plenty of liquids, avoid using alcohol and tobacco and, if necessary, take medications such as acetaminophen paracetamol to relieve the fever and muscle aches associated with the flu.
Antiviral medication may be effective, if given early within 48 hours to first symptoms , but some strains of influenza can show resistance to the standard antiviral medications and there is concern about the quality of the research.
Those with the emergency warning signs should visit the emergency room at once. The two classes of antiviral medications used against influenza are neuraminidase inhibitors oseltamivir , zanamivir , laninamivir and peramivir and M2 protein inhibitors adamantane derivatives.
Overall the benefits of neuraminidase inhibitors in those who are otherwise healthy do not appear to be greater than the risks.
The antiviral medications amantadine and rimantadine inhibit a viral ion channel M2 protein , thus inhibiting replication of the influenza A virus.
Influenza's effects are much more severe and last longer than those of the common cold. Most people will recover completely in about one to two weeks, but others will develop life-threatening complications such as pneumonia.
Thus, influenza can be deadly, especially for the weak, young and old, those with compromised immune systems, or the chronically ill.
The flu can worsen chronic health problems. People with emphysema, chronic bronchitis or asthma may experience shortness of breath while they have the flu, and influenza may cause worsening of coronary heart disease or congestive heart failure.
Even healthy people can be affected, and serious problems from influenza can happen at any age. People over 65 years old, pregnant women, very young children and people of any age with chronic medical conditions are more likely to get complications from influenza, such as pneumonia, bronchitis , sinus , and ear infections.
One review gives an incidence of about one case per million vaccinations. According to the Centers for Disease Control and Prevention CDC , "Children of any age with neurologic conditions are more likely than other children to become very sick if they get the flu.
Flu complications may vary and for some children, can include pneumonia and even death. These conditions can impair coughing, swallowing, clearing the airways, and in the worst cases, breathing.
Therefore, they worsen the flu symptoms. Influenza reaches peak prevalence in winter, and because the Northern and Southern Hemispheres have winter at different times of the year, there are actually two different flu seasons each year.
This is why the World Health Organization assisted by the National Influenza Centers makes recommendations for two different vaccine formulations every year; one for the Northern, and one for the Southern Hemisphere.
A long-standing puzzle has been why outbreaks of the flu occur seasonally rather than uniformly throughout the year. One possible explanation is that, because people are indoors more often during the winter, they are in close contact more often, and this promotes transmission from person to person.
Increased travel due to the Northern Hemisphere winter holiday season may also play a role. Dry particles are lighter and can thus remain airborne for a longer period.
However, seasonal changes in infection rates also occur in tropical regions, and in some countries these peaks of infection are seen mainly during the rainy season.
A combination of these small seasonal effects may be amplified by dynamical resonance with the endogenous disease cycles.
An alternative hypothesis to explain seasonality in influenza infections is an effect of vitamin D levels on immunity to the virus.
This could explain why influenza occurs mostly in winter and during the tropical rainy season, when people stay indoors, away from the sun, and their vitamin D levels fall.
Every year about , to , people die due to influenza globally, with an average of , Although the number of cases of influenza can vary widely between years, approximately 36, deaths and more than , hospitalizations are directly associated with influenza a year in the United States.
As influenza is caused by a variety of species and strains of viruses , in any given year some strains can die out while others create epidemics , while yet another strain can cause a pandemic.
Typically, in a year's normal two flu seasons one per hemisphere , there are between three and five million cases of severe illness,    which by some definitions is a yearly influenza epidemic.
Roughly three times per century, a pandemic occurs, which infects a large proportion of the world's population and can kill tens of millions of people see pandemics section.
New influenza viruses are constantly evolving by mutation or by reassortment. This is called antigenic drift , which slowly creates an increasing variety of strains until one evolves that can infect people who are immune to the pre-existing strains.
This new variant then replaces the older strains as it rapidly sweeps through the human population, often causing an epidemic.
In contrast, when influenza viruses reassort, they acquire completely new antigens—for example by reassortment between avian strains and human strains; this is called antigenic shift.
If a human influenza virus is produced that has entirely new antigens, everybody will be susceptible, and the novel influenza will spread uncontrollably, causing a pandemic.
From a public health point of view, flu epidemics spread rapidly and are very difficult to control. Most influenza virus strains are not very infectious and each infected individual will only go on to infect one or two other individuals the basic reproduction number for influenza is generally around 1.
However, the generation time for influenza is extremely short: the time from a person becoming infected to when he infects the next person is only two days.
The short generation time means that influenza epidemics generally peak at around 2 months and burn out after 3 months: the decision to intervene in an influenza epidemic, therefore, has to be taken early, and the decision is therefore often made on the back of incomplete data.
Another problem is that individuals become infectious before they become symptomatic, which means that putting people in quarantine after they become ill is not an effective public health intervention.
The word Influenza comes from the Italian language meaning "influence" and refers to the cause of the disease; initially, this ascribed illness to unfavorable astrological influences.
It was introduced into English in the mid-eighteenth century during a pan-European epidemic. An overall lack of data up until precludes meaningful search for the influenza outbreaks in the more distant past.
The first convincing record of an influenza pandemic was a minor pandemic chronicled in , which began in East Asia before spreading to North Africa and then Europe.
In Rome , over 8, people were killed. Several Spanish cities saw large scale deaths, among the fatalities the Queen of Spain, Anna of Austria.
Pandemics continued sporadically throughout the 17th and 18th centuries, with the pandemic of — being particularly widespread; it infected approximately a quarter of the people exposed.
The most famous and lethal outbreak was the flu pandemic Spanish flu type A influenza , H1N1 subtype , which lasted into One observer wrote, "One of the most striking of the complications was hemorrhage from mucous membranes , especially from the nose, stomach, and intestine.
Bleeding from the ears and petechial hemorrhages in the skin also occurred. The flu pandemic was truly global, spreading even to the Arctic and remote Pacific islands.
The unusually severe disease killed between two and twenty percent of those infected, as opposed to the more usual flu epidemic mortality rate of 0.
The total mortality of the — pandemic is not known, but it is estimated that 2. Later flu pandemics were not so devastating. In later pandemics antibiotics were available to control secondary infections and this may have helped reduce mortality compared to the Spanish flu of It was incorrectly assumed that the cause of influenza was bacterial in origin from with Haemophilus influenzae being discovered by and suggested as the origin of influenza by R.
The first significant step towards preventing influenza was the development in of a killed-virus vaccine for influenza by Thomas Francis, Jr.
This built on work by Australian Frank Macfarlane Burnet , who showed that the virus lost virulence when it was cultured in fertilized hen's eggs.
Influenza produces direct costs due to lost productivity and associated medical treatment, as well as indirect costs of preventive measures.
Preventive costs are also high. Governments worldwide have spent billions of U. It is still too early to determine whether the H1N1 pandemic has had any long-term economic effects.
Research on influenza includes studies on molecular virology , how the virus produces disease pathogenesis , host immune responses , viral genomics , and how the virus spreads epidemiology.
These studies help in developing influenza countermeasures; for example, a better understanding of the body's immune system response helps vaccine development, and a detailed picture of how influenza invades cells aids the development of antiviral drugs.
One important basic research program is the Influenza Genome Sequencing Project , which was initiated in to create a library of influenza sequences and help clarify which factors make one strain more lethal than another, which genes most affect immunogenicity , and how the virus evolves over time.
The sequencing of the influenza genome and recombinant DNA technology may accelerate the generation of new vaccine strains by allowing scientists to substitute new antigens into a previously developed vaccine strain.
There has been some research success towards a "universal flu vaccine" that produces antibodies against proteins on the viral coat which mutate less rapidly, and thus a single shot could potentially provide longer-lasting protection.
A number of biologics , therapeutic vaccines and immunobiologics are also being investigated for treatment of infection caused by viruses.
Therapeutic biologics are designed to activate the immune response to virus or antigens. Influenza models, such as murine influenza, are convenient models to test the effects of prophylactic and therapeutic biologics.
For example, lymphocyte T-cell immunomodulator inhibits viral growth in the murine model of influenza. An investigative panel looking into violent crimes and abuse at the Fort Hood Army base in Texas said on Tuesday it had found a command structure that was "permissive" of sexual assaults.
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